The Effects of Ferric Derisomaltose in Patients With Acute Heart Failure and Iron Deficiency on Exercise Capacity and Quality of Life

Study Overview
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Brief Summary
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This study will address whether the additional use of Ferric Derisomaltose on top of standard care will improve exercise capacity and quality of life in patients with acute heart failure and iron deficiency. One group of participants will receive treatment with Ferric Derisomaltose and the other group will receive normal saline 0.9% as placebo.

Detailed Description
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Acute heart failure is very common medical problem. Despite many clinical trials conducted to date in these patients, the rates of adverse outcomes remain very high. Previous comorbidities may account for it. Approximately 80% of patients hospitalized with AHF suffered from a combination of iron deficiency. A decline in exercise capacity may occur under this condition. Some research studies have suggested that giving CHF patients intravenous iron improves symptoms in the short term. It is unknown, however, whether correcting iron deficiency is beneficial to patients with AHF to improve excise capacity and whether it improves quality of life and accelerate recovery from acute duration. This study will help us answer these key questions. This is an investigator-initiated, randomised, parallel group, double-blind, placebo-controlled trial, evaluating the excise capacity improvement of using ferric derimaltose versus placebo in hospitalized patients with acute heart failure with preserved ejection fraction before discharge. Participants will be assessed daily using 6-minute walking test after IV iron injection until discharge from hospital, especially focus on the change from baseline to the 3rd day. Some questionnaire are also conducted to evaluate the self-reported status. Participants will be followed up at 2 weeks and 4 weeks. The primary and secondary endpoints will be examined in subgroups predefined by baseline variables reflecting demography, Hb level, etiology of HF, left ventricular ejection fraction, natriuretic peptide, index of iron metabolism, eGFR and others.

Official Title
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The Effects of Ferric Derisomaltose Administered Before Hospital Discharge in Stabilised Patients With Acute Heart Failure and Iron Deficiency on Exercise Capacity and Quality of Life: a Randomised, Parallel-group, Double-blind, Placebo Controlled Trial (COREVIVE-HFpEF)

Conditions
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Heart Failure With Preserved Ejection Fraction, Iron Deficiencies, Acute Heart Failure

Intervention / Treatment
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* Drug: Ferric derisomaltose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years. Clinical diagnosis of heart failure with preserved ejection fraction (HFpEF), defined as documented 2-dimensional echocardiography left ventricular ejection fraction (LVEF) ≥50% before randomization. Currently hospitalized for an episode of acute heart failure (AHF) where AHF was the primary reason for hospitalization, New York Heart Association (NYHA) class II - IV.N-terminal pro brain natriuretic peptide (NT-proBNP) ≥300 or brain natriuretic peptide (BNP) ≥100 pg/mL in sinus rhythm, or NT-proBNP≥600 or BNP ≥200 pg/mL in atrial fibrillation prior to randomization Reaching hemodynamic stability after standard treatment (if tolerated, initiate four pillars of guideline-directed medical therapies). All of the following (i.e., items a to c) must apply: Systolic blood pressure≥100mmHg, without symptoms of hypotension; Stop using intravenous diuretics; Neither intravenous inotropic drugs or vasodilators were used (including nitrates). Subject is iron deficient defined as serum ferritin <100 ng/mL or 100 ng/mL ≤ serum ferritin ≤299 ng/mL if TSAT <20%. Able and willing to provide informed consent and accomplish 6 minutes-walking test. Exclusion Criteria: Haematological criteria: ferritin >400ug/L; haemoglobin <9.0 g/dL, or >13.5 g/dL (for female), 14.5g/dL (for male). Renal dialysis or MDRD/CKD-EPI estimated glomerular filtration rate (eGFR) <15ml/min/1.73m2 Body weight<35kg at randomization. Heart failure was secondary to valvular diseases or congenital heart diseases. History of acquired iron overload or hemochromatosis (or first-degree relative of haemochromatosis) Known hypersensitivity reaction to any component of ferric derisomaltose (Monofer®) or any of its excipients (water for injections, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment)). Non-iron deficiency anaemia. Already receiving erythropoiesis stimulating agents (ESA) or other iron supplements in previous 4 weeks prior to randomization. Active infection (defined as currently treated with oral or intravenous antibiotics), bleeding (gastrointestinal haemorrhagia, menorrhagia, history of peptic ulcer with no evidence of healing or inflammatory bowel disease) and history of malignant tumor. Any of the following diseases that hinders exercise testing: severe musculoskeletal disease, unstable angina, obstructive cardiomyopathy, severe uncorrected valvular disease, or uncontrolled slow or rapid arrhythmia (mean heart rate> 100 beats / min at rest). Known positive HBsAg and/or HCV RNA; known HIV positivity; chronic liver disease (including active hepatitis), hepatic sclerosis, ALT or AST > 3x upper limit of normal. Within 3 months of any of the following: acute myocardial infarction (AMI) or acute coronary syndrome (ACS), transient ischemic attack (TIA) or stroke, uncontrolled hypertension. Revascularization therapy (coronary artery bypass grafting, percutaneous intervention, or major surgery) in the past 3 months; or planning cardiac surgery or revascularization. 14.6 minutes-walking distance>500m at baseline. 15.Treated with long-term oral high-dose or steroid-immunosuppression therapy. 16.Investigator considers a possible alternative diagnosis to explain the patient's HF symptoms: severe obesity, primary pulmonary hypertension, or chronic obstructive pulmonary disease (COPD). 17.Subject is pregnant (e.g., positive human chorionic gonadotropin test) or breast feeding. 18.Untreated hypothyroidism. 19.Currently enrolled in any other investigational device or drug study <30 days prior to screening or received other investigational agent(s).

