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| ID | Type | Description | Link |
|---|---|---|---|
| 052387 | Other Grant/Funding Number | Indiana Institute for Medical Research |
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The trial was stopped because of inability to reach target sample size.
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Early start | Active Comparator | Participants given study drug immediately at randomization |
|
| Delayed start | No Intervention | Participants given study drugs 12 weeks after randomization |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Darbepoetin | Drug | Used to treat anemia. In the group labeled no intervention, the intervention is simply delayed 12 weeks after randomization as noted in the description. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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 | 12 to 24 weeks compared to baseline to 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline to 12 weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Rajiv Agarwal, MD MBBS | Richard L. Roudebush VA Medical Center, Indianapolis, IN | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Richard L. Roudebush VA Medical Center, Indianapolis, IN | Indianapolis | Indiana | 46202-2884 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38227447 | Derived | 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. |
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65 individuals (41%) consented, of which, 27 (42%) were enrolled in the trial and underwent randomization stratified by the level of albuminuria (KDIGO stage A1, A2, or A3). 16 were assigned to waitlisted and 11 to immediate start group. In each of the two groups, two patients did not complete the study. The most common reason for randomization failure was either Hgb out of range (39%) or ambulatory BP out of range (39%). The trial was stopped because of inability to reach target sample size.
Between 18 December 2020, and 22 September 2023, 1699 individuals were assessed for study eligibility. These individuals were screened, 4398 times for a mean of 2.6 times per person. In all, 281 (17%) were noted to be potentially eligible, of which, 157 (56%) agreed to come for a consent visit.
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| ID | Title | Description |
|---|---|---|
| FG000 | Early Start | Participants given study drug immediately at randomization |
| FG001 | Delayed Start | Participants given study drugs 12 weeks after randomization |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Randomization was stratified by the level of albuminuria in a 1:1 ratio to either early or delayed treatment with ESA. A random permuted block design was used to avoid imbalance in assignment to the study drugs over time. After confirming eligibility, the principal investigator used a computer program to reveal the group assignment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Early Start | Participants given study drug immediately at randomization |
| BG001 | Delayed Start | Participants given study drugs 12 weeks after randomization |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Sex: Female, Male | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | 95% Confidence Interval | mmHg | Baseline to 12 weeks |
|
through study completion, at most 6 months
Harms will be assessed by monitoring changes in weight, eGFR, CBC, clinic BP, and ABPM. Safety of continued participation will be assessed at each study visit. The stop-points will be treatment-emergent severe adverse events that precludes further exposure to the drug, such as an allergic drug reaction, initiation of renal replacement therapy, or death. If the study drug is stopped, the subject will be continued to be studied so as to not violate the intention-to-treat principle.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Darbepoetin | Data from participants that were actively taking darbepoetin at the time of collection |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Falls | General disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Falls | General disorders | Systematic Assessment |
The trial was limited by the absence of enough patients to observe a meaningful change in 24-hour ambulatory BP or endothelial function.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Rajiv Agarwal MD MS | Richard L. Roudebush Veterans Affairs Medical Center | (317) 988-2241 | ragarwal@iu.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 26, 2022 | Oct 9, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D051436 | Renal Insufficiency, Chronic |
| D000740 | Anemia |
| ID | Term |
|---|---|
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
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| ID | Term |
|---|---|
| D000068256 | Darbepoetin alfa |
| ID | Term |
|---|---|
| D004921 | Erythropoietin |
| D003115 | Colony-Stimulating Factors |
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
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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.
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The groups are randomized not the study drug. The groups will be known by both the participant and the investigator.
