A Dose Ranging Phase IIa Study of 6 Hour Intravenous Dosages of CXL-1427 in Patients Hospitalized With Heart Failure
Condition: Heart Failure; Decompensated Heart Failure; Acute Heart Failure
MeSH terms: Heart Failure
Intervention: CXL-1427; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 70.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Acute Heart failure; Hemodynamics; Pharmacokinetics; Renal Function

Summary:

      A randomized, double-blinded, placebo-controlled study of continuous 6-hour IV infusions of
      CXL-1427 in hospitalized patients with systolic heart failure.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Inclusion Criteria -In order to be eligible for study participation, a patient MUST:

          -  Be ≥ 18 and ≤ 85 years of age;

          -  Have a left ventricular ejection fraction (LVEF) ≤40%, as assessed by
             echocardiography, a multigated acquisition (MUGA) scan or magnetic resonance imaging
             (MRI) within 3 months prior to or during the current hospitalization;

          -  Be hospitalized with a primary heart failure or heart failure-related reason, e.g.,
             acute decompensation of heart failure, transplant evaluation, hemodynamic optimization
             prior to ambulatory inotropes or left ventricular assist device placement;

          -  Have an indwelling pulmonary artery (PA) catheter in place for assessment of central
             hemodynamic parameters; [Note: The indwelling catheter may already be in place for
             medically-indicated reasons, OR be placed for the primary purpose of monitoring the
             hemodynamic effects of the study drug. If the pulmonary artery catheter is to be
             placed for the sole purpose of monitoring the hemodynamic effect of the study drug,
             the patient must have a cardiac index (CI) ≤ 2.2L/min•m2 as measured by a non-invasive
             cardiac output monitor (NICaS device) ≤6 hours prior to placement of the catheter. In
             this setting, Exclusion Criteria 3 below also applies.]

          -  Have a Fick and/or thermodilution determination of cardiac index ≤2.5L/min•m2 at
             screening, i.e., ≤4 hours before the intended start of the study drug infusion; [Note:
             For determinations of CI using the thermodilution method, a mean of three consecutive
             values measured approximately 5 minutes apart, none of which differs from the mean
             value by more than 15%, should be used.]

          -  Have a screening and baseline PCWP (or PAD, if a PCWP waveform cannot be reliably
             obtained) of ≥20 mmHg if systolic blood pressure is ≥100mmHg OR ≥22mmHg if systolic
             blood pressure is between 95-99mmHg (inclusive);

          -  Be considered sufficiently stable to be expected not to require administration of any
             IV or oral vasoactive medications, including diuretics, for at least ~10 hours, i.e.,
             from 4 hours before performing baseline hemodynamic assessments until after the
             completion of the 6-hour study drug infusion;

          -  Have a body weight of at least 50kg (110 pounds), but not more than 125kg (275
             pounds), and have a body mass index (BMI) <40kg/m2;

          -  Have adequate peripheral forearm vein access or an available central line port for
             administration of study drug;

          -  Be capable of understanding the nature of the trial; be willing and able to comply
             with the inpatient and outpatient study protocol requirements for the duration of the
             study (screening period, treatment period, and 30-day post-infusion follow-up period);
             and be willing to participate in the study, as documented by written informed consent.

        Exclusion Criteria- - In order to be eligible for study participation, a patient MUST NOT:

          -  Have a heart rate <50 or >110 beats per minute (bpm) at baseline;

          -  Have a screening OR baseline systolic blood pressure (SBP) of >150mmHg or <100mmHg, if
             PCWP ≥ 20mmHg, but <22mmHg OR <95mmHg, if PCWP ≥ 22mmHg;

          -  Have tricuspid or pulmonary valve prosthesis or endocarditis, right heart mass, a
             history of pneumothorax or hemothorax, a bleeding diathesis that would preclude
             placement of a PAL, or a history of complications from previous pulmonary artery
             catheter placement, when a pulmonary artery catheter is to be placed solely for the
             purposes of monitoring the hemodynamic effects of the study drug; In this setting,
             patients with multiple intracardiac leads and/or left bundle branch block should have
             such elective pulmonary artery catheter placement performed under radiologic guidance
             by experienced personnel, e.g. in the cardiac catheterization laboratory. [Note: Other
             pertinent history, such as trauma, vascular injury or previous surgery should guide
             selection of the vessel for PAL placement.]

