Hemoglobin Optimization to Prevent Transfusion and Adverse Events in Perioperative Patients With Iron Restricted Anemia (HOPE-Hb)

A Randomized Double-Blinded Phase II Study to Determine Treatment Protocol for Hemoglobin Optimization to Prevent Transfusion and Adverse Events in Perioperative Patients With Iron Restricted Anemia

The HOPE-Hb trial is a phase II study to determine the feasibility and impact of a combination treatment (intravenous iron plus erythropoietin) versus intravenous iron treatment alone on preoperative hemoglobin concentration before hip or knee arthroplasty.

Study Overview

• Status: Terminated
• Conditions: Anemia, Iron Deficiency; Knee Arthropathy; Hip Arthropathy; Anemia of Chronic Disease
• Intervention / Treatment: Drug: Iron sucrose; Drug: Epoetin Alfa; Drug: Placebo

Detailed Description

The purpose of the HOPE-Hb trial is to determine the feasibility and efficacy of intravenous iron plus erythropoietin versus intravenous iron alone for the treatment of iron restrictive anemia (iron deficiency anemia and anemia of chronic inflammation) prior to unilateral total hip or knee arthroplasty surgery. Half of the study population will be randomly assigned to receive intravenous iron (Venofer; iron sucrose) and Eprex (subcutaneous epoetin alfa), while the other half will be randomized to receive Venofer (intravenous iron sucrose) and placebo (subcutaneous saline). This trial will be conducted in two phases. The vanguard phase will be conducted at a single site with a primary outcome of evaluating feasibility of the study. The full study phase will be conducted at four sites with a primary outcome of determining the impact of a combination treatment (intravenous iron plus erythropoietin) versus intravenous iron treatment alone on preoperative hemoglobin concentration. This study will also examine the RBC transfusion rate and clinical outcomes such as death, stroke, myocardial infarction, pulmonary embolism, infection, kidney injury, and deep vein thrombosis as secondary outcomes.

Preoperatively, patients will be administered a total of 900mg of intravenous iron (Venofer, iron sucrose) over three visits (3-6 weeks before surgery). Then patients will be randomized to receive either two administrations of 40,000 IU of Erythropoietin (Eprex; Epoeitin alfa) or an identical placebo (saline) over two study visits (2-3 weeks before surgery). Study participants will be followed-up for 12 weeks after surgery.

Study assessments and potential adverse events reporting will be undertaken at each study visit.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B1W8
      • St. Michael's Hosptial

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 years of age or older at the time of consent
• Undergoing unilateral total hip or knee arthroplasty surgery (primary)
• Hemoglobin concentration of less than 120g/L; but greater than 60g/L

Exclusion Criteria:

