Randomized Placebo-controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency

This is a double-blind, multicenter, prospective, randomized, placebo-controlled study to
assess the effects of IV FCM compared to placebo on the 12-month rate of death,
hospitalization for worsening heart failure, and the 6-month change in 6 minute walk test
(6MWT) for patients in heart failure with iron deficiency.

After an initial screening period of up to 28 days, eligible participants will be stratified
by region and randomized in a 1:1 ratio to FCM or placebo for treatment.

Study drug administration will occur on Day 0 and Day 7 (±2) as an undiluted slow IV push,
with additional study visits planned at 3 month intervals, and additional dosing administered
every 6 months as applicable. In a subset of sites, all participants will return for
recurrent laboratory assessment (chemistry, hematology and iron indices) at Day 21 (± 7)
after each course of investigational treatment. For all participants, hematology, ferritin,
and transferrin saturation (TSAT), with appropriate safety evaluations, to determine
additional treatment, will occur at 6 month intervals.

Inclusion Criteria:

1. Adult (≥18 years of age) able to provide informed consent.

2. Stable heart failure (NYHA II-IV) on maximally-tolerated background therapy (as
determined by the site Principle Investigator) for at least 4 weeks with no dose
changes in heart failure drugs during the last 2 weeks.

3. Able and willing to perform a 6MWT at the time of randomization.

4. Reduced left ventricular ejection fraction. Assessment must be performed at least 12
weeks after major cardiac surgical intervention including coronary artery bypass graft
(CABG), valvular repair/replacement, or cardiac resynchronization therapy (CRT) device
implantation.

a. Left ventricular ejection fraction ≤35% obtained during the screening visit OR
either of the following i. Historical value of ejection fraction ≤35% within 12 months
of screening visit ii. Historical value of ejection fraction ≤25% within 24 months of
screening visit

5. Hemoglobin >9.0 g/dL and <13.5 g/dL (females) or <15.0 g/dL (males).

6. Serum ferritin <100 ng/mL or 100 to 300 ng/mL with TSAT <20%.

7. Either documented hospitalization for heart failure within 12 months of enrollment or
screening visit N-terminal-pro-brain natriuretic peptide (NT-proBNP) >600 pg/ml (or
BNP >200 pg/mL) for patients with normal sinus rhythm or NT-proBNP >1000 pg/ml (or BNP
>400 pg/mL) for patients with atrial fibrillation. NOTE: NT-proBNP must be used to
confirm eligibility for patients taking sacubitril/valsartan.

Exclusion Criteria:

1. Current or planned oral iron supplementation. Iron-containing multivitamins (<30 mgs
/day) are permitted.

2. Known hypersensitivity reaction to any component of FCM.

3. History of acquired iron overload, or the recent receipt (within 3 months) of
erythropoietin stimulating agent, IV iron therapy, or blood transfusion.

4. Acute myocardial infarction, acute coronary syndrome, transient ischemic attack, or
stroke within 3 months of enrollment.

5. Uncorrected severe aortic stenosis, severe valvular regurgitation, or left ventricular
outflow obstruction requiring intervention.

6. Current atrial fibrillation or atrial flutter with a mean ventricular response rate
>100 per minute (at rest).

7. Current or planned mechanical circulatory support or heart transplantation.

8. Hemodialysis or peritoneal dialysis (current or planned within the next 6 months).

9. Documented liver disease, or active hepatitis (i.e. alanine transaminase or aspartate
transaminase >3 times the upper limit of normal range).

10. Current or recent (within 3 years) malignancy with exception of basal cell carcinoma
or squamous cell carcinoma of the skin, or cervical intraepithelial neoplasia.

11. Known gastrointestinal bleeding. Patients with screening ferritin <15ng/ml must have
an appropriate evaluation within 3 months of screening.

12. Female participant of child-bearing potential who is pregnant, lactating, or not
willing to use adequate contraceptive precautions during the study and for up to 5
days after the last scheduled dose of study medication.

13. Inability to return for follow up visits within the necessary windows