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A Dose-Defining Study of CXL-1020 in Patients With Systolic Heart Failure

Primary Purpose

Heart Failure

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Placebo
Strata 1 CXL-1020
Strata 2 CXL-1020
Strata 3 CXL-1020
Sponsored by
Bristol-Myers Squibb
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring Heart Failure, ADHF

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

In order to be eligible for randomization, a patient MUST:

  • Be a male or post menopausal or surgically sterile female requiring inpatient evaluation or treatment and be between 18 and 85 years of age
  • Not require immediate emergent treatment with conventional parenteral inotropes or vasodilators
  • Be receiving standard background heart failure therapies as indicated, but not receive an oral dose of a hemodynamically active treatment or diuretic within 3 hours of baseline hemodynamic assessments
  • Have chronic Systolic HF due to primary/idiopathic dilated cardiomyopathy, coronary artery disease or hypertension
  • For inclusion in the Non-Invasive Strata B, have a baseline (within 48 hours prior to dosing) left ventricular ejection fraction ≤ 35% estimated from a baseline 2D-Echocardiogram
  • For inclusion in the Invasive Strata A and C, have baseline hemodynamic values (mean of 3 consecutive CI measurements taken within 1 hours preceding dosing within 10% of one another with a mean CI of less than or equal to (≤) 2.5L/min AND a mean PCWP of greater than 20mmHg
  • Have an elevated baseline BNP of at least 400pg/ml in all protocol strata
  • Be capable of understanding the nature of the trial and be willing to participate as documented by written informed consent
  • Be willing and able to comply with the inpatient and outpatient study protocol requirements for the duration of the study (treatment plus 30 follow up at days)
  • If a post-menopausal or surgically sterile female, confirmation of sterility status (post-menopausal or surgically sterile for at least 6 months; post-menopausal subjects will require a urine pregnancy test for confirmation)
  • If a fertile male, must be using 2 approved contraceptive methods (a condom and a spermicidal agent, even if partner(s) is using birth control) for 10 days following participation in the study and further agree to not donate sperm for 10 days after participation in the study
  • Must have a negative urine test for drugs of abuse and a negative ethanol breath test or blood test at baseline before dosing
  • Have required local laboratory safety data within protocol required or local laboratory non-exclusionary ranges before dosing
  • May be receiving ICD, Bi V pacing or rate control pacing at the time of randomization so long as no alteration of settings are anticipated within the day of study drug administration

    • Exclusion Criteria:

In order to be eligible for randomization, a patient MUST NOT:

  • Have participated in any investigational drug study, SERCa gene therapy or cellular myocardial transplant study within 30 days preceding randomization or have previously received therapy with CXL-1020
  • Have received a parenteral or oral dose of diuretics or other hemodynamically active therapy within 3 hours of the baseline hemodynamic assessment
  • Have received intravenous inotropes, inodilators or vasodilators (amrinone, digoxin, dopamine, dobutamine, enoximone, levosimendan, milrinone, nesiritide, nitroglycerine or nitroprusside) for more than 4 hours and within 12 hours prior to randomization to treatment with study drug
  • Have a heart rate <50 or ≥ 90 BPM at baseline prior to randomization
  • Have a blood pressure >150 Systolic and/or >95 diastolic mmHg at baseline prior to randomization
  • Have a systolic blood pressure of less than 100 mmHg at baseline prior to randomization
  • Be in atrial fibrillation/flutter at the time of randomization or have a history of recent intermittent A-fib/flutter within the previous week
  • Have non-sustained VT (HR > 120 bpm) of 10 beats or more during bedside monitoring prior to randomization or excessive VPB's or complex multifocal ventricular ectopy exceeding 10 beats per minute on a 2 minute rhythm strip taken within 10 minutes prior to randomization
  • Have a history of successful cardiac resuscitation within the past 2 years. (Inappropriate ICD firings for non lethal arrhythmias 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 stroke (CVA) or transient ischemic attack (TIA) within six months prior to randomization
  • Have a concurrent history of CCS Class III or IV angina
  • Be a patient whose HF etiology is attributable to either restrictive/obstructive cardiomyopathy, idiopathic hypertrophic cardiomyopathy (as defined by any wall thickness > 1.8 cm) or uncorrected severe valvular disease
  • Be receiving concomitant oral or parenteral therapy with any antiarrhythmic drugs other than amiodarone or dronedarone. (only oral therapy is allowed for these agents)
  • Have unsuitable echocardiographic windows for the Echo assessments (applies only to Strata B)
  • Have a screening or baseline serum Na < 130 mEq/l or > 145 mEq/l; a serum K < 3.5 mEq/l or > 5.5 mEq/l; a serum Ca < 7.5 mg/dl or > 10.2 mg/dl; or a serum Mg < 1.6 mEq/l or > 3.0 mEq/l., or a digoxin level above 1ng/ml
  • Have a baseline serum creatinine > 2.5 mg/dl; an ALT or AST >3 times the upper normal limit; or a hemoglobin < 10 g/dl
  • Have taken ethanol within 24 hours (with a positive ethanol breath test or blood test) or a PDE5 inhibitor within 96 hours of study drug administration
  • Have other clinically significant laboratory or medical conditions that, in the opinion of the Investigator, make the patient unsuitable for evaluation in the study
  • Be receiving a drug which is expected to possess the potential for a clinically significant pharmacokinetic interaction with CXL-1020, as defined in the investigational drug brochure (IDB).
  • Be the recipient of a myocardial restraint device or flap
  • Have an anticipated survival of less than 90 days for any reason Note: Patients receiving cardiac resynchronization therapy for HF are eligible and pacemaker settings have not been changed on this hospitalization and can be left unchanged for the study.

