Chronic Kidney DiseasePhase 2EPICNCT03810911

Mechanisms of EPO-induced Hypertension

A Phase 2 study testing Darbepoetin in people with Chronic Kidney Disease and Blood Pressure, run by VA Office of Research and Development at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Chronic Kidney Disease, Blood Pressure, Anemia
What is being tested?: Darbepoetin
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 27 participants
Where: 1 siteUnited States
Study dates: 4 Jan 2021to 31 Jul 2025
Phase: Phase 2
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

Stage 3 or 4 chronic kidney disease
Controlled hypertension with 24 hour ambulatory blood pressure monitoring less than 140/90 mmHg at baseline and treatment with at least 1 antihypertensive medication
Hemoglobin between 8 and 10 g/dL
No treatment with erythropoiesis-stimulating agents (ESA) within 3 previous months

Who cannot join

Need for packed red blood cells (RBC) transfusion in the previous 2 months
Myocardial infarction, stroke or hospitalization for heart failure in the past 2 months
In the assessment of the investigator, have hematologic, inflammatory, infectious, or other conditions that might interfere with the erythropoietic response

Trial locations and contacts

1 site in 1 country.

United States1 site

Richard L. Roudebush VA Medical Center, Indianapolis, IN
Indianapolis, Indiana, 46202-2884

Other trials in United States

About this study

Official title: Mechanisms of Erythropoietin Induced Hypertension

The investigators hypothesize that compared to untreated controls, erythropoietin (EPO) therapy in anemic patients with chronic kidney disease will raise diastolic blood pressure (BP). The magnitude of increase in diastolic BP at 12 weeks after treatment will be related to two factors. First, endothelial dysfunction and worsening of endothelial function from baseline to 4 weeks and second, the change of forearm blood flow in response to breathing oxygen and the change in this measure from baseline to 4 weeks. Study procedures include fasting blood draws, ambulatory blood pressure, urine collection, and forearm blood flow tests. The study hopes to accrue 160 subjects.

Read the detailed description

Hypertension is a common but frequently overlooked and underreported adverse effect of erythropoietin (EPO) therapy. Recent trials have noted substantial cardiovascular risks associated with normalization of hemoglobin. The risk of strokes is strongly related to poorly controlled hypertension. Blood pressure was not measured the way it usually is in hypertension trials, so the investigators cannot be completely confident that the risk of strokes in this large randomized trial was not related to EPO-induced hypertension. New therapies, such as hypoxia-inducible factor (HIF) stabilizers are on the horizon but it remains to be seen whether these new drugs would have a lower or a higher risk for hypertension compared to EPO. Accordingly, understanding the mechanism of EPO-induced hypertension is urgent. The investigators hypothesize that compared to untreated controls, EPO therapy in anemic patients with chronic kidney disease (CKD) will raise diastolic blood pressure. The magnitude of increase in diastolic BP at 12 weeks after treatment will be related to endothelial dysfunction and worsening of endothelial function from baseline to 4 weeks. If the investigators understood the time course, the magnitude, and the mechanisms of EPO-induced hypertension (EIH) the investigators will better be able to design studies to compare the vascular effects of EPO and HIF stabilizers in the future. Thus, this study has the potential of improving the investigators' understanding of a common side effect of EPO by precisely quantifying the magnitude of BP change, its effects on endothelial function, and discovering the biomarkers of these adverse effects. Thus, the investigators can in the future robustly compare these effects of EPO with HIF stabilizers. This study is innovative because it will focus on the potential mechanisms by which EPO induces an increase in BP. The time-course and magnitude of change in BP will be assessed using the gold-standard measurement of 24 hour ambulatory BP recordings. The more frequent clinic BP recordings using validated methods will better allow us to track changes in BP over time. The investigators' lab is uniquely qualified to carry out these experiments due to a large experience with such types of studies. The investigators will examine endothelial function using a reference method -- that of flow-mediated dilatation -- which is established in the investigators' laboratory. The investigators will directly test the hypothesis whether endothelial function is responsible for the BP increase.

Conditions: Chronic Kidney Disease, Blood Pressure, Anemia
Being tested: Darbepoetin
Keywords: Flow mediated dilatation
Medical subject headings: Renal Insufficiency, Chronic, Anemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

DarbepoetinDrug
Also called EPO
Used to treat anemia. In the group labeled no intervention, the intervention is simply delayed 12 weeks after randomization as noted in the description.

Study groups in NCT03810911
Study group	Role	What they receive
Early start	Active comparator	Participants given study drug immediately at randomization Receives: Drug: Darbepoetin
Delayed start	No intervention	Participants given study drugs 12 weeks after randomization

What is being measured

The primary outcome is the main question the study is designed to answer.

