A single center, randomized, open-label, cross-over exploratory study to evaluate the pharmacodynamic and pharmacokinetic response to a subcutaneous administration or oral administration of furosemide in subjects presenting with chronic fluid overload

The term heart failure (HF) is used both for acute decompensated heart failure
(ADHF) and its chronic/stable form, also referred to as congestive heart
failure (CHF). We will study HF patients with chronic fluid overload despite
maintenance doses of furosemide. These patients have signs and symptoms of HF,
typically dyspnea, edema, and fatigue, and some of these patients may
periodically require parenteral administration of furosemide to relief signs
and symptoms. The novel scFurosemide subcutaneous therapy may be used as an
alternative to periodic iv treatment in patients with chronic fluid overload,
in patients with worsening heart failure/early decompensation to prevent
progression to the more serious acutely decompensated heart failure (ADHF), and
to continue a course of parenteral loop diuretics started in the hospital to
achieve the desired reduction in fluid overload. Furosemide is a potent,
rapid-onset, loop diuretic commonly used in the treatment of HF and edema.
Furosemide is currently approved for oral, intravenous (i.v.) and intramuscular
(i.m.) administration. Oral furosemide is the standard of care for chronic
administration in patients with congestive heart failure. Intravenous
furosemide therapy is the standard of care in the treatment of edema associated
with congestive heart failure in patients who temporarily require greater
diuretic potential than what can be achieved with oral furosemide alone. Many
patients require from time to time parenteral administration of furosemide to
effectively treat fluid overload and its associated signs and symptoms.
Consequently iv furosemide has become the cornerstone of the treatment of CHF
patients with chronic fluid overload. Furosemide was first introduced in the
1960s and at that time obtained approval for i.m. administration. Furosemide is
poorly soluble and a clinical dose would require administration of 5 mL or
more. Administration of a clinical dose of furosemide in this way may be
suitable in emergency situations, but would not be suitable in a clinical
setting due to the extreme pain. Both i.v. and i.m. administration are
unsuitable for self-administration or administration by a care giver in an
alternative setting (e.g., home). Subcutaneous administration of furosemide
offers an alternative method to overcome these limitations. In general, sc
delivery of medicinal agents offers multiple theoretical advantages, including:
• Bioavailability generally equal to that of i.v. administration • Reduced
costs of administration when compared to i.v. • Potential for delivery in
alternative settings, reducing personal and economic burden of heart failure. •
Reduced risk of complications when compared to i.v. • Reduced pain and higher
clinical acceptance than i.m. The pharmacologic characteristics of furosemide
make it well-suited for sc administration: low viscosity, non-cytotoxic,
non-irritating, and well-absorbed from adipose and connective tissues. However
its relatively poor solubility would require administration of 5mL or more in
most circumstances making this unsuitable for a regular s.c. injection by
syringe. Commercial furosemide products for injection have an alkaline pH
(range 8.3-9.0) and are unsuitable for subcutaneous injection.
scPharmaceuticals developed new furosemide formulation for injection which is
isotonic and buffered to physiologic pH (7.4). The proposed pilot study will
investigate this new formulation. The solution is buffered with a low
concentration of tromethamine - a widely used inactive ingredient in injectable
pharmaceutical products. scFurosemide will be delivered using a biphasic
delivery profile with 30mg of furosemide delivered over the first hour followed
by 12.5mg/hour for four hours. This delivery profile was optimized to improve
diuretic efficacy and reduce potential for renal toxicity. The available
clinical evidence regarding subcutaneous administration of furosemide is
limited but compelling. In a randomized, double-blind, cross-over study of 12
healthy volunteers, 20 mg of furosemide administered s.c. induced a rapid and
marked diuresis and natriuresis (Verma et al, 2004). The current study is
designed to provide information on response to subcutaneous administration of
scFurosemide when compared to oral administration of the same dose. This
information is of importance for the design and power calculations of pivotal
studies in support of regulatory filings and claims of clinical utility for
scFurosemide. A cross-over design was chosen to facilitate the interpretation
of results. Fluid overload and associated symptoms are inherently variable and
differences in fluid overload between the two treatment periods may exist.
However the use of bioimpedance measurements provides a measure for fluid
overload (total body water) allowing diuretic response to be interpreted as a
function of fluid overload. Further, we will measure the B-type natriuretic
peptide, which is a marker of myocardial stretch and a very well established
surrogate marker of loading status of the heart. Although bioimpedance and
B-type natriuretic peptide (BNP) can be used to compare the degree of fluid
overload within an individual over time, measurements between individuals are
difficult to interpret. Additionally, the within subject variability between
two periods is inherently smaller than the inter subject variability. So by
using a randomized cross over design, the interpretation of diuretic response
is markedly enhanced by allowing the diuretic response to be interpreted in the
context of differences in bioimpedance and BNP measurements. No or minimal
carry-over effect is expected following the single treatment and resumption of
baseline oral therapy. .