Sites / Locations

  • University of Florida
  • University of Florida
  • Florida Hospital Transplant Center
  • Ochsner Clinic Foundation
  • University of Maryland Medical Center
  • DMC Cardiovascular Institute
  • Henry Ford Health System
  • University of Medicine & Dentistry of New Jersey - New Jersey Medical School
  • Montefiore Medical Center
  • Wake Forest University Health Sciences
  • University of Cincinnati
  • University Hospitals Case Medical Center
  • Davis Heart & Lung Research Institute
  • Medical University of South Carolina
  • Stern Cardiovascular Center PA

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Experimental

Experimental

Experimental

Arm Label

Placebo

Strata 1 CXL-1020

Strata 2 CXL-1020

Strata 3 CXL-1020

Arm Description

Each Strata of the study will have a placebo control. In strata A, the chance of getting active drug is 4 out of 5, in Strata B the chance of getting active drug is 3 ot of 4, and in Strata C, the chance of getting active Drug is 4 out of 5. In the event that a patient is allocated to receive placebo, the treatment may be stopped if the patient's condition fails to improve or worsens during the placebo infusion.

Patients assigned to CXL-1020 in strata one will have their dose increased from the initial dose 2 times during the study period. The treatment may be stopped if the patient's condition fails to improve or worsens during the infusion.

In strata 2, patients who are assigned to active treatment will receive one of up to 3 possible fixed dose levels of CXL-1020 for a period of 6 hours. The treatment may be stopped if the patient's condition fails to improve or worsens during the infusion.

In strata 3, patients assigned to receive CXL-1020 will receive a fixed dose of CXL-1020 for 6 hours, and then the dose may be increased or decreased, based on the investigators assessment of the patient. The treatment may be stopped if the patient's condition fails to improve or worsens during the infusion.

Outcomes

Primary Outcome Measures

Safety and Hemodynamic Effects
Define the safety and hemodynamic benefit of CXL-1020 based upon the change from baseline in hemodynamic measurements at the 6 hour time point in all strata

Secondary Outcome Measures

Measurement of Plasma BNP Levels
Evaluate the effects of CXL-1020 on change from baseline in circulating BNP levels after 6 hours of treatment in all strata.
Assessment of the dose/plasma concentration/effect relationship of CXL-1020
Correlation of plasma concentrations of the CXL-1020 metabolites with Drug Hemodynamic Effects
Effects of CXL-1020 on Renal Function
Evaluate effects of CXL-1020 on renal function parameters (serum creatinine, Cystatin C, and plasma NGAL)
Signs and Symptoms of Heart failure
Evaluate heart failure symptoms in using a Likert 7-point heart failure symptom scale completed by the Investigator and a visual analogue scale completed by the patient and after the 6 hour timepoint in Stratum C
Evaluation of all Adverse Events
Assess adverse events within 30 days of treatment as adjudicated by an independent safety committee (all strata)