Change in Diastolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls
In the delayed start group (the control group), the investigators will measure the change in diastolic blood pressure from 0 weeks to 12 weeks compared to the change in diastolic BP from 0 to 12 weeks in the immediate start group.
Measured: Baseline to 12 weeks
Within Group Change in Diastolic Blood Pressure in the Delayed Start Group
Within group change in diastolic blood pressure from 12 weeks to 24 weeks compared to change in diastolic blood pressure from baseline to 12 weeks in the delayed start group
Measured: 12 to 24 weeks compared to baseline to 12 weeks

Secondary outcomes (5)

Change in Systolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls
In the delayed start group (the control group), the investigators will measure the change in systolic blood pressure change from 0 weeks to 12 weeks compared to the change in systolic BP from 0 to 12 weeks in the immediate start group.
Measured: Baseline to 12 weeks
Number of Participants With Worsened Hypertension Status in Immediate Start Group Compared to Delayed Start Controls
Worsening of hypertension at any time point will be defined as either an increase in blood pressure medication, an increase in seated clinic diastolic blood pressure by greater than or equal to 10 mmHg or systolic blood pressure increase of greater than or equal to 20 mmHg. Between-group change in hypertension status from baseline to 12 weeks will be compared in the immediate start and delayed start groups.
Measured: Baseline to 12 weeks
Number of Participants With Worsened Hypertension Status in Delayed Start Group Participants When They Were Not on EPO Compared to When They Were on EPO
Worsening of hypertension at any time point will be defined as either an increase in blood pressure medication, an increase in seated clinic diastolic blood pressure by greater than or equal to 10 mmHg or systolic blood pressure increase of greater than or equal to 20 mmHg. Within-group change in hypertension status from 12 weeks to 24 weeks will be compared to the control period of 0 weeks to 12 weeks in the delayed start group.
Measured: baseline to 12 weeks vs 12 weeks to 24 weeks
Change in Endothelial Function in Those Treated With EPO Compared to the Waitlisted Group
The investigators used the high-resolution ultrasound of brachial artery to assess flow-mediated dilatation (FMD). FMD measures the dilation of blood vessels in response to increased blood flow and is the reference standard for assessing endothelial function. The mean percentage change in endothelial function of those treated with EPO were compared to that of the delayed start group. The hypothesis being tested is that EPO will cause impairment in endothelial function.
Measured: Baseline to 4 weeks
Change in Urine Albumin to Urine Creatinine Ratio in the Delayed Start Group
Change in urine albumin to urine creatinine ratio in the delayed start group baseline to 16 weeks (which is 4 weeks of exposure to darbepoetin), from baseline to 20 weeks (8-week exposure), and from baseline to 24 weeks (12-week exposure)
Measured: Baseline to 16 weeks, baseline to 20 weeks, and baseline to 24 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

4 Jan 202131 Jul 2025

First posted22 Jan 2019
Study start4 Jan 2021
Primary completion31 Dec 2024
Study completion31 Jul 2025

Why it stopped: The trial was stopped because of inability to reach target sample size.

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 (1)Papers the sponsor has linked to this study.
Other trials for Chronic Kidney DiseaseStudies 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 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Sequential
Model description: All subjects will receive darbepoetin during the study. One group, the immediate start group, will receive the drug the day of randomization. The other group, the delayed start group, will receive the drug 12 weeks later.
Masking: None (open label)
Enrolment: 27 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03810911
Sponsor's protocol ID: NEPH-005-18S
Other IDs: 052387
Acronym: EPIC
Status last verified: Nov 2025
First submitted: 7 Jan 2019
Last updated: 15 Dec 2025
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Publications

Georgianos PI, Agarwal R. Resistant Hypertension in Dialysis: Epidemiology, Diagnosis, and Management. J Am Soc Nephrol. 2024 Apr 1;35(4):505-514. doi: 10.1681/ASN.0000000000000315. Epub 2024 Jan 16.
PubMed 38227447

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 15 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Mechanisms of Erythropoietin Induced Hypertension
ClinicalTrials.gov ID: NCT03810911
Acronym / sponsor ID: EPIC / NEPH-005-18S
Conditions: Chronic Kidney Disease, Blood Pressure, Anemia
Keywords: Flow mediated dilatation
Phase: Phase 2
Study type: Interventional
Recruitment status: TerminatedReason stopped: The trial was stopped because of inability to reach target sample size.
Enrolment: 27 participants (actual)
Lead sponsor: VA Office of Research and DevelopmentUS federal agency
Study start: 4 Jan 2021 (actual)
Primary completion: 31 Dec 2024 (actual)
Study completion: 31 Jul 2025 (actual)
First posted: 22 Jan 2019 (actual)
Results: Posted 15 Dec 2025

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Sequential
Masking: None (open label)
Number of arms: 2
Model description: All subjects will receive darbepoetin during the study. One group, the immediate start group, will receive the drug the day of randomization. The other group, the delayed start group, will receive the drug 12 weeks later.

