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A Dose Ranging Phase IIa Study of 6 Hour Intravenous Dosages of CXL-1427 in Patients Hospitalized With Heart Failure

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified June 2014 by Cardioxyl Pharmaceuticals, Inc
Sponsor:
Information provided by (Responsible Party):
Cardioxyl Pharmaceuticals, Inc
ClinicalTrials.gov Identifier:
NCT02157506
First received: May 28, 2014
Last updated: June 4, 2014
Last verified: June 2014
  Purpose

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


Condition Intervention Phase
Heart Failure
Decompensated Heart Failure
Acute Heart Failure
Drug: CXL-1427
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Phase IIa Study of the Safety, Tolerability and Hemodynamic Effects of a Continuous 6 Hour Intravenous Infusion of CXL-1427 in Hospitalized Patients With Systolic Heart Failure

Resource links provided by NLM:


Further study details as provided by Cardioxyl Pharmaceuticals, Inc:

Primary Outcome Measures:
  • The safety and tolerability of 6-hour infusions of CXL-1427 in patients with systolic congestive heart failure [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    Assess the number of and and severity of clinical and laboratory related adverse events for 30 days following the initiation of treatment as a measure of safety and tolerability.

  • The effects of 6-hour intravenous infusions of CXL-1427 on a composite of hemodynamic values including pulmonary capillary wedge pressure (PCWP), pulmonary artery diastolic pressure (PAD) and cardiac index (CI) [ Time Frame: 8 hours ] [ Designated as safety issue: No ]
    Assess of hemodynamic changes in indices of cardiac function before, during the 6 hour infusion and for 2 hours following the completion of the infusion


Secondary Outcome Measures:
  • The effects of CXL-1427 on other hemodynamic parameters [ Time Frame: 8 hours ] [ Designated as safety issue: No ]
    Evaluate the effects of CXL-1427 on a composite of other hemodynamic parameters [e.g., right atrial pressure (RAP), pulmonary artery pressures (systolic and mean), peripheral arterial systolic and diastolic blood pressures (SBP and DBP, by sphygmomanometry); calculated mean peripheral arterial blood pressure (MAP); and heart rate (HR)].

  • Plasma concentrations of CXL-1427 [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
    Assess plasma concentrations of CXL-1427 and its metabolites in heart failure patients in order to assess a composite of PK parameters including Cmax, T1/2, Tmax and Clearance

  • The relationship of plasma concentration of CXL-1427 to Change in Cardiac Index and PCWP and PAD [ Time Frame: 8 hours ] [ Designated as safety issue: No ]
    Compare the plasma concentration of CXL-1427 at the end of infusion to the change from baseline in Cardiac Index (CI) and Pulmonary Capillary Wedge Pressure (PCWP) and Pulmonary Artery Diastolic pressure (PAD).


Other Outcome Measures:
  • The effects of CXL-1427 on plasma B-type natriuretic peptide (BNP) concentration [ Time Frame: 24 hours ] [ Designated as safety issue: Yes ]
    Plasma BNP Levels

  • The effects of CXL-1427 on a composite of renal safety and functional biomarkers [ Time Frame: 24 hours ] [ Designated as safety issue: Yes ]
    Evaluate the effects of CXL-1427 on a composite of serum creatinine concentration, serum cystatin C concentration, Urine neutrophil gelatinase-associated lipocalin (NGAL) concentration and urinary excretion of sodium and potassium


Estimated Enrollment: 48
Study Start Date: June 2014
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: CXL-1427 Starting Dose
The Starting dose of CXL-1427 in the dose escalation arms will be 3mcg/kg/min
Drug: CXL-1427
Experimental: CXL-1427 Dose Level 2
The Second Dose level of CXL-1427 will be evaluated in the Dose Escalation Arm of the study as determined by the independent dose escalation committee
Drug: CXL-1427
Experimental: CXL-1427 Dose Level 3
The Third Dose level of CXL-1427 will be evaluated in the Dose Escalation Arm of the study as determined by the independent dose escalation committee
Drug: CXL-1427
Experimental: CXL-1427 Dos Level 3
The Third Dose level of CXL-1427 will be evaluated in the Dose Escalation Arm of the study as determined by the independent dose escalation committee
Drug: CXL-1427
Experimental: CXL-1427 Dose Level 4
The forth level of CXL-1427 will be evaluated in the Dose Escalation Arm of the study as determined by the independent dose escalation committee
Drug: CXL-1427
Experimental: Expansion Cohort 1
Up to 16 Patients will be enrolled across 1 or more of the previously evaluated Dose escalation Levels as determined by the independent dose escalation committee
Drug: CXL-1427
Placebo Comparator: Placebo for Dose Escalation and Expansion Cohort
Each Dose escalation Arm of the study will have a placebo group in a 2:1 ratio to active treatment for the first 3 patients enrolled and 4:1 to active treatment in the remaining 5 patients so that the overall randomization ratio in each Dose escalation arm will be 3:1 active to placebo. In the expansion Cohort of the study, the ratio of patients randomized to receive a 6-hour infusion of active CXL-1427 or placebo will be 3:1
Drug: Placebo
Other Name: 5% Dextrose & 10mM potassium acetate as same IV solution diluents used in active

Detailed Description:

This is a dose finding, randomized, double-blinded, placebo-controlled study of continuous 6-hour IV infusions of CXL-1427 in hospitalized patients with systolic heart failure which will first evaluate up to four ascending dose levels of CXL-1427 in up to four cohorts of 8 patients each (the "Dose Escalation" cohorts). Subsequently, up to three of the initial dose levels of CXL-1427 may be assessed in the additional "Expansion" cohorts of up to approximately 16 patients to gain further confidence in the results at these dose levels. The CXL-1427 dose that will be evaluated in the first cohort will be 3µg/kg/min. The dose levels for the next three sequential Dose Escalation cohorts will be dependent on clinical safety and tolerability, as well as the results of the invasive hemodynamic measurements.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02157506

Contacts
Contact: Robert Venuti, BS 919-869-8585 rvenuti@cardioxyl.com
Contact: Doug Cowart, Pharm D 919-869-8585 dcowart@cardioxyl.com

Locations
United States, Michigan
Henry Ford Hospital Not yet recruiting
Detroit, Michigan, United States, 48202
Contact: Karen Leszcrynski, R.N. CCRC    313-916-3502    kleszcz2@hfhs.org   
Sponsors and Collaborators
Cardioxyl Pharmaceuticals, Inc
Investigators
Study Director: ShiYin Foo, MD, PhD, MMSc Cardioxyl Chief Medical Officer
  More Information

No publications provided

Responsible Party: Cardioxyl Pharmaceuticals, Inc
ClinicalTrials.gov Identifier: NCT02157506     History of Changes
Other Study ID Numbers: CXL-1427-02
Study First Received: May 28, 2014
Last Updated: June 4, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Cardioxyl Pharmaceuticals, Inc:
Acute Heart failure
Hemodynamics
Pharmacokinetics
Renal Function

Additional relevant MeSH terms:
Heart Failure
Heart Failure, Systolic
Heart Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on August 28, 2014