          -  Have a primary HF etiology attributable to either restrictive/obstructive
             cardiomyopathy, idiopathic hypertrophic cardiomyopathy (as defined by any wall
             thickness > 1.8cm) or uncorrected severe valvular disease as defined by AHA/ACC/ESC
             criteria;

          -  Have been treated with dopamine, dobutamine, enoximone, nesiritide, nitroglycerine or
             nitroprusside within 4 hours, or with levosimendan, amrinone or milrinone within 8
             hours, prior to performing baseline hemodynamic assessments, or have an anticipated
             need to be treated with any of these agents before the completion of the 6-hour study
             drug infusion;

          -  Be receiving concomitant parenteral therapy with any antiarrhythmic drugs (oral
             therapy is allowed);

          -  Be in atrial fibrillation/flutter with an uncontrolled rate (≥100bpm) at the time of
             randomization; [Note: Patients with a history of A-fib/flutter are eligible, if heart
             rate is controlled with a ventricular rate not exceeding 100bpm.]

          -  Have non-sustained ventricular tachycardia (NSVT) of 10 beats or more during any
             bedside monitoring within 2 hours prior to randomization, or have excessive premature
             ventricular contractions (PVCs) or complex multifocal ventricular ectopy exceeding 10
             beats per minute on a 2-minute rhythm strip taken within 2 hours prior to
             randomization;

          -  Require, or be expected to require, any alteration of settings to an implantable
             cardioverter-defibrillator (ICD), single chamber or biventricular pacemaker, if
             applicable, from 2 hours before the intended start of the study drug infusion, until
             after the completion of the study drug infusion;

          -  Have a history of sudden cardiac death/resuscitation or other appropriate ICD firing
             within the past 1 year. (Inappropriate ICD firings are not exclusionary);

          -  Be hospitalized with acute coronary syndrome or acute myocardial infarction during the
             previous 90 days prior to randomization;

          -  Have a history of a cerebral vascular accident (CVA or stroke) or of a transient
             ischemic attack (TIA) within 6 months prior to randomization;

          -  Have a digoxin level above 1ng/ml (1.281nmol/L) within 8 hours before initiation of
             the study drug infusion;

          -  Have persistent abnormal serum electrolytes at baseline, as defined by: a Na+
             concentration <130 or >145 mEq/L, or a K+ or Mg2+ concentration outside the normal
             range (according to the local laboratory); [Note: Any observed electrolyte
             abnormalities during screening or earlier should be corrected by electrolyte
             supplementation and within normal acceptable concentrations should be confirmed prior
             to dosing. Any serum electrolyte abnormalities with associated clinical instability
             within 8 hours before initiation of the study drug infusion is exclusionary.]

          -  Have an ALT or AST >3 times the upper normal limit or a hemoglobin <10g/dl (100g/L)
             within 8 hours before initiation of the study drug infusion;

          -  Have a serum creatinine >2.5mg/dl (221µmol/L) or severe renal insufficiency [based on
             any standard limit and equation employed by the local lab, such as a GFR <
             30mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD)
             equation] within 8 hours before initiation of the study drug infusion;

          -  Have taken an oral phosphodiesterase type 5 inhibitor (PDE5) inhibitor within 96 hours
             before initiation of the study drug infusion;

          -  If female, be pregnant or of child-bearing potential (i.e., female patients must be
             post-menopausal or surgically sterilized);

          -  Be receiving a drug which is expected to possess a potential for a clinically
             significant pharmacokinetic interaction with CXL-1427, as defined in the CXL-1427
             Investigator's Brochure;

          -  Be the recipient of a myocardial restraint device or flap;

          -  Have an anticipated survival of less than 90 days, for any reason;

          -  Have received an investigational drug, device or biologic product within 30 days (or
             if longer, 5 half-lives for a drug or biologic agent) prior to randomization, or be
             planning to receive an investigational agent at any time throughout the full duration
             of the study until at least 30 days after discontinuation of study drug;

          -  Have any other clinically significant laboratory abnormality, medical condition or
             social circumstance that, in the investigator's opinion, makes it inappropriate for
             the patient to participate in this clinical trial.