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|
| 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. | 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. | 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. | 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) | Baseline to 16 weeks, baseline to 20 weeks, and baseline to 24 weeks |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Weight -- kg (SD) | Mean | Standard Deviation | kg |
|
| Age, Customized | Mean | Standard Deviation | Years |
|
| Medical History | Count of Participants | Participants |
|
| Hemoglobin -- g/dL (SD) | Mean | Standard Deviation | g/dL |
|
| Serum ferritin -- ng/mL (25th-75th percentile) | Mean | Inter-Quartile Range | ng/mL |
|
| Transferrin saturation -- percent (SD) | Mean | Standard Deviation | % |
|
| Baseline eGFR -- mL/min/1.73m^2 (SD) | Estimated glomerular filtration rate (eGFR) is an estimate of kidneys' ability to filter blood. A lower eGFR can indicate a greater risk or progression of CKD. An eGFR <60 ml/min/1.73 m² that persists for a minimum of 3 months indicates the presence of CKD. | Mean | Standard Deviation | mL/min/1.73m^2 |
|
| Glomerular filtration rate (GFR) category (G1-G5) | KDIGO glomerular filtration rate (GFR) category (G1-G5) is one marker of CKD. The categories are defined as the following and must be present for at least 3 months (ml/min/1.73): G1 - GFR range: ≥ 90 G2 - GFR range: 60-89 G3a - GFR range: 45-59 G3b - GFR range: 30-44 G4 - GFR range: 15-29 G5 - GFR range: < 15 A lower eGFR, or a higher eGFR category, can indicate a greater progression or risk of CKD. This study included only patients with Stage 3 or 4 CKD defined as eGFR category G3 or G4 or those with persistent albuminuria category A2 or A3, hence the single participant in G2. | Count of Participants | Participants |
|
| Albuminuria category (A1-A3) | KDIGO persistent albuminuria category is one marker of CKD. The categories are defined as the following using urine-albumin-to-creatinine ratio (UACR) and must be present for at least 3 months (mg/g): A1 - UACR range: <30 A2 - UACR range: 30-300 A3 - UACR range: >300 A greater the amount of albuminuria, or a higher persistent albuminuria category, can indicate a greater progression or risk of CKD. This study included only patients with Stage 3 or 4 CKD defined as eGFR category G3 or G4 or those with persistent albuminuria category A2 or A3, hence the single participant in G2. | Count of Participants | Participants |
|
| Baseline UACR -- mg/g creatinine median (25th-75th) | Urine albumin-to-creatinine ratio (UACR) is a measurement of the amount of protein (albumin) in a patient's urine. A UACR ≥30 mg/g indicates the presence of albuminuria, and greater UACR value can indicate a greater risk or progression of CKD.. A UACR ≥30 mg that persists for a minimum of 3 months indicates the presence of CKD. | Median | Inter-Quartile Range | mg/g |
|
| Baseline clinic blood pressure | Mean | Standard Deviation | mmHg |
|
| Antihypertensive drugs -- n (SD) | Mean | Standard Deviation | Drugs |
|
| Nature of antihypertensive drugs | Count of Participants | Participants |
|
| Clinic heart rate -- beats per minute (SD) | Mean | Standard Deviation | beats per minutes |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Secondary | 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. | Posted | Mean | 95% Confidence Interval | mmHg | Baseline to 12 weeks |
|
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | Baseline to 12 weeks |
|
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | baseline to 12 weeks vs 12 weeks to 24 weeks |
|
|
|
| Secondary | 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. | Posted | Mean | 95% Confidence Interval | percentage of endothelial function | Baseline to 4 weeks |
|
|
|
| Primary | 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 | Posted | Mean | 95% Confidence Interval | mmHg | 12 to 24 weeks compared to baseline to 12 weeks |
|
|
|
| Secondary | 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) | Posted | Mean | 95% Confidence Interval | percentage change in UACR from baseline | Baseline to 16 weeks, baseline to 20 weeks, and baseline to 24 weeks |
|
|
|
| 2 |
| 27 |
| 8 |
| 27 |
| 6 |
| 27 |
| EG001 | No Darbepoetin | Data from participants that were not taking darbepoetin at the time of collection | 0 | 16 | 5 | 16 | 7 | 16 |
| Congestive heart failure | Cardiac disorders | Systematic Assessment |
|
| Arrhythmia | Cardiac disorders | Systematic Assessment |
|
| Hypertensive crisis | Cardiac disorders | Systematic Assessment |
|
| Peripheral vascular disorder | Cardiac disorders | Systematic Assessment |
|
| Seizures | Nervous system disorders | Systematic Assessment |
|
| Venous thromboembolism | Blood and lymphatic system disorders | Systematic Assessment |
|
| Empyema | Infections and infestations | Systematic Assessment |
|
| Abnormal renal labs | Renal and urinary disorders | Systematic Assessment |
|
| GI bleed | Gastrointestinal disorders | Systematic Assessment |
|
| Right leg weakness following cardiac catheterization | General disorders | Systematic Assessment |
|
| Unfit living conditions | General disorders | Systematic Assessment |
|
| Acute cholecystitis | Infections and infestations | Systematic Assessment |
|
| Skin irritation or rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Cellulitis | Infections and infestations | Systematic Assessment |
|
| Musculoskeletal injury | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Hypoglycemia | General disorders | Systematic Assessment |
|
| Hyperkalemia | Renal and urinary disorders | Systematic Assessment |
|
| Delerium | General disorders | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | Systematic Assessment |
|
| Kidney transplant hydronephrosis | Renal and urinary disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Gastroenteritis | Gastrointestinal disorders | Systematic Assessment |
|
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| D005261 |
| Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D002241 |
| Carbohydrates |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |