AnemiaPhase 4NCT03277183
Frequent, Low-Dose Erythropoietin A Mechanistic Approach to Mitigate Adverse Cardiovascular Effects of Erythropoietin
A Phase 4 study testing Low dose erythropoietin and High dose erythropoietin in people with Anemia and CKD, run by VA Office of Research and Development at 1 site in United States.
Trial summary
Although several large well designed clinical trials have shown that erythropoietin which is commonly used to treat anemia associated with kidney disease, increases the risk of stroke and heart disease, the mechanism for this increased risk is unknown. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Anemia, CKD, Atherosclerosis
- What is being tested?
- Low dose erythropoietin and High dose erythropoietin
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 5 participants
- Where
- 1 siteUnited States
- Study dates
- 2 Nov 2017to 3 Jun 2019
- Phase
- Phase 4
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- The investigators will enroll Veterans who fulfill the following criteria:
- stage 3, 4, or 5 CKD (estimated glomerular filtration rate of less than 60 ml/min/1.73 m2) on at least two separate occasions greater than 3 months apart; and
- candidates for EPO therapy as per the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative guidelines (hemoglobin < 10 gm/dL and anemia of CKD).
Who cannot join
- The investigators will exclude any Veteran who meets any of the following criteria:
- pregnant, planning to become pregnant in the next year, or breast feeding;
- uncontrolled hypertension (blood pressure > 180/100 mm Hg despite optimal antihypertensive medications);
- active gastrointestinal bleeding (visible blood or positive tests for stool occult blood accompanied by a decrease in hemoglobin);
- likely to have EPO resistance;
- an adverse cardiovascular event in the prior three months;
Show all 12Show fewer
- active or recent (within the last 3 months) severe, systemic infection;
- active inflammatory disease such as lupus, rheumatoid arthritis, or vasculitis requiring immunosuppressive or immunomodulatory medications;
- history of solid organ transplantation;
- expected off-dialysis survival of less than one year (as determined by the estimated glomerular filtration slope and the treating physician;
- active cancer (undergoing chemotherapy or radiation within the last 3 months) or primary bone marrow disease such as myelofibrosis; or
- a contraindication for an MRI or individuals who cannot comply with the study protocol. The investigators will exclude healthy subjects that meet a, b, f, g, h, or j.
Trial locations and contacts
1 site in 1 country.
United States1 site
North Florida/South Georgia Veterans Health System, Gainesville, FL
Gainesville, Florida, 32608
About this study
Official title: Frequent, Low-Dose Erythropoietin: A Mechanistic Approach to Mitigate Adverse Cardiovascular Effects of Erythropoietin Therapy in Patients With Chronic Kidney Disease
Although several large well designed clinical trials have shown that erythropoietin which is commonly used to treat anemia associated with kidney disease, increases the risk of stroke and heart disease, the mechanism for this increased risk is unknown. The investigators' preliminary studies show that the adverse effects of erythropoietin are from activation of the heterodimeric erythropoietin/ beta common receptor which only occurs with high doses of erythropoietin. The investigators propose a clinical trial of 120 patients assigned to low doses of erythropoietin given more frequently or the same cumulative dose of erythropoietin administered as a high dose once every two weeks and assess effects on the beta common receptor activation, inflammation and vascular disease as evidence by MRI of the carotid arteries.
Read the detailed description
Erythropoietin (EPO) is the most widely prescribed cytokine, yet the benefits and potential side effects of different dosing regimens are poorly understood. It is now recognized that erythropoietin administered at high doses to patients with chronic kidney disease, results in an increased risk of morbidity and mortality from heart disease and stroke. However, the mechanisms that mediate this increased risk of cardiovascular disease is not known. There are two receptors for erythropoietin the homodimeric EPO receptor (EPOR) and the heterodimeric beta common receptor ( CR)/EPOR. The investigators have demonstrated that activation of the heterodimeric CR/EPOR only occurs with high doses of EPO. Our exciting, published, preliminary data also demonstrates that the CR is in a complex with vascular endothelial growth factor receptor-2 (VEGFR-2) and that high doses of EPO activate VEGFR-2 through the CR, resulting in the deleterious effects of VEGFR-2 activation on the cardiovascular system. This is particularly important in patients with kidney disease since they are already at a high risk of cardiovascular disease. Moreover in advanced kidney disease cyanate derived from the high urea levels can non-enzymatically form an amide bond with EPO. This carbamylated EPO (cEPO) has no effect on hemoglobin, but still activates the heterodimeric CR/EPOR. To date there have been no studies that have directly measured levels of cEPO or activation of the CR/EPOR in patients with kidney disease. Our hypothesis is that the administration of low-doses of EPO more frequently will result in lower levels of total and carbamylated erythropoietin decreased activation of VEGFR-2 via the heterodimeric CR/EPOR and consequently decreased inflammation and atherosclerosis. The investigators will directly test this hypothesis by randomly allocating 120 patients with chronic kidney disease to either low- dose EPO given thrice weekly or the same cumulative dose, a high-dose, administered once every 2 weeks. Our hypothesis predicts that low-dose EPO will be as effective at correcting anemia, but will demonstrate less progression of carotid artery plaque, as assessed by non-contrast magnetic resonance imaging, as compared to the high-dose, EPO given every 2 weeks. To delineate how EPO affects blood vessels, the investigators will isolate endothelial cells from blood vessels in 20 patients who are assigned to low-dose EPO and 20 allocated to high-dose EPO. Within these cells the investigators will investigate the signaling pathways that are triggered by activation of CR/EPOR. In a substudy of 20 subjects with kidney disease randomized to low-dose EPO or to high-dose EPO, as well as 20 healthy controls receiving a single dose of high- or low-dose EPO, the investigators will determine how kidney function and dosing affects levels of total and carbamylated erythropoietin. The investigators' study will not only provide us with a thorough understanding of the mechanism by which EPO mediates the increased risk of atherosclerosis, but a clinical strategy to avoid the side effects of EPO therapy and a tool to quantify the cardiovascular risk of EPO and newer erythropoiesis stimulating agents by assessing activation of the heterodimeric CR/EPOR.
