Intravenous Iron in paTients With Heart failURe and Reduced Ejection fracTion (HFREF) pLus Iron dEficiency (Iron Turtle)

Intravenous Iron in paTients With Heart failURe and Reduced Ejection fracTion (HFREF) pLus Iron dEficiency: Effects Upon Phosphate and FGF23 Metabolism

Effects of ferric carboxymaltose single HD (1000 mg) infusion upon FGF23 in patients with isolated HFREF compared to patients with HFREF+CKD (all pts with iron deficiency). This study aims at identification of the optimal target population for a follow-up ("main") study.

Study Overview

• Status: Completed
• Conditions: Iron Deficiency; Heart Failure, Systolic
• Intervention / Treatment: Drug: Ferric Carboxymaltose; Other: blood withdrawal

Detailed Description

Iron deficiency is highly prevalent in patients with HFREF and intravenous high-dose (HD) iron application has significantly improved clinically meaningful endpoints in such patients. The best evidence is existent for ferric carboxymaltose. Intravenous HD iron may influence phosphate metabolism via increases in levels of intact FGF23 and hence induce prolonged hypophosphatemia. Such increases in FGF23 may particularly occur depending on the type of iron carrier.

FGF23 is a significant risk factor for mortality and morbidity in patients with HFREF and other cardiac populations at risk and may directly cause left ventricular hypertrophy and dysfunction. Hence, the application of i.v. HD iron may have potentially beneficial effects on cardiac function but harmful effects via FGF23-induction and hypophosphatemia at the same time. However, FGF23 metabolism has not yet been evaluated in HFREF patients following i.v. HD iron.

FGF23 is elevated in patients with chronic kidney disease. Patients with HFREF + CKD = chronic cardio-renal syndrome are at particular risk regarding elevated morbidity and mortality. The effects of intravenous HD iron upon phosphate and FGF23 metabolism in patients with HFREF + CKD is unknown and effects in this setting may be different compared to effects in patients without pre-existing FGF23 stimulation.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • NRW
    • Aachen, NRW, Germany, 52074
      • Department of Medicine, Division of Cardiology, Pulmonary Diseases and Vascular Medicine at the University Hospital, RWTH Aachen

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:

• Written informed consent.
• Age > 18 yrs
• Symptomatic HFREF (LV ejection fraction < 45%) with optimal medical therapy (OMT) for at least 2 months
• Iron deficiency as indicated by by ferritin <100 ng/mL or ferritin 100-299 ng/ml when transferrin saturation (TSAT) <20% and Hb value < 13mg/dl (women) and <14 mg/dl (men)
• Group A: Stable CKD for at least 2 months, defined by estimated glomerular filtration rate (eGFR) (CKD-EPI formula) as 15-60 ml/min/1,73 m3 (CKD III, IV, V-non D)
• Group B: patients with stable eGFR > 60 ml/min/1,73 m3

Exclusion Criteria:

• Known hypersensitivity to ferric carboxymaltose or any constituents of the formulation,
• Plasma Phosphate < 2.5 mg/dL at screening,
• Renal replacement therapy/transplantation,
• Pregnancy or lactation
• iron substitution therapy or erythropoetin (epo) therapy within 6 weeks before
• participation in another clinical trial with an experimental drug
• expectation of missing compliance
• alcohol or drug abuse
• The subject is mentally or legally incapacitated
• patients who are in a relationship of dependence or in a working relationship to the sponsor, the investigator or his representative

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Patients with HFREF & CKD; treated with intravenous single-shot 1000mg Ferric Carboxymaltose infusion; additional intervention: blood withdrawal	Drug: Ferric Carboxymaltose; single shot infusion; Other Names: Ferinject; Other: blood withdrawal; for determination of serum and urinary biomarkers of chronic kidney disease metabolism and other parameters
ACTIVE_COMPARATOR: Patients with HFREF; treated with intravenous single-shot 1000mg Ferric Carboxymaltose infusion; additional intervention: blood withdrawal	Drug: Ferric Carboxymaltose; single shot infusion; Other Names: Ferinject; Other: blood withdrawal; for determination of serum and urinary biomarkers of chronic kidney disease metabolism and other parameters

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
changes in blood intact FGF23 after infusion of 1000 mg ferric carboxymaltose	intact FGF23 concentration in kRU/l	4 weeks
changes in blood c-term FGF23 after infusion of 1000 mg ferric carboxymaltose	c-terminal FGF23 concentration in kRU/l	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
changes of serum biomarkers of chronic kidney disease metabolism	PTH, Vitamin D, ALP, s-klotho, PINP, proBNP	4 weeks
changes of urinary marker of tubular damage	NGAL, KIM-1	4 weeks
phosphate level	< 1,25 mg/dL	4 weeks
changes of Inflammatory mediators	IL1, IL6, TNF-alpha, hsCRP	4 weeks

Collaborators and Investigators

• Sponsor: RWTH Aachen University

Publications and helpful links

General Publications

• Stohr R, Sandstede L, Heine GH, Marx N, Brandenburg V. High-Dose Ferric Carboxymaltose in Patients With HFrEF Induces Significant Hypophosphatemia. J Am Coll Cardiol. 2018 May 15;71(19):2270-2271. doi: 10.1016/j.jacc.2018.03.448. No abstract available.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 10, 2017
• Primary Completion (ACTUAL): October 25, 2017
• Study Completion (ACTUAL): October 25, 2017

Study Registration Dates

• First Submitted: March 3, 2017
• First Submitted That Met QC Criteria: March 8, 2017
• First Posted (ACTUAL): March 14, 2017

Study Record Updates

• Last Update Posted (ACTUAL): December 6, 2017
• Last Update Submitted That Met QC Criteria: December 5, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: FGF23; ferric carboxymaltose; iron deficiency; HFREF
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Hematologic Diseases; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Heart Failure; Anemia, Iron-Deficiency; Heart Failure, Systolic
• Other Study ID Numbers: 16-047

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will not be shared due to publication afterwards

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No