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: Ferric derisomaltose<br>Iron to be administered as ferric derisomaltose. The treatment dose (mL) to be administered will be determined by the patient's body weight and haemoglobin (Hb) value. Where Hb ≥10 g/dL, dosage according to body weight is as follows: Body weight <50 kg: 20 mg/kg; Body weight 50 to <70 kg: 1000 mg; Body weight ≥70 kg: 20 mg/kg up to a maximum of 1500 mg. Where Hb <10 g/dL, dosage according to body weight is as follows: Body weight <50 kg: 20 mg/kg; Body weight 50 to <70 kg: 20 mg/kg; Body weight ≥70 kg: 20 mg/kg up to a maximum of 2000 mg. Infused over a minimum of 15mins for doses up to and including 1000mg, and a minimum of 30 mins for doses >1000mg | Drug: Ferric derisomaltose<br>* After baseline assessments patients will be randomised in a 1:1 ratio to receive ferric derisomaltose IV or placebo (normal saline). In the Treatment group, Ferric derisomaltose will be administered according to the dosing schedule.<br>* Other names: Iron (III) isomaltoside 1000;|
| Placebo Comparator: Placebo<br>Participants in this arm will receive normal saline 0.9% in analogy to treatment arm. | Drug: Placebo<br>* n the placebo group, patients will receive the equivalent number of normal saline injections.<br>* Other names: Normal saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6-minute walking distance | The difference of 6-minute walking distance in meters from baseline to day3 after IV iron injection. | Up to 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 6-minute walking distance | The difference of 6-minute walking distance in meters from baseline at 2 weeks, 4weeks after IV iron injection. | At 2 weeks, 4weeks after IV iron injection | 
| Change From Baseline in the KCCQ Clinical Summary Score | KCCQ was a 23-item, self-administered questionnaire that measure the participant's perception of their health status, including their heart failure (HF) symptoms, impact on physical and social function and how their HF impacts the quality of life. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 to 100, with 0 denoting the worst and 100 the best possible status. KCCQ-clinical summary score was average of domains- physical limitation and total symptoms (average of symptom frequency and symptom burden), and transformed to a single score which ranged from 0 (worst) -100 (the best possible status), where the higher score reflected better health status. | At 2 weeks, 4weeks after IV iron injection | 
| Change From Baseline in the EQ-5D-5L Questionnaire Indexed Value | EQ-5D-5L: European Quality of Life-5 Dimensions-5 Levels The EQ 5D questionnaire consists of a health descriptive system for participants to self-classify and rate their health status on the day of administration. The descriptive system includes 5 items/dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression, which are coded from 1 (best state) to 5 (worst state). | At 3 days, 2weeks, 4weeks after IV iron injection | 
| Change From Baseline in NYHA Functional Class | NYHA = New York Heart Association NYHA functional class was assessed as Class I, II, III, IV: Class I - No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, climbing stairs etc. Class II - Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity. Class III - Marked limitation in activity due to symptoms, even during less-than-ordinary activity. Comfortable only at rest. Class IV - Severe limitations. Experiences symptoms even while at rest. Lower response categories are better for score NYHA. | At 3 days, 2weeks, 4weeks after IV iron injection | 
| Change From Baseline in PGA quality of life questionnaire | PGA:Patient Global Assessment PGA questionnaire consists of a health descriptive system for participants to self-reported and rate their medical condition after participate this study. The descriptive system includes 7 choices：has much improved, has (moderately) improved, has a little improved, is unchanged, is a little worse, is (moderately) worse, is much worse, which are coded from 1 (best state) to 7 (worst state). | At 3 days, 2weeks, 4weeks after IV iron injection | 
| Change From Baseline in Concentration of hemoglobin (Hb) | Hemoglobin (Hb) is a commonly used clinical test for assessing anaemia, with units of g/L. | At 3 days, 2weeks, 4weeks after IV iron injection | 
| Change From Baseline in proportion of reticulocyte (Ret%) | The reticulocyte ratio is often used to reflect the hematopoiesis of the bone marrow erythrocyte with units of percentage(%). | At 3 days, 2weeks, 4weeks after IV iron injection | 
| Change From Baseline in Concentration of ferritin | To assess the effect of ferric derisomaltose vs. placebo on change in ferritin from baseline to 3 days, 2weeks and 4weeks | At 3 days, 2weeks, 4weeks after IV iron injection | 
| Change From Baseline in Concentration of transferrin saturation | To assess the effect of ferric derisomaltose vs. placebo on change in transferrin saturation from baseline to 3 days, 2weeks and 4weeks | At 3 days, 2weeks, 4weeks after IV iron injection | 
| Change From Baseline in Concentration of serum transferrin receptors (sTfR) | To assess the effect of ferric derisomaltose vs. placebo on change in serum transferrin receptors (sTfR) from baseline to 3 days, 2weeks and 4weeks | At 3 days, 2weeks, 4weeks after IV iron injection | 
| Change From Baseline in Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | To assess the effect of ferric derisomaltose vs. placebo on change in NT-proBNP from baseline to 3 days, 2weeks and 4weeks | At 3 days, 2weeks, 4weeks after IV iron injection | 
| Change From Baseline in Left Ventricular Diastolic Function | Indicators of diastolic function including E/A、E、E/e' are assessed by two-dimensional directed pulse-doppler echocardiography. | At 2weeks, 4weeks after IV iron injection | 
| Change From Baseline in Left Atrial Diameter | Left ventricular end-diastolic diameter is assessed by two-dimensional directed M-mode echocardiography. | At 2weeks, 4weeks after IV iron injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise capacity, Quality of life, Acute Heart Failure