Primary Objective • To assess the effects of 80mg of furosemide delivered by
subcutaneous delivery in the abdominal area over 5 hours when compared to oral
administration in patients with heart failure with chronic fluid overload.
Secondary Objective(s) • To assess the effects of the furosemide regimen on
natriuresis • To assess the effects on signs and symptoms of heart failure
(e.g. dyspnea) • To investigate if furosemide induced diuresis correlates with
changes in bioimpedance parameters • To investigate if pretreatment
bioimpedance measurements predict diuretic response to furosemide • To
investigate injection site reactions and discomfort during sc administration •
To obtain plasma samples for pharmacokinetic analyses.

This is a single center, randomized, open-label, cross-over, exploratory study
in subjects with heart failure with chronic fluid overload. The study will
enroll participants after presenting with signs or symptoms of chronic fluid
overload to the heart failure outpatient clinic. Participants must be on oral
furosemide (40 mg oid or bid) or therapeutic equivalent (e.g. bumetianide 1 mg
oid or bid) for a period 90 days, Subjects visiting the heart failure
outpatient clinic will be assessed for eligibility criteria for the study as
part of their routine care. If the eligibility criteria are met, the subject
will be informed of the study, invited to participate, and provided with study
information to review at home. Approximately 7 days later, the subjects will
contact the site and if they agree to participate, they will be scheduled for a
screening visit. . The informed consent will be reviewed and signed at the
screening visit and a number of assessments will be done to evaluate
eligibility. Eligible patients will be invited for the first study period if
they agree to participateParticipants will be planned for 2 visits, and on the
day of the first treatment period, they will be randomized to subcutaneous or
oral therapy for the first treatment period with the other treatment being
administered at the second treatment period which is to take place 14 + 3 days
later. One each treatment day, participants will be subject to an observation
period of 8 hours from the start of the treatment. Urine will be collected
during the observation period for assessment of diuresis, natriuresis, albumin,
creatinine clearance and pharmacokinetics (PK). Blood samples will be taken at
specified intervals for PK analyses and for assessment of routine biochemical
parameters and selected routine cardiac markers including NT Pro-BNP (ng/l),
hs-Trop T (ng/l), and Galectin-3 (ng/mL). Safety assessments will include
physical examinations, vital signs, investigator assessments of signs and
symptoms, inspection of injection site (sc therapy only) standard clinical
laboratory evaluations (hematology, blood chemistry, and urinalysis), adverse
event and serious adverse event monitoring. Bioimpendance measurements will be
performed at selected time points during the study.

In this cross-over study, each of the study subjects will be randomly assigned
to one of two treatment groups. Group 1 will first receive 80 mg scFurosemide
(8mg/mL) administered abdominally via standard sc infusion set with the use of
a commercial infusion pump, over 5 hours (30mg in first hour followed by
12.5mg/hour over 4 hours) followed by oral furosemide (80 mg tablet) in the
second period. Group 2 will receive the same treatments in the reverse order,
starting with oral furosemide followed by scFurosemide treatment in the second
period. All treatments are open label. Participants will be supine or in a
reclined sitting position with the legs elevated during the 8-hour observation
period with the legs elevated. Patients are allowed to stand and walk as
needed.

Although clinical reports have described the successful subcutaneous
administration and clinical use of the unbuffered alkaline commercial
furosemide scPharmaceuticals developed a buffered isotonic formulation at
neutral pH. Use of isotonic formulations at neutral pH for injection is
consistent with current pharmaceutical standards and reduce the risk of pain or
discomfort upon administration. The scFurosemide product uses a standard
buffering agent in the form of tromethamine (TRIS or THAM). Tromethamine is
widely used as an excipient in approved solutions for injection and in topical
formulations. Additionally tromethamine is approved as a standalone
pharmaceutical product known as THAM SOLUTION (Tromethamine Injection
manufactured by Hospira, Lake Forrest, IL). THAM SOLUTION is indicated to be
administered intravenously for the prevention and correction of metabolic
acidosis. Each 100 mL THAM SOLUTION contains 3.6 g (30 mEq) tromethamine in
water for injection. The solution is hypertonic 389 mOsmol/L (calc.) with a pH
8.6 (8.4-8.7). (FDA Application No. (NDA) 013025; Company HOSPIRA; Approval
Date December 16, 1965). There are no known risks associated with the use of
tromethamine as a buffering agent and tromethamine is listed as an approved
inactive ingredient list, which exempt companies from having to perform
additional preclinical or clinical safety studies upon adding the ingredient to
a pharmaceutical product. Risks of the study may include pain and discomfort
from study-related procedures including vena puncture and sc drug
administration of the drug product. Additional risk may also include the risk
of orthostatic hypotension following the administration of the drug as a result
of ensuing diuresis. During each of the two study phases 14 samples of blood
(5mL each) will be obtained for pharmacokinetic analysis. This volume is
required for analysis of samples in duplicate. The total volume of blood
samples is less than 200mL during the study or approximately 40% of what is
normally donated for a blood transfusion.