- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03810911
Mechanisms of EPO-induced Hypertension (EPIC)
March 7, 2024 updated by: VA Office of Research and Development
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.
Study Overview
Status
Active, not recruiting
Conditions
Intervention / Treatment
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.
Study Type
Interventional
Enrollment (Actual)
27
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: Rajiv Agarwal, MD MBBS
- Phone Number: (317) 988-2241
- Email: ragarwal@iu.edu
Study Locations
-
-
Indiana
-
Indianapolis, Indiana, United States, 46202-2884
- Richard L. Roudebush VA Medical Center, Indianapolis, IN
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Description
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Sequential Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Early start
Participants given study drug immediately at randomization
|
Used to treat anemia.
In the group labeled no intervention, the intervention is simply delayed 12 weeks after randomization as noted in the description.
Other Names:
|
No Intervention: Delayed start
Participants given study drugs 12 weeks after randomization
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
Baseline to 12 weeks
|
Change in flow mediated dilatation (FMD)
Time Frame: Baseline to 4 weeks
|
Those treated with EPO compared to the delayed start group.
The hypothesis being tested is that EPO will cause impairment in endothelial function.
|
Baseline to 4 weeks
|
Predictors of change in flow mediated dilatation (FMD)
Time Frame: Baseline to 4 weeks
|
A multivariable model will be created to predict the change in FMD from baseline to 4 w.
Model 1 will have an indicator variable of those treated with EPO compared to time controls (this is outcome 2 essentially).
Model 2 will have the following predictors of this change in addition: baseline values of urine albumin/creat ratio, asymmetric dimethylarginine (ADMA), urine nitrate and nitrite, renin, aldosterone, and plasma endothelin-1.
Model 3 will include all the variables in Model 1 and 2 and also include change from baseline to 4 weeks in the same variables reported in Model 2.
|
Baseline to 4 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in systolic blood pressure in EPO treated patients
Time Frame: Baseline to 12 weeks
|
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.
|
Baseline to 12 weeks
|
Between group change in hypertension status
Time Frame: Baseline to 12 weeks
|
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.
|
Baseline to 12 weeks
|
Within group change in hypertension status
Time Frame: baseline to 12 weeks vs 12 weeks to 24 weeks
|
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.
|
baseline to 12 weeks vs 12 weeks to 24 weeks
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Investigators
- Principal Investigator: Rajiv Agarwal, MD MBBS, Richard L. Roudebush VA Medical Center, Indianapolis, IN
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
January 4, 2021
Primary Completion (Estimated)
December 31, 2024
Study Completion (Estimated)
July 31, 2025
Study Registration Dates
First Submitted
January 7, 2019
First Submitted That Met QC Criteria
January 16, 2019
First Posted (Actual)
January 22, 2019
Study Record Updates
Last Update Posted (Actual)
March 12, 2024
Last Update Submitted That Met QC Criteria
March 7, 2024
Last Verified
March 1, 2024
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Urologic Diseases
- Disease Attributes
- Renal Insufficiency
- Chronic Disease
- Female Urogenital Diseases
- Female Urogenital Diseases and Pregnancy Complications
- Urogenital Diseases
- Male Urogenital Diseases
- Hypertension
- Kidney Diseases
- Renal Insufficiency, Chronic
- Hematinics
- Darbepoetin alfa
Other Study ID Numbers
- NEPH-005-18S
- 052387 (Other Grant/Funding Number: Indiana Institute for Medical Research)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
NO
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
product manufactured in and exported from the U.S.
Yes
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Anemia
-
SanofiActive, not recruitingWarm Autoimmune Hemolytic Anemia (wAIHA)United States, Austria, China, Denmark, Germany, Hungary, Italy, Spain, United Kingdom
-
SanofiTerminatedWarm Autoimmune Hemolytic Anemia (wAIHA)United Kingdom, Belgium, Netherlands, France, United States, Germany, Hungary, Italy
-
Hospital Universitario Dr. Jose E. GonzalezCompletedPernicious Anemia | Megaloblastic Anemia NosMexico
-
Assistance Publique - Hôpitaux de ParisNot yet recruitingSevere Aplastic Anemia | Idiopathic Aplastic Anemia | Moderate Aplastic Anemia Requiring Transfusions
-
Abdelwahed, Mai Mahmoud Mohamed, M.D.UnknownAnemia During PregnancyEgypt
-
University of California, DavisInstituto Mexicano del Seguro Social; Thrasher Research Fund; Mexican National... and other collaboratorsCompleted
-
Incyte CorporationActive, not recruitingWarm Autoimmune Hemolytic Anemia (wAIHA)Spain, United States, Austria, Belgium, Canada, France, Germany, Israel, Italy, Japan, Netherlands, Poland, United Kingdom
-
Peking Union Medical College HospitalRecruiting
-
Alexion PharmaceuticalsWithdrawnWarm Autoimmune Hemolytic AnemiaUnited States
Clinical Trials on Darbepoetin
-
University of New MexicoUniversity of UtahCompletedHypoxic-Ischemic Encephalopathy Mild | Neonatal EncephalopathyUnited States
-
St. Bartholomew's HospitalUnknownMyelodysplastic SyndromesUnited Kingdom
-
Groupe Francophone des MyelodysplasiesUnknown
-
AmgenCompletedAnemia | Non-Myeloid Malignancies
-
The Hospital for Sick ChildrenCompletedKidney Failure, ChronicCanada
-
AmgenCompleted
-
Kyowa Kirin Co., Ltd.Completed