Evaluating Iron Protein Succinylate Oral Solution in Treating Chronic Heart Failure and Iron Deficiency

Study Overview
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Brief Summary
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This study aims to evaluate the effect of standard heart failure therapy plus oral solution with protein succinylate iron compared to placebo on the primary end point of 6 minute walk distance at 24th week in patients with chronic ejection fraction reduction heart failure and iron deficiency.

Detailed Description
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This clinical trial was designed as a multicenter, prospective, randomized, double-blind controlled study. Patients were randomly divided into one of two treatment groups: Control group: standard treatment + placebo（1 bottle orally, twice daily, take orally before meals, duration of treatment 16-24 weeks）. Test group: standard treatment + Iron protein succinylate oral solution (1 bottle orally, twice daily, take orally before meals, duration of treatment 16-24 weeks）. Sample size calculation is according to the change of 6 Minute walk distance from the baseline at 24 weeks, it is estimated the mean difference between two groups is 20 meter, standard deviation 80 meter, statistical power 80%, type I error 0.05, follow up loss 15%，estimated total sample size 600.

Official Title
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A Randomized, Double-blind, Multi-center Clinical Trial Prospectively Evaluating Iron Protein Succinylate Oral Solution in Treating Patients With Chronic Heart Failure and Iron Deficiency

Conditions
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Chronic Heart Failure, Iron-deficiency

Intervention / Treatment
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* Drug: Iron protein succinylate oral solution
* Other: standard treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sign informed consent form; Between 18 to 80 years old, male or female; Patients with chronic ejection fraction reduction heart failure, has been accepted the medication recommended by the Guidelines for treatment of heart failure in China (2014) for at least 4 weeks (that comply with the following requirements): if there is no contraindications or intolerance, patients should receive the renin angiotensin aldosterone system inhibitors, B blockers, and no dose adjustment within 4 weeks (not including diuretics). For patients who do not follow the guidelines for the use and titration of the renin angiotensin aldosterone system inhibitor and B blocker drugs, the cause should be recorded; LVEF< 40% (determined by Simpson method) (valid for one week before randomization); NYHA heart function II-III Grade; NT-proBNP>400pg/ml, it should be .900pg/ml at atrial fibrillation; Upper limit of hemoglobin: women less than 120g/L, men less than 130g/L. Lower limit of hemoglobin: more than 90g/L for both men and women. Accompanied by Iron deficiency (iron deficiency is defined as serum ferritin<100ug/L, or serum ferritin between 100 300ug/L with transferrin saturation (Tsat) <20%); Capable of 6 Minute walk test. Exclusion Criteria: Patients with significant bleeding: gastrointestinal bleeding, menorrhagia, history of gastrointestinal bleeding and no evidence of gastrointestinal disease healing; History of oral iron supplementation and intolerance; History of acquired iron overload; Exclude if receiving erythropoietin, intravenous iron, transfusion therapy and oral iron (including iron contained in compound vitamins or other compound medicine) ≧75mg/day within 6 weeks before enrollment; Patients in urgent need of blood transfusion; VtaminB12 and/or folate deficiency, unless correctable; and Non-iron deficiency anemia; Severe renal insufficiency（eGFR < 20ml/min/1.73m2, MDRD formula）, renal anemia; or history of kidney dialysis, need of kidney dialysis at present or in 6 months; Chronic liver disease, cirrhosis, active hepatitis, transaminases (increase of alanine aminotransferase and aspartate aminotransferase 3 times above the normal upper limit. Total bilirubin 3 times higher than the normal upper limit); Intestinal diseases which affect iron absorption such as inflammatory bowel disease and chronic pancreatitis; Active infection; History of syncope within 3 months, diagnosed as cardiogenic shock over the past 1 months; Active myocarditis, constrictive pericarditis and other pericardial diseases; Acute decompensated heart failure with unstable hemodynamics; Symptomatic bradycardia or second or third-degree cardiac conduction block with no pacemaker installed; Severe chronic obstructive pulmonary disease, pulmonary heart disease, severe pulmonary vascular disease, pulmonary hypertension caused by autoimmune diseases and any type of severe pulmonary hypertension; Valvular heart disease and congenital heart disease without operation; hypertrophic cardiomyopathy, restricted cardiomyopathy, and other secondary cardiomyopathy; Patients with malignancy; Patients combined with other organ diseases such as hematopoietic system, nervous system, endocrine system like thyroid, and combined with psychosis; There is uncontrolled hypertension, systolic pressure is greater than 180mmHg and/or diastolic pressure is greater than 110mmHg; Heart rate ≥ 130 times/minute before randomization, or malignant ventricular arrhythmia affecting hemodynamic; Neuromuscular disease, disability or other non-cardiac causes influencing the performance of 6 Minute walk test; Occurred within 3 months: acute coronary syndrome, stroke, transient cerebral ischemic attack; cardiac, carotid artery or other major vascular surgery; percutaneous coronary intervention (PCI) or carotid artery angioplasty or coronary bypass surgery and other cardiac surgery; or scheduled for percutaneous intervention and surgery surgical treatment within 6 months; Has been implanted pacemaker/defibrillator (CRT-P/D) of cardiac resynchronization therapy within 6 months, or the intention to implant a similar device within 6 months after randomization; Has been received major surgery within 6 months prior to randomization, or intend to receive major surgical treatment within 6 months; History of heart transplantation or waiting for transplantation or using a left ventricular assist device (LVAD) or a heart transplant intention (waiting for transplantation) or intend to use VAD over the next 6 months; Nursing or pregnant women, or women of childbearing age without contraception, or patients planned pregnancy in 6 months; History of major organ transplant (such as lung, liver, bone marrow, kidney) Patients have been involved or to be involved in other clinical trials within one month; Patients cannot understand the informed consent form or cannot make decisions or of poor compliance; Patients judged as unsuitable for the study and life expectancy less than 1 year by investigators.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: standard treatment + Iron succinylate<br>1 bottle orally, twice daily, take orally before meals | Drug: Iron protein succinylate oral solution<br>* Iron protein succinylate oral solution<br>Other: standard treatment<br>* standard treatment<br>|
| Placebo Comparator: standard treatment + placebo<br>1 bottle orally, twice daily, take orally before meals | Other: standard treatment<br>* standard treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change of 6 Minute walk distances | The change of 6 Minute walk distances compared to baseline after patients receiving 24 week treatment. | 24 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variety of overall status score（PGA）after patients receiving 24 week treatment |  | 24 week | 
| Kansas City Cardiomyopathy Questionnaire (KCCQ) rating change after patients receiving 24 week treatment |  | 24 week | 
| Change of 6 Minute walk distance after patients receiving 16 week treatment |  | 16 week | 
| Change of blood NT-proBNP after patients receiving 24 week treatment |  | 24 week | 
| Cardiovascular death or heart failure re-hospitalization after patients receiving 24 week treatment |  | 24 week | 
| Comprehensive cause mortality after patients receiving 52 week treatment |  | 24 week | 
| EQ-5D Questionnaire score after patients receiving 24 week treatment |  | 24 week | 
| Change of NYHA grading after patients receiving 24 weeks treatment |  | 24 week |