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
Condition: Heart Failure
MeSH terms: Heart Failure
Study type: Interventional
Phase: Phase 1/Phase 2

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
      30 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 primary objective of the study is to estimate the absolute bioavailability of furosemide
      administered by subcutaneous infusion compared with an equivalent dose of furosemide
      administered by IV bolus administration.
    

Detailed description: 
      This study will be an open-label, single-dose, randomized, two-way, two-period crossover
      study in 20 adult subjects previously diagnosed with mild to moderate heart failure (New York
      Health Association [NYHA] class II/III) being treated with oral furosemide therapy at a dose
      of ≥40 mg/day. Each subject will complete Screening, Admission, Treatment, and Follow-up
      Phone Call phases. The Screening Phase will be conducted on an outpatient basis between 28
      and 3 days prior to admission. Subjects will be instructed to reduce sodium intake (target <2
      g sodium/day) starting 3 days prior to each of the clinical research unit (CRU) admissions.
      Admission (Day -1) consists of CRU admission and final qualification assessments. The
      Treatment Phase will comprise two crossover periods separated by a 7-day outpatient fluid
      re-equilibration washout. Subjects will discontinue oral furosemide at least 24 hours prior
      to administration of study drug for each Crossover Period (e.g., no oral furosemide should be
      administered after 10pm the night prior to CRU admission). Subjects will be randomly assigned
      in a 1:1 ratio to 1 of 2 treatment sequences (AB or BA) to receive both subcutaneous
      furosemide (Treatment A; Test) and IV furosemide (Treatment B; Reference) in Crossover
      Periods (i.e., subcutaneous followed by IV or vice versa). Subjects will remain domiciled in
      the CRU for each treatment Period during the Treatment Phase through 24 hours after
      administration of study drug, after which time they will be discharged from the CRU if safety
      parameters are acceptable to the Investigator. Oral furosemide therapy will be re-initiated
      at discharge after Treatment 1 (i.e., during the 7-day fluid re-equilibration washout) and
      after Treatment 2 (i.e., between discharge and Follow-up Phone Call). The Follow-up Phone
      Call Phase will occur 7 days (± 1) after discharge from the CRU following Treatment 2,
      completing subjects' study participation.
    

Intervention name(s): Furosemide Injection Solution for subcutaneous administration (80 mg); Furosemide Injection, USP; Medfusion 3500 (v6) precision infusion pump
Intervention type(s): Drug; Drug; Device
Intervention description(s): Furosemide Injection Solution for subcutaneous administration (80 mg); Furosemide Injection, USP (10 mg/mL), 80 mg by intravenous administration; Furosemide Injection Solution for subcutaneous administration (80 mg)
Intervention MeSH terms: Furosemide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment