Hemoglobin Optimization to Prevent Transfusion and Adverse Events in Perioperative Patients With Iron Restricted Anemia

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Anemia, Iron Deficiency, Anemia of Chronic Disease, Hip Arthropathy, Knee Arthropathy

Intervention / Treatment
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* Drug: Iron sucrose
* Drug: Epoetin Alfa
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preoperative Anemia, Intravenous Iron, Erythropoietin