Arm	Type	Receives
Early start	Active comparator	Drug: DarbepoetinParticipants given study drug immediately at randomization
Delayed start	No intervention	–Participants given study drugs 12 weeks after randomization

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (4 listed)

Stage 3 or 4 chronic kidney disease
Controlled hypertension with 24 hour ambulatory blood pressure monitoring less than 140/90 mmHg at baseline and treatment with at least 1 antihypertensive medication
Hemoglobin between 8 and 10 g/dL
No treatment with erythropoiesis-stimulating agents (ESA) within 3 previous months

Key exclusion criteria (3 listed)

Need for packed red blood cells (RBC) transfusion in the previous 2 months
Myocardial infarction, stroke or hospitalization for heart failure in the past 2 months
In the assessment of the investigator, have hematologic, inflammatory, infectious, or other conditions that might interfere with the erythropoietic response

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
DarbepoetinAlso: EPOUsed to treat anemia. In the group labeled no intervention, the intervention is simply delayed 12 weeks after randomization as noted in the description.	Drug	Early start

Primary outcome

Change in Diastolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls
Time frame: Baseline to 12 weeks
In the delayed start group (the control group), the investigators will measure the change in diastolic blood pressure from 0 weeks to 12 weeks compared to the change in diastolic BP from 0 to 12 weeks in the immediate start group.
Within Group Change in Diastolic Blood Pressure in the Delayed Start Group
Time frame: 12 to 24 weeks compared to baseline to 12 weeks
Within group change in diastolic blood pressure from 12 weeks to 24 weeks compared to change in diastolic blood pressure from baseline to 12 weeks in the delayed start group

5 secondary outcomes

Change in Systolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls
Time frame: Baseline to 12 weeks
Number of Participants With Worsened Hypertension Status in Immediate Start Group Compared to Delayed Start Controls
Time frame: Baseline to 12 weeks
Number of Participants With Worsened Hypertension Status in Delayed Start Group Participants When They Were Not on EPO Compared to When They Were on EPO
Time frame: baseline to 12 weeks vs 12 weeks to 24 weeks
Change in Endothelial Function in Those Treated With EPO Compared to the Waitlisted Group
Time frame: Baseline to 4 weeks
Change in Urine Albumin to Urine Creatinine Ratio in the Delayed Start Group
Time frame: Baseline to 16 weeks, baseline to 20 weeks, and baseline to 24 weeks

Results and safety

Results posted to the registry on 15 Dec 2025, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Early Start	11	9
Delayed Start	16	14

Primary outcome: Change in Diastolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls

Time frame: Baseline to 12 weeks. Mean (95% Confidence Interval). Unit: mmHg

Measure	Early Start n = 11	Delayed Start n = 16
Value	1.4 (-1.8 to 4.6)	-0.5 (-4.7 to 3.8)

Primary outcome: Within Group Change in Diastolic Blood Pressure in the Delayed Start Group

Time frame: 12 to 24 weeks compared to baseline to 12 weeks. Mean (95% Confidence Interval). Unit: mmHg

Measure	No Darbepoetin n = 16	Darbepoetin n = 14
Value	-1.9 (-5.4 to 1.6)	3.2 (-0.5 to 6.8)

5 secondary outcomes are reported in the full results.

Adverse events

Time frame: through study completion, at most 6 months. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Darbepoetin	8 of 27 (29.6%)	6 of 27 (22.2%)	2 of 27
No Darbepoetin	5 of 16 (31.3%)	7 of 16 (43.8%)	0 of 16

Limitations and caveats (from the sponsor): The trial was limited by the absence of enough patients to observe a meaningful change in 24-hour ambulatory BP or endothelial function.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 15 Dec 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 38227447Georgianos PI, Agarwal R. Resistant Hypertension in Dialysis: Epidemiology, Diagnosis, and Management. J Am Soc Nephrol. 2024 Apr 1;35(4):505-514. doi: 10.1681/ASN.0000000000000315. Epub 2024 Jan 16.
Individual participant dataSharing planned: No

Related trials for Chronic Kidney Disease

Active, not recruitingPhase 2
Safety and Efficacy of Empagliflozin in Hemodialysis
End Stage Renal Disease
RecruitingPhase 3
Study to Assess the Efficacy, Pharmacokinetics, Safety and Tolerability of Atrasentan in Pediatric Patients With Primary IgAN
Berger Disease, Bergers Disease
Recruiting
Investigating Vascular Properties of HEMI and SPG Signals in Individuals With or at Risk for Chronic Kidney Disease
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Not yet recruiting
Hypothermic Kidney Machine Perfusion With Omnisol
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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.

Rajiv Agarwal, MD MBBS principal investigator

Richard L. Roudebush VA Medical Center, Indianapolis, IN

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Darbepoetin in people with Chronic Kidney Disease and Blood Pressure, 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 3 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 15 Dec 2025. 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.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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 15 Dec 2025). 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 Diastolic Blood Pressure in EPO Treated Patients Compared to Delayed Start Controls (time frame: Baseline to 12 weeks). The study lists 2 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 NCT03810911, which also lists 1 linked publication.

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 15 Dec 2025.