Iron Substitution With Ferric Carboxymaltose as Treatment Strategy for Heart Failure Patients With Preserved Ejection Fraction: A Prospective, Double-blind, Randomized, Placebo-controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 撤回
- 发起方
- 主要终点
- Change in peak oxygen uptake (VO2peak)
研究概览
简要总结
This study aims to investigate the effects of treatment with intravenous ferric carboxymaltose on exercise tolerance measured as VO2peak in patients with HFpEF and iron deficiency, compared to placebo.
详细描述
Iron deficiency is a common comorbidity associated with chronic heart failure (HF) in both, patients with preserved (HFpEF) and reduced ejection fraction (HFrEF), which has unfavorable clinical and prognostic effects. Previous studies have confirmed that HF patients with iron deficiency have a lower exercise tolerance than those without iron deficiency. In iron deficient patients with HFrEF, treatment with intravenous ferric carboxymaltose (FCM) improved symptoms, exercise tolerance and quality of life (QoL). Since the latest guidelines published by the European Society of Cardiology (ESC) in 2016, iron substitution is an official class IIa recommendation in HFrEF, while it has not yet been endorsed in the treatment guidelines for HFpEF. To date, no evidence is available on iron supplementation in HFpEF. Therefore, a clear rationale exists for examining the effects of correcting iron deficiency in this high-risk and steadily growing patient group.
The proposed study will be a single-centre, prospective, double-blind, randomized, placebo-controlled trial in a primary care setting including 86 patients with stable HFpEF and iron deficiency. Participants will undergo three study visits: a baseline visit, a status control visit, and a post-intervention visit. At the baseline visit, measurements of exercise tolerance (using spiroergometry), laboratory parameters and disease-specific biomarkers (using blood samples), tHb-mass (using the carbon monoxide rebreathing method), cardiac and arterial vessel structure and function (using electrocardiogram, echocardiography and PVW), QoL (using 3 validated questionnaires), body composition (using BMI and WHR), and habitual physical activity (using a wrist-worn accelerometer) will be performed. Then, patients randomized to the treatment group will receive FCM (Vifor Pharma AG, Villars-sur-Glâne, Switzerland), whereas those in the control group will receive placebo. At week 6, iron deficiency status will be re-evaluated in all patients and, if necessary, another application of FCM or placebo will be administered, respectively. After the 12-week treatment period, the study measurements will be repeated in all patients (post-intervention visit) to investigate the effects of the intervention.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Each administration of the study drug will be carried out after completion of all applicable study related assessments. FCM is a dark brown solution and cannot be easily masked from placebo (0.9% saline). Therefore, unblinded study personnel (at least one study nurse) who will not be involved in any study procedures for efficacy or safety will be responsible for preparing the infusion and packing bag and tube in an opaque wrapping. Preparation and wrapping will take place in a different room to maintain subject blinding. Administration of the study drug will take place by blinded study personnel. The results of the central laboratory on iron deficiency status and Hb will be sent only to the unblinded study personnel, who will be responsible for evaluating these parameters for subsequent dosing and/or other intervention, if applicable.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed consent as documented by signature
- •NYHA functional classes II-III
- •Signs and symptoms of chronic HF, such as:
- •Paroxysmal nocturnal dyspnea
- •Reduced exercise tolerance
- •Extended recovery after exercising
- •Peripheral edema (lower leg, ankle)
- •EF (ejection fraction) >50%
- •Structural or functional changes in echocardiography:
