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

Study Overview
=================
Brief Summary
-----------------
The proposed study aims to compare the pharmacokinetics and bioavailability of intravenous and subcutaneous Furosemide. Although these regimens are not intended to be bioequivalent, they are both expected to achieve therapeutic plasma levels and induce effective diuresis. The test formulation in this study is a buffered solution, Furosemide Injection Solution at 8 mg/mL at pH 7.4 (range 7.0 to 7.8) and is intended for SC injection according to the instructions in the protocol. A commercial formulation of Furosemide Injection, USP will serve as the reference drug in this study, which will be administered by IV bolus. It contains furosemide 10 mg/mL in solution at alkaline pH of 8.0 to 9.3 and is marketed for IV and IM injection. The objectives of this study are: To characterize the pharmacokinetics of furosemide administered by continuous subcutaneous infusion using a biphasic delivery profile. To estimate the absolute bioavailability of furosemide administered by continuous subcutaneous infusion compared with an equivalent dose of furosemide administered by intravenous bolus administration.

Detailed Description
-----------------
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.

Official Title
-----------------
Open-label, Single-dose, Randomized, Two-way (Two-period) Crossover Study to Compare the Pharmacokinetics and Bioavailability of a Novel Furosemide Regimen Administered Subcutaneously Versus the Same Dose (80mg) Administered Intravenously in Subjects With Chronic Heart Failure

Conditions
-----------------
Heart Failure

Intervention / Treatment
-----------------
* Drug: Fursemide Injection Solution for subcutaneous administration (80 mg)
* Drug: Furosemide Injection, USP


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence 1<br>Furosemide Injection Solution for subcutaneous administration (80mg) over 5 hours followed by i.v. Furosemide Injection, USP (80 mg)by i.v. bolus in second period | Drug: Fursemide Injection Solution for subcutaneous administration (80 mg)<br>* Furosemide Injection Solution, 10mL of undiluted buffered furosemide solution (8mg/mL)<br>Drug: Furosemide Injection, USP<br>* Furosemide Injection, USP (10mg/mL), 80 mg by intravenous administration.<br>|
| Experimental: Treatment Sequence 2<br>Furosemide Injection, USP (80 mg) by i.v. bolus, followed by Furosemide Injection Solution for subcutaneous administration (80mg) over 5 hours in second period. | Drug: Fursemide Injection Solution for subcutaneous administration (80 mg)<br>* Furosemide Injection Solution, 10mL of undiluted buffered furosemide solution (8mg/mL)<br>Drug: Furosemide Injection, USP<br>* Furosemide Injection, USP (10mg/mL), 80 mg by intravenous administration.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Maximum observed plasma concentration of Furosemide | 0, 5 min, 15 min, 30 min, 45 min, 60 min, 1.5 hours, 2 hours, 2:05 min, 2:15 min, 2:30 min, 2:45 min, 3 hours, 3:30 min, 4, 5, 6, 8, 10, 12, 14, and 16 hours post-dose | 
| Tmax | Time to achieve maximum observed Furosemide plasma concentration | 0, 5 min, 15 min, 30 min, 45 min, 60 min, 1.5 hours, 2 hours, 2:05 min, 2:15 min, 2:30 min, 2:45 min, 3 hours, 3:30 min, 4, 5, 6, 8, 10, 12, 14, and 16 hours post-dose | 
| AUClast | The area under the plasma concentration versus time curve from time 0 (pre-dose) to the last quantifiable time point. | 0, 5 min, 15 min, 30 min, 45 min, 60 min, 1.5 hours, 2 hours, 2:05 min, 2:15 min, 2:30 min, 2:45 min, 3 hours, 3:30 min, 4, 5, 6, 8, 10, 12, 14, and 16 hours post-dose | 
| AUCinf | The area under the plasma concentration-time curve from time 0 (pre-dose) to time of last measurable plasma concentration. | 0, 5 min, 15 min, 30 min, 45 min, 60 min, 1.5 hours, 2 hours, 2:05 min, 2:15 min, 2:30 min, 2:45 min, 3 hours, 3:30 min, 4, 5, 6, 8, 10, 12, 14, and 16 hours post-dose | 
| AUCext | The percentage of AUC that is extrapolated beyond the last measurable concentration | 0, 5 min, 15 min, 30 min, 45 min, 60 min, 1.5 hours, 2 hours, 2:05 min, 2:15 min, 2:30 min, 2:45 min, 3 hours, 3:30 min, 4, 5, 6, 8, 10, 12, 14, and 16 hours post-dose | 
| λz | Apparent plasma terminal-phase elimination rate constant | 24 hours | 
| t 1/2 | Terminal-phase half life | 24 hours | 
| Volume of Distribution, Terminal Phase | Systemic Volume of distribution, terminal phase for IV furosemide and Apparent Volume of distribution, terminal phase for SC furosemide | 24 hours | 
| CL | Systemic Clearance for IV furosemide and Apparent Systemic Clearance for SC furosemide | 24 hours |