- Conditions
- Anemia, CKD, Atherosclerosis, Cardiovascular
- Being tested
- Low dose erythropoietin, High dose erythropoietin
- Keywords
- erythropoietin
- Medical subject headings
- Anemia, Atherosclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Low dose erythropoietinDrug
Also called Low dose
Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly
High dose erythropoietinDrug
Also called High dose
Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks
| Study group | Role | What they receive |
|---|---|---|
| Low dose erythropoietin | Placebo comparator | Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly Receives: Drug: Low dose erythropoietin |
| High dose erythropoietin | Experimental | Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks Receives: Drug: High dose erythropoietin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Carotid Total Plaque Volume From Baseline to Approximately 1 Year, as Assessed by Non-contrast MRI
The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.
Measured: 1 year
Secondary outcomes (3)
Severity of Maximal Stenosis at Baseline and Upon Follow-up.
The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.
Measured: 1 year
Percentage of Total Plaque Area at Baseline and Upon Follow-up.
The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.
Measured: 1 year
Characteristics of Plaques (Soft or Fibrous and Stable or Unstable) at Baseline and Upon Follow-up.
The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Sep 2017
- Study start2 Nov 2017
- Primary completion3 Jun 2019
- Study completion3 Jun 2019
Why it stopped: Lack of enrollment
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.
- Other trials for AnemiaStudies 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 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Patients will be randomly assigned two different erythropoietin dosing strategies. One group will be given more frequent, low-doses of EPO and the other group will be given the same, cumulative dose given every 2 weeks.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Mark S. Segal, MD PhD, Principal investigator, North Florida/South Georgia Veterans Health System, Gainesville, FL
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03277183
- Sponsor's protocol ID
- CARA-019-16F
- Other IDs
- I01CX001449
- Status last verified
- Jul 2020
- First submitted
- 6 Sep 2017
- Last updated
- 13 Aug 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Frequent, Low-Dose Erythropoietin: A Mechanistic Approach to Mitigate Adverse Cardiovascular Effects of Erythropoietin Therapy in Patients With Chronic Kidney Disease
- ClinicalTrials.gov ID
- NCT03277183
- Acronym / sponsor ID
- CARA-019-16F
- Conditions
- Anemia, CKD, Atherosclerosis, Cardiovascular
- Keywords
- erythropoietin
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Lack of enrollment
- Enrolment
- 5 participants (actual)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- 2 Nov 2017 (actual)
- Primary completion
- 3 Jun 2019 (actual)
- Study completion
- 3 Jun 2019 (actual)
- First posted
- 8 Sep 2017 (actual)
- Results
- Posted 13 Aug 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Although several large well designed clinical trials have shown that erythropoietin which is commonly used to treat anemia associated with kidney disease, increases the risk of stroke and heart disease, the mechanism for this increased risk is unknown. The investigators' preliminary studies show that the adverse effects of erythropoietin are from activation of the heterodimeric erythropoietin/ beta common receptor which only occurs with high doses of erythropoietin. The investigators propose a clinical trial of 120 patients assigned to low doses of erythropoietin given more frequently or the same cumulative dose of erythropoietin administered as a high dose once every two weeks and assess effects on the beta common receptor activation, inflammation and vascular disease as evidence by MRI of the carotid arteries.