Full Information

First Posted
March 22, 2010
Last Updated
November 14, 2016
Sponsor
Bristol-Myers Squibb
Collaborators
Cardioxyl Pharmaceuticals, Inc
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1. Study Identification

Unique Protocol Identification Number
NCT01096043
Brief Title
A Dose-Defining Study of CXL-1020 in Patients With Systolic Heart Failure
Official Title
A Phase IIa, 3 Strata Dose-Defining Study Evaluating the Hemodynamic Effects, Safety and Tolerability of CXL-1020 in Patients With Systolic Heart Failure
Study Type
Interventional

2. Study Status

Record Verification Date
April 2012
Overall Recruitment Status
Completed
Study Start Date
April 2010 (undefined)
Primary Completion Date
February 2012 (Actual)
Study Completion Date
February 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bristol-Myers Squibb
Collaborators
Cardioxyl Pharmaceuticals, Inc

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Study CXL-1020-02 employs is designed to further define suitable clinical dosages for CXL-1020 which will be utilized in a later Phase IIb study. The study is conducted in 3 different stages called 'strata" and evaluates the potential utility of this drug for the treatment of patents who are hospitalized with heart failure.
Detailed Description
Each of the 3 strata are described below: Invasive Strata 1: This is a randomized, double-blinded stratum that will enroll up to 65 patients who are hospitalized with symptomatic heart failure who have indwelling PA catheters allowing invasive hemodynamic evaluation. Each patient will receive a six hour intravenous infusion of either placebo or CXL-1020. Non-Invasive Strata 2: This is a randomized, double-blinded stratum which will enroll up to approximately 72 patients (in several cohorts with 12-24 patients each) who neither require, nor have in place, an indwelling PA catheter for hemodynamic monitoring, but meet study entrance criteria for symptoms of heart failure, (dyspnea at rest)and systolic dysfunction by specific echocardiography criteria. Monitoring of drug effects will be performed by Echocardiography. Invasive-Strata 3: This is a randomized, double-blinded stratum that will begin after an evaluation of a substantial number of patients in Strata A and B and will enroll approximately 15-30 patients using the same general enrollment criteria as in Invasive Strata A.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure
Keywords
Heart Failure, ADHF

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
69 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Each Strata of the study will have a placebo control. In strata A, the chance of getting active drug is 4 out of 5, in Strata B the chance of getting active drug is 3 ot of 4, and in Strata C, the chance of getting active Drug is 4 out of 5. In the event that a patient is allocated to receive placebo, the treatment may be stopped if the patient's condition fails to improve or worsens during the placebo infusion.
Arm Title
Strata 1 CXL-1020
Arm Type
Experimental
Arm Description
Patients assigned to CXL-1020 in strata one will have their dose increased from the initial dose 2 times during the study period. The treatment may be stopped if the patient's condition fails to improve or worsens during the infusion.
Arm Title
Strata 2 CXL-1020
Arm Type
Experimental
Arm Description
In strata 2, patients who are assigned to active treatment will receive one of up to 3 possible fixed dose levels of CXL-1020 for a period of 6 hours. The treatment may be stopped if the patient's condition fails to improve or worsens during the infusion.
Arm Title
Strata 3 CXL-1020
Arm Type
Experimental
Arm Description
In strata 3, patients assigned to receive CXL-1020 will receive a fixed dose of CXL-1020 for 6 hours, and then the dose may be increased or decreased, based on the investigators assessment of the patient. The treatment may be stopped if the patient's condition fails to improve or worsens during the infusion.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
BMS-986233
Intervention Description
An infusion of an identically appearing solution of sugar water will be intravenously administered.
Intervention Type
Drug
Intervention Name(s)
Strata 1 CXL-1020
Other Intervention Name(s)
BMS-986233
Intervention Description
Intravenous infusion of CXL-1020, up-titrated, so that 3 different dosages are administered over 6 hours
Intervention Type
Drug
Intervention Name(s)
Strata 2 CXL-1020
Other Intervention Name(s)
BMS-986233
Intervention Description
One of 3 different dosages of CXL-1020 administered at a fixed dosage level for 6 hours.
Intervention Type
Drug
Intervention Name(s)
Strata 3 CXL-1020
Other Intervention Name(s)
BMS-986233
Intervention Description
A fixed dose level of CXL-1020 will be administered for the initial 6 hours of treatment in Strata 3 and then dosage will be altered up or downward based on the investigators observation of the patient's condition.
Primary Outcome Measure Information:
Title
Safety and Hemodynamic Effects
Description
Define the safety and hemodynamic benefit of CXL-1020 based upon the change from baseline in hemodynamic measurements at the 6 hour time point in all strata
Time Frame
At 6 Hours following start of dosing
Secondary Outcome Measure Information:
Title
Measurement of Plasma BNP Levels
Description
Evaluate the effects of CXL-1020 on change from baseline in circulating BNP levels after 6 hours of treatment in all strata.
Time Frame
At 6 hours following the start of dosing
Title
Assessment of the dose/plasma concentration/effect relationship of CXL-1020
Description
Correlation of plasma concentrations of the CXL-1020 metabolites with Drug Hemodynamic Effects
Time Frame
At 6 hours following start of dosing
Title
Effects of CXL-1020 on Renal Function
Description
Evaluate effects of CXL-1020 on renal function parameters (serum creatinine, Cystatin C, and plasma NGAL)
Time Frame
24 hours post dosing
Title
Signs and Symptoms of Heart failure
Description
Evaluate heart failure symptoms in using a Likert 7-point heart failure symptom scale completed by the Investigator and a visual analogue scale completed by the patient and after the 6 hour timepoint in Stratum C
Time Frame
At 6 hours following the start of dosing
Title
Evaluation of all Adverse Events
Description
Assess adverse events within 30 days of treatment as adjudicated by an independent safety committee (all strata)
Time Frame
Through 30 days following study drug dosing

