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

NCT02157506 | Completed Phase 2 Results DMC

• 2 other identifiers: CXL-1427-02CV013-006
• Study Type: interventional
• Target: 70
• Locations: 5 countries
• Sites: 35

Brief Summary

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

Conditions

Heart Failure; Decompensated Heart Failure; Acute Heart Failure

Keywords

Acute Heart failure; Hemodynamics; Pharmacokinetics; Renal Function

Outcome Measures

Primary Outcomes (4)

• Number of Participants With Treatment-Emergent Adverse Events

  A treatment-emergent adverse event (TEAE) was defined as an AE with onset after the start of the study drug infusion at Hour 00:00 through 30 days after the stop of the study drug infusion. All TEAEs and pertinent subsets of TEAEs (e.g., TEAEs with onset during the infusion of study drug, serious TEAEs, etc.) were summarized by system organ class (SOC), preferred term (PT) and treatment group

  30 days following the initiation of treatment

• Mean Time Averaged Change From Baseline in Adjudicated Pulmonary Capillary Wedge Pressure (PCWP) During Infusion

  The effect of CXL-1427 on PCWP is presented as the mean time-averaged change from baseline over the course of infusion of CXL-1427 or placebo in adjudicated pulmonary capillary wedge pressure (PCWP) on a modified intent-to-treat population

  Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion

• Mean Time-Averaged Change From Baseline in Adjudicated Pulmonary Artery Diastolic Pressure (PAD) During the Infusion

  Pulmonary artery diastolic pressure (PAD) was measured by an indwelling PA catheter. Pulmonary artery diastolic pressure (PAD) approximates pulmonary capillary wedge pressure in normal individuals. The effects of CXL-1427 on time-averaged PAD during the course of the infusion are presented.

  Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion initiation

• Mean Time-Averaged Percent Change From Baseline in Cardiac Index (Fick)

  Cardiac index is a measure of cardiac function, relating the cardiac output from the left ventricle in one minute to body surface area. It is calculated using the Fick principle, using oxygen consumption measured with a metabolic cart, hemoglobin levels, and the difference between arterial and superior vena cava oxygen saturation measured by co-oximetry. Cardiac index as calculated by the Fick method was performed using an assumed oxygen consumption value of 125 ml/min per m2 of body surface area. i.e., an assumed Fick method.

  Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion initiation

Secondary Outcomes (6)

• Mean Time-Averaged Change From Baseline in Adjudicated Pulmonary Artery Systolic Pressure (PAS) During the Infusion

  Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion initiation

• Mean Time-Averaged Change From Baseline in Adjudicated Right Atrial Pressure (RAP) During the Infusion

  Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion initiation

• Mean Time-Averaged Change From Baseline in Mean Arterial Blood Pressure (MAP) During the Infusion

  Baseline, Hour 24 after infusion, Follow-up visit 1

• Mean Time-Averaged Change From Baseline in Systolic Blood Pressure (SBP) During the Infusion

  Baseline, Hour 24 after infusion, Follow-up visit 1

• Mean Time-Averaged Change From Baseline in Diastolic Blood Pressure (DBP) During the Infusion

  Baseline, Hour 24 after infusion, Follow-up visit 1

Study Arms (7)

CXL-1427 Starting Dose

EXPERIMENTAL

The Starting dose of CXL-1427 in the dose escalation arms will be 3mcg/kg/min

Drug: CXL-1427

CXL-1427 Dose Level 2

EXPERIMENTAL

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

CXL-1427 Dose Level 3

EXPERIMENTAL

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

CXL-1427 Dos Level 3

EXPERIMENTAL

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

CXL-1427 Dose Level 4

EXPERIMENTAL

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

Expansion Cohort 1

EXPERIMENTAL

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 for Dose Escalation and Expansion Cohort

PLACEBO COMPARATOR

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

Interventions

CXL-1427 DRUG

Also known as: BMS-986231

CXL-1427 Dos Level 3; CXL-1427 Dose Level 2; CXL-1427 Dose Level 3; CXL-1427 Dose Level 4; CXL-1427 Starting Dose; Expansion Cohort 1

