Crossover Study to Compare the Pharmacokinetics and Bioavailability of a Novel Furosemide Regimen Administered Subcutaneously vs. the Same Dose Administered Intravenously in Subjects With Chronic Heart Failure

This study will be an open-label, single-center, single-dose, randomized, two-way
(two-period) crossover study in 16 adult subjects previously diagnosed with mild to moderate
heart failure (NYHA class II/III) being treated concomitantly with oral furosemide therapy at
a dose of ≥ 40 mg/day. Each subject will complete Screening, Baseline, Treatment, and
Follow-Up Phases. The Screening Phase will be conducted on an outpatient basis between 14 and
3 days prior to Baseline. Subjects will be instructed to maintain a < 2 gm sodium diet within
3 days prior to Baseline. Baseline (Day 0) consists of clinical research unit (CRU) admission
and final qualification assessments. The Treatment Phase will comprise two crossover periods
separated by a 7-day outpatient fluid re-equilibration washout. Following CRU admission,
subjects will discontinue oral furosemide at least 24 hours prior to administration of study
drug for each Crossover Period. Subjects will be randomly assigned in a 1:1 ratio to 1 of 2
treatment sequences to receive both intravenous (IV) and subcutaneous (SC) furosemide in
Crossover Periods (i.e., IV followed by SC or vice versa). Subjects will remain domiciled in
the CRU for each Crossover Period during the Treatment Phase through 24 hours after
administration of study drug, after which time they will be discharged if safety parameters
are acceptable to the Investigator. Oral furosemide therapy will be re-initiated at discharge
after Crossover Period 1 (i.e., during the 7-day fluid re-equilibration washout) and after
Crossover Period 2. The Follow-Up Phase will occur 7 days (± 1) after discharge from the CRU
following Crossover Period 2, completing subjects' study participation.

Inclusion Criteria:

- An Institutional Review Board (IRB) approved informed consent is signed and dated
prior to any study-related activities.

- Male and female subjects ≥18 years of age, with body volume and weight <130 kg and
body mass index (BMI) <38 kg/m2

- Females will be non-pregnant, non-lactating, and post-menopausal, surgically sterile
(e.g., tubal ligation, hysterectomy), or use TWO (2) of the following forms of
contraception: IUD, IUD with spermicide, female condom with spermicide, contraceptive
sponge with spermicide, an intravaginal system, diaphragm with spermicide, cervical
cap with spermicide, a male sexual partner who agrees to use a male condom with
spermicide, a sterile sexual partner, OR abstinence

- History of at least 3 months treated heart failure (NYHA class II/III) with presence
of symptoms of chronic volume overload requiring ongoing treatment with oral
furosemide at a dose of ≥ 40 mg per day for at least 30 days prior to baseline

- NT-proBNP > 300 pg/mL or BNP > 100 pg/mL

- Agrees to abstain from using alcohol, caffeine-containing products, and
tobacco-/nicotine-containing products through CRU discharge (period 2).

- Able to participate in the study in the opinion of the investigator

- Has the ability to understand the requirements of the study and is willing to comply
with all study procedures

Exclusion Criteria:

- Acute Decompensated Heart Failure (ADHF) or recent history of hospitalization for
heart failure in the last 4 weeks

- Worsening of signs or symptoms of heart failure in the two weeks prior to the
Screening, or those expected to require intravenous loop diuretics or in-patient
treatment for heart failure during the study

- Systolic BP (SBP) < 90 mm Hg

- Temperature > 38°C (oral or equivalent) or sepsis or active infection requiring IV
anti-microbial treatment

- Serum sodium < 130 mEq/L and Serum potassium < 3.0 mEq/L

- Significant other cardiac abnormalities which may interfere with study participation
or study assessments

- Current or planned treatment during the study with any IV therapies, including
inotropic agents, vasopressors, levosimendan, nesiritide or analogues; or mechanical
support (intra-aortic balloon pump, endotracheal intubation, mechanical ventilation,
or any ventricular assist device)

- Diagnosed with Type I diabetes mellitus or Type II diabetes requiring insulin therapy

- Presence or need for urinary catheterization, urinary tract abnormality, or disorder
interfering with urination

- Impaired renal function, defined as an estimated glomerular filtration rate (eGFR) on
admission < 45 mL/min/1.73m2, calculated using the simplified Modification of Diet in
Renal Disease (sMDRD) equation

- Indication of moderate-to-severe hepatic dysfunctions as determined by the
investigator

- Administration of intravenous radiographic contrast agent within 72 hours prior to
Screening or acute contrast-induced nephropathy at the time of Screening

- Major surgery within 30 days prior to Screening

- Administration of an investigational drug or implantation of investigational device,
or participation in another interventional trial, within 30 days prior to Screening

- Any surgical or medical condition which in the opinion of the investigator may
interfere with participation in the study or which may affect the outcome of the study

- Positive test for hepatitis B, hepatitis C, or HIV at Screening

- Positive urine drug screen at Screening or Baseline

- Concomitant use of any drugs known to interact with furosemide

- History of alcohol abuse within 6 months prior to screening, as determined by the
Investigator

- Positive alcohol breath test on admission to the CRU

- History of severe allergic or hypersensitivity reactions to furosemide

- Donation of greater than 100 mL of either whole blood or plasma within 30 days prior
to study drug administration