Detailed description
Erythropoietin (EPO) is the most widely prescribed cytokine, yet the benefits and potential side effects of different dosing regimens are poorly understood. It is now recognized that erythropoietin administered at high doses to patients with chronic kidney disease, results in an increased risk of morbidity and mortality from heart disease and stroke. However, the mechanisms that mediate this increased risk of cardiovascular disease is not known. There are two receptors for erythropoietin the homodimeric EPO receptor (EPOR) and the heterodimeric beta common receptor ( CR)/EPOR. The investigators have demonstrated that activation of the heterodimeric CR/EPOR only occurs with high doses of EPO. Our exciting, published, preliminary data also demonstrates that the CR is in a complex with vascular endothelial growth factor receptor-2 (VEGFR-2) and that high doses of EPO activate VEGFR-2 through the CR, resulting in the deleterious effects of VEGFR-2 activation on the cardiovascular system. This is particularly important in patients with kidney disease since they are already at a high risk of cardiovascular disease. Moreover in advanced kidney disease cyanate derived from the high urea levels can non-enzymatically form an amide bond with EPO. This carbamylated EPO (cEPO) has no effect on hemoglobin, but still activates the heterodimeric CR/EPOR. To date there have been no studies that have directly measured levels of cEPO or activation of the CR/EPOR in patients with kidney disease. Our hypothesis is that the administration of low-doses of EPO more frequently will result in lower levels of total and carbamylated erythropoietin decreased activation of VEGFR-2 via the heterodimeric CR/EPOR and consequently decreased inflammation and atherosclerosis. The investigators will directly test this hypothesis by randomly allocating 120 patients with chronic kidney disease to either low- dose EPO given thrice weekly or the same cumulative dose, a high-dose, administered once every 2 weeks. Our hypothesis predicts that low-dose EPO will be as effective at correcting anemia, but will demonstrate less progression of carotid artery plaque, as assessed by non-contrast magnetic resonance imaging, as compared to the high-dose, EPO given every 2 weeks. To delineate how EPO affects blood vessels, the investigators will isolate endothelial cells from blood vessels in 20 patients who are assigned to low-dose EPO and 20 allocated to high-dose EPO. Within these cells the investigators will investigate the signaling pathways that are triggered by activation of CR/EPOR. In a substudy of 20 subjects with kidney disease randomized to low-dose EPO or to high-dose EPO, as well as 20 healthy controls receiving a single dose of high- or low-dose EPO, the investigators will determine how kidney function and dosing affects levels of total and carbamylated erythropoietin. The investigators' study will not only provide us with a thorough understanding of the mechanism by which EPO mediates the increased risk of atherosclerosis, but a clinical strategy to avoid the side effects of EPO therapy and a tool to quantify the cardiovascular risk of EPO and newer erythropoiesis stimulating agents by assessing activation of the heterodimeric CR/EPOR.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- Patients will be randomly assigned two different erythropoietin dosing strategies. One group will be given more frequent, low-doses of EPO and the other group will be given the same, cumulative dose given every 2 weeks.
| Arm | Type | Receives |
|---|---|---|
| Low dose erythropoietin | Placebo comparator | Drug: Low dose erythropoietinSubjects randomized to this arm will receive low-dose of EPO administered thrice weekly |
| High dose erythropoietin | Experimental | Drug: High dose erythropoietinSubjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- stage 3, 4, or 5 CKD (estimated glomerular filtration rate of less than 60 ml/min/1.73 m2) on at least two separate occasions greater than 3 months apart; and
- candidates for EPO therapy as per the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative guidelines (hemoglobin < 10 gm/dL and anemia of CKD).
Key exclusion criteria (12 listed)
- pregnant, planning to become pregnant in the next year, or breast feeding;
- uncontrolled hypertension (blood pressure > 180/100 mm Hg despite optimal antihypertensive medications);
- active gastrointestinal bleeding (visible blood or positive tests for stool occult blood accompanied by a decrease in hemoglobin);
- likely to have EPO resistance;
- an adverse cardiovascular event in the prior three months;
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 |
|---|---|---|
| Low dose erythropoietinAlso: Low doseSubjects randomized to this arm will receive low-dose of EPO administered thrice weekly | Drug | Low dose erythropoietin |
| High dose erythropoietinAlso: High doseSubjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks | Drug | High dose erythropoietin |
Primary outcome
Change in Carotid Total Plaque Volume From Baseline to Approximately 1 Year, as Assessed by Non-contrast MRI
Time frame: 1 year
The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.
3 secondary outcomes
Severity of Maximal Stenosis at Baseline and Upon Follow-up.
Time frame: 1 year
Percentage of Total Plaque Area at Baseline and Upon Follow-up.
Time frame: 1 year
Characteristics of Plaques (Soft or Fibrous and Stable or Unstable) at Baseline and Upon Follow-up.
Time frame: 1 year
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Aug 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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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.
Mark S. Segal, MD PhD principal investigator
North Florida/South Georgia Veterans Health System, Gainesville, FL
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Low dose erythropoietin and High dose erythropoietin in people with Anemia and CKD, 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 3 inclusion and 12 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 13 Aug 2020. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Aug 2020). 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?
Change in Carotid Total Plaque Volume From Baseline to Approximately 1 Year, as Assessed by Non-contrast MRI (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 13 Aug 2020.