Frequent, Low-Dose Erythropoietin A Mechanistic Approach to Mitigate Adverse Cardiovascular Effects of Erythropoietin

NCT03277183 | Terminated Phase 4 Results DMC FDA Drug

• 2 other identifiers: CARA-019-16FI01CX001449
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Anemia; CKD; Atherosclerosis; Cardiovascular

Keywords

erythropoietin

Outcome Measures

Primary Outcomes (1)

• 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.

  1 year

Secondary Outcomes (3)

• Severity of Maximal Stenosis at Baseline and Upon Follow-up.

  1 year

• Percentage of Total Plaque Area at Baseline and Upon Follow-up.

  1 year

• Characteristics of Plaques (Soft or Fibrous and Stable or Unstable) at Baseline and Upon Follow-up.

  1 year

Study Arms (2)

Low dose erythropoietin

PLACEBO COMPARATOR

Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly

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

Drug: High dose erythropoietin

Interventions

Low dose erythropoietin DRUG

Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly

Also known as: Low dose

Low dose erythropoietin

High dose erythropoietin DRUG

Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks

Also known as: High dose

High dose erythropoietin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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;
• 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.

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (1)

North Florida/South Georgia Veterans Health System, Gainesville, FL

Gainesville, Florida, 32608, United States

Location

MeSH Terms

Conditions

Anemia; Atherosclerosis

Interventions

Erythropoietin; Contraceptives, Oral

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Contraceptive Agents, Female; Contraceptive Agents; Reproductive Control Agents; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses

Results Point of Contact

• Title: Dr. Mark Segal
• Organization: NFSGVA

mark.segal@va.gov

3523761611

Study Officials

• Mark S. Segal, MD PhD

  North Florida/South Georgia Veterans Health System, Gainesville, FL

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The outcome is the progression of carotid plaque. John Forder, PhD, who will read the MRIs will be blinded to the subject and treatment group.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: September 6, 2017
• First Posted: September 8, 2017
• Study Start: November 2, 2017
• Primary Completion: June 3, 2019
• Study Completion: June 3, 2019
• Last Updated: August 13, 2020
• Results First Posted: August 13, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)