• Anemia attributed to something other than iron deficiency anemo/ACI:
• Any other diagnosed or suspected cause of anemia (e.g. macrocytic anemia , lead toxicity, myelodysplastic syndrome)
• Suspected of having acute blood loss due to any diagnosed condition (e.g. malignancy or gastric ulcer)
• Mean Cell Volume (MCV) > 97fL
• Known deficiency of vitamin B12 and/or folate
• A known history of acquired iron overload, haemochromatosis, thalassemia or other hereditary hemoglobinopathy.
• Received an erythropoiesis stimulating agent, IV iron therapy, or red blood cell transfusion in the previous 12 weeks (from the time of consent), or planned use prior to operation
• Blood pressure measured at >180mmHg systolic or >100mmHg diastolic
• Known current or prior history of liver disease or elevation of alanine transaminase (ALT), or aspartate transaminase (AST) more than two times the upper limit of normal
• A known hypersensitivity to IV iron or erythropoietin alfa (Eprex)
• Renal dialysis (current or historical)
• Active infection (currently receiving antibiotics)
• Not eligible for venous thromboembolism prophylaxis
• Prior history of seizures or medical conditions associated with a predisposition to seizure activity such as central nervous system infections and brain metastases
• History of thromboembolic disease or active coronary artery disease
• Women who are pregnant or lactating (women of childbearing potential must be surgically sterile, or more than 1 year postmenopausal, or else must have a negative pregnancy test prior to randomization)
• Recipient of an investigational drug within the past 30 days
• Inability to speak, read, or understand the English language (required for cognitive testing)
• Participation in a preoperative autologous blood donation program for current operation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Epoetin alfa; Preoperative treatment of anemia with iron sucrose (Venofer) plus Epoetin Alfa (Eprex)	Drug: Iron sucrose; Intravenous iron to be administered to all patients (9 x 5 mL Single Dose Vials @ 20mg elemental iron/mL; 900 mg total); Other Names: Venofer; Drug: Epoetin Alfa; Erythropoietin to be administered to half of study participants (40,000 IU x 1-2 subcutaneous injections); Other Names: Eprex
PLACEBO_COMPARATOR: Intravenous Iron; Preoperative treatment of anemia with iron sucrose (Venofer) plus placebo (saline)	Drug: Iron sucrose; Intravenous iron to be administered to all patients (9 x 5 mL Single Dose Vials @ 20mg elemental iron/mL; 900 mg total); Other Names: Venofer; Drug: Placebo; Saline to be administered to half of study participants (equal volume to Eprex x 1-2 subcutaneous injections); Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vanguard Phase (Initial 12 patients): Feasibility of using Erythropoietin + Intravenous Iron to Treat Preoperative Iron Restrictive Anemia	The primary outcome of the vanguard phase is to determine the feasibility of using erythropoietin + intravenous iron to treat preoperative iron restrictive anemia. Feasibility will be measured according to subject enrollment rates, with adherence to the treatment schedule of >80%.	18 weeks from randomization
Full Study: Preoperative Hemoglobin Concentration	The primary outcome of the full study is preoperative hemoglobin concentration, as measured on the day of surgery in patients with iron restricted anemia.	6 weeks from randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-Treatment Hemoglobin Concentration	Change in post-treatment hemoglobin concentration from baseline	12 weeks from randomization
Change in Hemoglobin Concentration from Initiation of Treatment	Rate of hemoglobin change from initiation of treatment to final preoperative hemoglobin	6 weeks from randomization
Postoperative Hemoglobin Concentration	Hemoglobin concentration on postoperative day 2 (prior to hospital discharge); and 4-6 weeks after surgery	0 weeks from surgery and 12 weeks from surgery
Red Blood Cell Transfusions	Rate of RBC transfusion and number of units transfused during surgery and up to 6 weeks postoperatively	6 weeks from surgery
Deep Vein Thrombosis	Incidence of DVT up to 12 weeks postoperatively	12 weeks from surgery
Composite of Morbidity	Incidence of a composite clinical outcome including death, stroke, myocardial infarction, pulmonary embolism, infection, acute kidney injury, and deep vein thrombosis from treatment to up to 3 months post surgery	3 months from surgery
Surgical Wound Infection	Incidence of superficial and deep wound infection from treatment to 4-6 weeks post surgery	6 weeks from surgery
Assessment of Iron Status	Hematological outcomes for treatment efficacy including: Hb, ferritin, hepcidin, and transferrin saturation (TSAT) pre-operatively and 4-6 weeks postoperatively	6 weeks from surgery
Digit Span Test	Cognitive assessment of memory span	6 weeks from surgery
California Verbal Learning Test	Cognitive assessment of word learning, recall and recognition, as well as episodic memory	6 weeks from surgery
Neuropsychological Impairment Scale	A subjective cognitive assessment of cognitive functioning. This is a 95-item questionnaire, with all items rated on a scale from 0 (not at all) to 5 (extremely). From the 95 total items, 80 items describe neurophysiological symptoms (Global measure of impairment; GMI), 10 items describe affective disturbance, and 5 items assess test-taking attitudes. A total GMI score can range from 0-320, with higher scores indicating an increased impairment index.	6 weeks from surgery
Trail Making Test	Cognitive assessment of processing speed	6 weeks from surgery
Digit Symbol	Cognitive assessment of response speed, sustained attention, and visual spatial skills	6 weeks from surgery
Montreal Cognitive Assessment	Cognitive assessment of global cognitive functioning	6 weeks from surgery
Stroop Colour and Word Test	Cognitive assessment of processing speed	6 weeks from surgery
Wisconsin Card Sorting Test	Cognitive assessment of a participant's ability to set-shift (display flexibility in the face of changing conditions)	6 weeks from surgery
Hospital Anxiety and Depression Scale	Cognitive assessment of anxiety and depression levels. A total score between 0-7 indicates normal levels of depression or anxiety; a total score between 8-10 indicates borderline abnormal levels of anxiety or depression; and a total score between 11-21 indicates abnormal levels of depression or anxiety	6 weeks from surgery
Cost Analysis	Assessment of relative cost of treatment and cost savings associated with transfusion avoidance will be assessed (see projected cost analysis; appended)	12 weeks from randomization

Collaborators and Investigators

• Sponsor: Unity Health Toronto
• Investigators: Principal Investigator: Gregory MT Hare, MD PhD, St. Michael's Hospital; University of Toronto

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2019
• Primary Completion (ACTUAL): May 31, 2021
• Study Completion (ACTUAL): May 31, 2021

Study Registration Dates

• First Submitted: April 9, 2018
• First Submitted That Met QC Criteria: May 4, 2018
• First Posted (ACTUAL): May 18, 2018

Study Record Updates

• Last Update Posted (ACTUAL): June 18, 2021
• Last Update Submitted That Met QC Criteria: June 14, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Erythropoietin; Intravenous Iron; Preoperative Anemia
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Disease Attributes; Hematologic Diseases; Musculoskeletal Diseases; Anemia, Hypochromic; Iron Metabolism Disorders; Anemia, Iron-Deficiency; Chronic Disease; Joint Diseases; Anemia; Hematinics; Epoetin Alfa; Ferric Oxide, Saccharated
• Other Study ID Numbers: HOPE-Hb

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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