Placebo DRUG

Also known as: 5% Dextrose & 10mM potassium acetate as same IV solution diluents used in active

Placebo for Dose Escalation and Expansion Cohort

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;

You may not qualify if:

• 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.
• 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;

Sponsors & Collaborators

• Bristol-Myers Squibb: lead
• Cardioxyl Pharmaceuticals, Inc: collaborator

Study Sites (35)

Cardioxyl Study Site

Gainesville, Florida, 32610, United States

Location

Cardioxyl Study Site

Jacksonville, Florida, 32209, United States

Location

Cardioxyl Study Site

Jacksonville, Florida, 32224, United States

Location

Cardioxyl Study Site

Macon, Georgia, 31201, United States

Location

Cardioxyl Study Site

Baltimore, Maryland, 21201, United States

Location

Cardioxyl Study Site

Detroit, Michigan, 48202, United States

Location

Cardioxyl Study Site

Newark, New Jersey, 07103, United States

Location

Cardioxyl Study Site

Chapel Hill, North Carolina, 27517, United States

Location

Cardioxyl Study Site

Cincinnati, Ohio, 45267, United States

Location

Cardioxyl Study Site

Columbus, Ohio, 43201, United States

Location

Cardioxyl Study Site

Charleston, South Carolina, 29425, United States

Location

Cardioxyl Study Site

Nashville, Tennessee, 37232, United States

Location

Cardioxyl Study Site

Salt Lake City, Utah, 84132, United States

Location

Cardioxyl Study Site

Richmond, Virginia, 23298, United States

Location

Cardioxyl Study Site

Bad Neuheim, 61231, Germany

Location

Cardioxyl Study Site

Cologne, 50937, Germany

Location

Cardioxyl Study Site

Frankfurt, 60590, Germany

Location

Cardioxyl Study Site

Göttingen, 37075, Germany

Location

Cardioxyl Study Site

Greifswald, 17475, Germany

Location

Cardioxyl Study Site

Kiel, 2105, Germany

Location

Cardioxyl Study Site

Regensberg, 93053, Germany

Location

Cardioxyl Study Site

Amman, 11193, Jordan

Location

Cardioxyl Study Site

Irbid, 22110, Jordan

Location

Cardioxyl Study Site

Lodz, 93487, Poland

Location

Cardioxyl Study SIte

Warsaw, 01211, Poland

Location

Cardioxyl Study Site

Warsaw, 04-628, Poland

Location

Cardioxyl Study Site

Wroclaw, 50981, Poland

Location

Cardioxyl Study Site

Kemerovo, 650002, Russia

Location

Cardioxyl Study Site

Moscow, 111539, Russia

Location

Cardioxyl Study Site

Moscow, 121309, Russia

Location

Cardioxyl Study Site

Moscow, 12134, Russia

Location

Cardioxyl Study Site

Moscow, 127644, Russia

Location

Cardioxyl Study Site

Saint Petersburg, 19242, Russia

Location

Cardioxyl Study Site

Saint Petersburg, 199106, Russia

Location

Cardioxyl Study Site

Tomsk, 634012, Russia

Location

MeSH Terms

Conditions

Heart Failure

Interventions

Glucose; Potassium Acetate; Exercise

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Hexoses; Monosaccharides; Sugars; Carbohydrates; Potassium Compounds; Inorganic Chemicals; Acetic Acid; Acetates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Results Point of Contact

• Title: EU Study Start-Up Unit
• Organization: Bristol-Myers Squibb International Corporation

clinical.trials@bms.com

Study Officials

• ShiYin Foo, M.D., Ph D.

  Cardioxyl Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 28, 2014
• First Posted: June 6, 2014
• Study Start: June 30, 2014
• Primary Completion: May 31, 2015
• Study Completion: July 31, 2015
• Last Updated: July 31, 2019
• Results First Posted: May 20, 2019

Record last verified: 2019-07

Locations

RU (8); DE (7); PL (4); US (14); JO (2)