A randomised, controlled, observer-blinded phase III clinical trial to compare the effect of intravenous ferric carboxymaltose to placebo on exercise capacity and cardiac function in patients with chronic heart failure and iron deficiency - EFfect of Ferric Carboxymaltose on exercIse CApacity and Cardiac function in patients with iron deficiencY and chronic Heart Failure

HF (heart failure) results in poor life expectancy, impaired quality of life,
repeated hospitalisations and is a considerable economic burden, accounting for
1*2% of health care expenditure in European countries. Estimates of the
prevalence of anaemia and/or iron deficiency in patients with chronic CHF vary
from 4% to 61% (median 18%). In CHF patients, even mild anaemia is associated
with worsening symptoms, increa¬sed NYHA class and impaired functional
capacity, quality of life and survival. Recent data show that CHF patients with
persistent anaemia have a 2.43-fold higher long-term mortality rate than those
whose anaemia resolved after 6 months of follow-up. Anaemia in patients with
CHF is often related to iron deficiency and has been shown to be remediable
with elemental iron, with or without EPO (erythropoietin). Nonetheless, the
pathophysiologic mechanism involved is not completely under¬stood. Possible
causes that have been suggested are: chronic inflammation associ-ated with CHF,
iron deficiency caused by prophylactic intake of aspirin or other
anti-thrombotic agents, down-regulation of EPO by ACE (angiotensin converting
enzyme) inhibitors, presence of chronic renal failure, bone marrow depression
related to the presence of cytokines such as tumour necrosis factor, and
interference with iron release and utilisation.Sandek et al. have described
significant morphological and functional alterations of the intestine in CHF
patients. It has been hypothesised that, because of the inflammatory changes
caused by CHF, the absorption of iron from the intestine is impaired. The
adverse effects of anaemia and iron deficiency on cardiac function are
multiple. In anaemic CHF patients, hemodynamic mechanisms that increase cardiac
output and compensate for hypoxia are activated. These compensatory mechanisms
(i.e. activa¬tion of the renin angiotensin aldosterone system and tachycardia)
are well establish¬ed risk factors in CHF for induction of progressive LV
(left-ventricular) hypertrophy and dilation. In comparison to non-anaemic CHF
patients, this results in, amongst others, increased mortality, a reduction in
LVEF (LV ejection fraction), impaired cardiac function, exercise capacity and
quality of life, a progressive reduction in renal function, an increase in of
the need for hospitalisations and the need for high-dose diuretic use and signs
of malnutrition. Current guidelines for the diagnosis and treatment of chronic
CHF* do not contain any specific recommendations for the evaluation or
treatment of anaemia and/or iron deficiency in patients with CHF. Corroboration
earlier observations,* Toblli et al. showed that 6 months i.v. iron treatment
of CHF patients who at baseline were in NYHA class III or IV, and who had a
baseline LVEF <35%, improved quality of life, 6-minute walk test distance and
LVEF, and reduced the number of hospitalisations compared to controls. NTproBNP
(amino-terminal fragment of the *-type natriuretic peptide molecule) and CRP
(C-reactive protein) levels also decreased. A similar study showed a
significant improvement of peak VO2 (oxygen consumption). Mancini et al.*
compared EPO plus oral ferrous gluconate and folate to placebo EPO only, and
observed significant improvements of Hb, peak VO2 and exercise capacity. A
recently reported randomised double-blind trial compared oral iron plus EPO
versus oral iron alone, and showed that, compared to oral iron alone, oral iron
plus EPO increased Hb from a mean of 10.4 to 12.4 g/dl. To date, effects of
iron therapy on LV function have been studied only in small clinical trials. It
is therefore opportune to investigate the effect of iron therapy on remodelling
to corroborate earlier findings and to relate remodelling to changes in
symptoms and exercise capacity.