- •Left atrial volume index (LAVI) >34 ml/m2 OR
- •Left ventricular mass index (LVMI) >115 g/m2 (men), >95 g/m2 (women) OR
- •E/E' (ratio between mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E')) >13 AND mean E' septal and lateral wall <9 cm/s
- •NT-proBNP >125 pg/ml
- •At least 4 weeks on stable medical treatment or without signs and symptoms of cardiac decompensation
- •Iron deficiency defined as:
- •Ferritin <100 ng/ml OR
- •Ferritin <300 ng/ml with a transferrin saturation (TSAT) <20%
排除标准
- •Age <18 years
- •Pregnancy or lactation
- •Life-expectancy <6 months
- •Planned cardiac interventions in the following 6 months
- •Unstable angina pectoris
- •Uncontrolled brady- or tachyarrhythmia
- •Severe uncorrected valvular heart disease
- •Paroxysmal atrial fibrillation
- •Clinically significant concomitant disease states (e.g. hypertension grades 2-3 (>160/100 mmHg), severe renal failure (GFR <30 ml/min/1.73m2), hepatic dysfunction (ALT or AST >3x upper limit of normal, chronic obstructive pulmonary disease (COPD) grades III-IV)
- •On-going cancer treatment
- •Significant musculoskeletal disease limiting exercise tolerance
- •Active infection
- •Immunosuppressive medical therapy
- •Earlier hypersensitivity to parenteral iron preparation
- •Anemia and iron deficiency due to active and/or chronic bleeding
- •Blood transfusion within the previous 30 days
- •Red cell, folate and vitamin B12 deficiency
- •Known or suspected non-compliance, drug or alcohol abuse
- •Inability to follow the procedures of the study, e.g. due to insufficient language skills, psychological disorders, dementia, etc.
- •Participation in another intervention study
- •Enrolment of the investigators, their family members, and other persons involved in the study procedures
- •Hemoglobin < 120 ng/ml in male patients or < 110 ng/ml in female patients
研究组 & 干预措施
Iron substitution
Iron deficiency status will be assessed at the baseline visit (Day 0) as well as after 6 weeks of iron substitution (Week 6). The study drug will be given as FCM solution (Ferinject®, Vifor Pharma AG, Villars-sur-Glâne, Switzerland) by intravenous injection. Infusions of 10 or 20 mL (which is the amount of FCM that is equivalent to 500 or 1000 mg of iron, respectively) will be administered in ≥6 minutes diluted in ≈100 mL of sterile 0.9% sodium chloride solution (NaCl) for 10 mL, or in ≥15 minutes diluted in ≈200 mL for 20 mL. Dosing will be based on screening Hb level and weight, rather than on ferritin and TSAT results. On Day 0 (baseline visit), patients with Hb ≤14 g/dL, both <70 kg and >70 kg will receive 1000 mg FCM (20 mL), whereas patients with Hb >14g/dL will receive 500 mg FCM (10 mL).
干预措施: Ferric carboxymaltose (Drug)
Placebo
Patients in the control group will receive a placebo solution administered as normal saline (0.9% weight/volume (w/v) NaCl) by intravenous injection as per the instructions for active treatment.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in peak oxygen uptake (VO2peak)
时间窗: 12 weeks
Change of VO2peak will be measured by spiroergometry at the baseline and post-intervention visit.
次要结局
- Change in body composition measured by body mass index (BMI)(12 weeks)
- Change in baseline quality of life (QoL) by the Kansas City Cardiomyopathy Questionnaire (KCCQ) at 12 weeks.(12 weeks)
- Change in ventriculo-arterial coupling (VAC)(12 weeks)
- Change in New York Heart Association (NYHA) functional class(12 weeks)
- Change in quality of life (QoL) by the 36-Item Short Form Health Survey (SF-36)(12 weeks)
- Change in pulse wave velocity (PWV)(12 weeks)
- Change in arteriovenous oxygen difference (Da-vO2)(12 weeks)
- Change in quality of life (QoL) by the Minnesota Living with Heart Failure Questionnaire (MLWHFQ) at 12 weeks.(12 weeks)
- Change in habitual physical activity(12 weeks)
- Change in baseline body composition measured by waist to hip ratio (WHR)(12 weeks)
- Change in total hemoglobin mass (tHb-mass)(12 weeks)
研究者
Maria Bösing
Principal Investigator
Cantonal Hosptal, Baselland