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: In order to be eligible for randomization, a patient MUST: Be a male or post menopausal or surgically sterile female requiring inpatient evaluation or treatment and be between 18 and 85 years of age Not require immediate emergent treatment with conventional parenteral inotropes or vasodilators Be receiving standard background heart failure therapies as indicated, but not receive an oral dose of a hemodynamically active treatment or diuretic within 3 hours of baseline hemodynamic assessments Have chronic Systolic HF due to primary/idiopathic dilated cardiomyopathy, coronary artery disease or hypertension For inclusion in the Non-Invasive Strata B, have a baseline (within 48 hours prior to dosing) left ventricular ejection fraction ≤ 35% estimated from a baseline 2D-Echocardiogram For inclusion in the Invasive Strata A and C, have baseline hemodynamic values (mean of 3 consecutive CI measurements taken within 1 hours preceding dosing within 10% of one another with a mean CI of less than or equal to (≤) 2.5L/min AND a mean PCWP of greater than 20mmHg Have an elevated baseline BNP of at least 400pg/ml in all protocol strata Be capable of understanding the nature of the trial and be willing to participate as documented by written informed consent Be willing and able to comply with the inpatient and outpatient study protocol requirements for the duration of the study (treatment plus 30 follow up at days) If a post-menopausal or surgically sterile female, confirmation of sterility status (post-menopausal or surgically sterile for at least 6 months; post-menopausal subjects will require a urine pregnancy test for confirmation) If a fertile male, must be using 2 approved contraceptive methods (a condom and a spermicidal agent, even if partner(s) is using birth control) for 10 days following participation in the study and further agree to not donate sperm for 10 days after participation in the study Must have a negative urine test for drugs of abuse and a negative ethanol breath test or blood test at baseline before dosing Have required local laboratory safety data within protocol required or local laboratory non-exclusionary ranges before dosing May be receiving ICD, Bi V pacing or rate control pacing at the time of randomization so long as no alteration of settings are anticipated within the day of study drug administration Exclusion Criteria: In order to be eligible for randomization, a patient MUST NOT: Have participated in any investigational drug study, SERCa gene therapy or cellular myocardial transplant study within 30 days preceding randomization or have previously received therapy with CXL-1020 Have received a parenteral or oral dose of diuretics or other hemodynamically active therapy within 3 hours of the baseline hemodynamic assessment Have received intravenous inotropes, inodilators or vasodilators (amrinone, digoxin, dopamine, dobutamine, enoximone, levosimendan, milrinone, nesiritide, nitroglycerine or nitroprusside) for more than 4 hours and within 12 hours prior to randomization to treatment with study drug Have a heart rate <50 or ≥ 90 BPM at baseline prior to randomization Have a blood pressure >150 Systolic and/or >95 diastolic mmHg at baseline prior to randomization Have a systolic blood pressure of less than 100 mmHg at baseline prior to randomization Be in atrial fibrillation/flutter at the time of randomization or have a history of recent intermittent A-fib/flutter within the previous week Have non-sustained VT (HR > 120 bpm) of 10 beats or more during bedside monitoring prior to randomization or excessive VPB's or complex multifocal ventricular ectopy exceeding 10 beats per minute on a 2 minute rhythm strip taken within 10 minutes prior to randomization Have a history of successful cardiac resuscitation within the past 2 years. (Inappropriate ICD firings for non lethal arrhythmias 