Secondary objectives are to evaluate the effect of intravenous FCM compared to
pla¬cebo on:
1. Evolution from baseline of cardiac function parameters as assessed by 2D
Echo/Doppler cardiography 4, 12 and 24 weeks after start of study treatment.
2. Self-reported patient global assessment (PGA) of treatment at 4, 12 and 24
weeks after start of study treatment.
3. Health related quality of life (HRQoL) as assessed by the EQ-5D (European
quality of life * 5 dimensions) and KCCQ (Kansas City Cardiomyopathy
Questionnaire) self-administered questionnaires 4, 12 and 24 weeks after start
of study treatment.
Objectives for safety are to evaluate the effect of intravenous FCM compared to
pla¬cebo on:
1. Evolution of estimated glomerular filtration rate, vital signs,
electrocardiographic findings and laboratory test results (haematology,
clinical chemistry, iron status, urinalysis, neurohormone and inflammatory
markers).
2. Number and duration of hospitalisations (total and for cardiovascular
conditions).
3. Total and cardiovascular mortality.
4. (Serious) adverse events

Evaluation of health economics
At the 4, 12 and 24 week planned out-patient visits (POVs), the patient*s
health care resource utilisation since the previous visit when the patient was
seen or contacted will be recorded to allow for the calculation of direct,
indirect and total costs for at least one country from two perspectives
(payer*s and societal perspective). FCM and placebo treatment arms will be
compared to assess the cost-effectiveness of FCM using relevant parameters

EFFICACY-HF is a randomised, controlled, observer-blinded multi-centre
clinical trial with two parallel groups of equal size.

Active: FCM (ferric carboxymaltose) solution containing 50 mg iron/mL given as
an i.v. bolus of 2 or 4 mL.
Placebo: 0.9% weight/volume NaCl (normal saline).

The parenteral iron preparation (Ferinject®) that will be used in this trial
has been approved for the treatment of anaemia in most European countries. The
approval was without any stipulation with regard to the extent of any elevation
of haemoglobin. The only known potential risks of participation in this trial
are the occurrence of elevated iron status parameters (including haemoglobin)
or hypersensitivity reactions in patients assigned FCM (ferric carboxymaltose),
and severe anaemia in patients assigned placebo. The IgE mediated anaphylactic
reactions that have been associated with i.v. iron dextran preparations cannot
occur in patients treated with FCM. Non-IgE mediated anaphylactoid reactions
have thus far not been reported. Drug related hypersensitivity reactions to FCM
(rash, urticaria, hyperthermia) are infrequent (less than 1% of patients) and
transitory without sequel.*

To limit the occurrence of elevated iron status parameters (including
haemoglobin) and of severe anaemia in this trial, the following precautions are
taken:
(a) The total iron repletion dose to be administered to each patient will be
calculated using the widely-accepted and validated Ganzoni formula.*
(b) In patients assigned FCM, i.v. iron (200mg or 100 mg) will be administered
as FCM once weekly during the correction phase until the total iron repletion
dose has been administered. Blood tests to determine the patient*s iron status
will be performed every second week in conjunction with weekly administrations
of study treatment.
(c) In patients assigned FCM, 200 mg i.v. iron will be administered as FCM once
monthly during the maintenance phase. Blood tests to determine the patient*s
iron status will be performed monthly in conjunction with monthly
administra-tions of study treatment.
(d) If laboratory test results suggest elevated iron status parameters in a
patient assigned FCM, study treatment will be continued with pla-cebo.
(e) If severe anaemia develops, study treatment will be discontinued


Although there are currently no guidelines for the treatment of anaemia in
patients with chronic CHF,* data from small studies have shown that patients
with chronic CHF and anaemia receiving i.v. iron therapy may benefit from an
improved quality of life and cardiac function. In patients with chronic CHF and
iron deficiency, treatment with oral iron alone was not shown to be effective.
Oral iron has gastro-intestinal side effects and limited absorption, in
particular when the iron transport inhibitor hepcidin is upregulated.
Erythropoeisis stimulating proteins are at present still under clinical
investigation in patients with anaemia and CHF. Their safety has been a matter
of concern.*

The current assessment of the risk/benefit ratio of the treatment modality
concerned suggests that participation can be considered in the patient*s
interest. Importantly in this regard, this trial does not require any unusual
investigational procedures that could present a risk independent of study
treatment