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 stroke (CVA) or transient ischemic attack (TIA) within six months prior to randomization Have a concurrent history of CCS Class III or IV angina Be a patient whose HF etiology is attributable to either restrictive/obstructive cardiomyopathy, idiopathic hypertrophic cardiomyopathy (as defined by any wall thickness > 1.8 cm) or uncorrected severe valvular disease Be receiving concomitant oral or parenteral therapy with any antiarrhythmic drugs other than amiodarone or dronedarone. (only oral therapy is allowed for these agents) Have unsuitable echocardiographic windows for the Echo assessments (applies only to Strata B) Have a screening or baseline serum Na < 130 mEq/l or > 145 mEq/l; a serum K < 3.5 mEq/l or > 5.5 mEq/l; a serum Ca < 7.5 mg/dl or > 10.2 mg/dl; or a serum Mg < 1.6 mEq/l or > 3.0 mEq/l., or a digoxin level above 1ng/ml Have a baseline serum creatinine > 2.5 mg/dl; an ALT or AST >3 times the upper normal limit; or a hemoglobin < 10 g/dl Have taken ethanol within 24 hours (with a positive ethanol breath test or blood test) or a PDE5 inhibitor within 96 hours of study drug administration Have other clinically significant laboratory or medical conditions that, in the opinion of the Investigator, make the patient unsuitable for evaluation in the study Be receiving a drug which is expected to possess the potential for a clinically significant pharmacokinetic interaction with CXL-1020, as defined in the investigational drug brochure (IDB). Be the recipient of a myocardial restraint device or flap Have an anticipated survival of less than 90 days for any reason Note: Patients receiving cardiac resynchronization therapy for HF are eligible and pacemaker settings have not been changed on this hospitalization and can be left unchanged for the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wilson Colucci, M.D.
Organizational Affiliation
Boston University
Official's Role
Study Chair
Facility Information:
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
University of Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32209
Country
United States
Facility Name
Florida Hospital Transplant Center
City
Orlando
State/Province
Florida
ZIP/Postal Code
32804
Country
United States
Facility Name
Ochsner Clinic Foundation
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70121
Country
United States
Facility Name
University of Maryland Medical Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
DMC Cardiovascular Institute
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Henry Ford Health System
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
University of Medicine & Dentistry of New Jersey - New Jersey Medical School
City
South Orange
State/Province
New Jersey
ZIP/Postal Code
07103
Country
United States
Facility Name
Montefiore Medical Center
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Facility Name
Wake Forest University Health Sciences
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Facility Name
University of Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Facility Name
University Hospitals Case Medical Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Davis Heart & Lung Research Institute
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Stern Cardiovascular Center PA
City
Germantown
State/Province
Tennessee
ZIP/Postal Code
38138
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
24107588
Citation
Sabbah HN, Tocchetti CG, Wang M, Daya S, Gupta RC, Tunin RS, Mazhari R, Takimoto E, Paolocci N, Cowart D, Colucci WS, Kass DA. Nitroxyl (HNO): A novel approach for the acute treatment of heart failure. Circ Heart Fail. 2013 Nov;6(6):1250-8. doi: 10.1161/CIRCHEARTFAILURE.113.000632. Epub 2013 Oct 9.
Results Reference
derived

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A Dose-Defining Study of CXL-1020 in Patients With Systolic Heart Failure

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