Safety and Hemodynamic Effects and Pharmacokinetics of CXL-1020 in Patients With Stable Heart Failure

Study Overview
=================
Brief Summary
-----------------
A Phase 1-2a Study of CXL-1020-01 in Patients with Stable Heart Failure

Detailed Description
-----------------
This is a Phase I/IIa Dose-Escalation, First exposure in Humans, Study Evaluating the Safety and Tolerability of CXL-1020 and Specific Effects on Electrocardiographic and Non-Invasive Hemodynamic Parameters in Patients with Chronic Heart Failure. 4 weekly four-hour treatments involving ascending dosages of CXL-1020 with a randomly interspersed placebo dose within two or more unique patient cohorts. Separate echocardiography cohorts (Echo Cohort A and Echo Cohort B) will evaluate a sustained dose over 4 hours (ECHO A), and an ascending two dose level, 4-hour infusion (2 hours each) (ECHO B), in individual patients. Echo Cohort dosages will be determined from responses observed in previous cohort exposures.

Official Title
-----------------
A Phase I/IIa Dose-Escalation Study Evaluating the Safety and Tolerability of CXL-1020 and Specific Effects on Electrocardiographic and Non-Invasive Hemodynamic Parameters in Patients With Chronic Heart Failure

Conditions
-----------------
Heart Failure

Intervention / Treatment
-----------------
* Drug: CXL-1020
* Drug: CXL-1020
* Drug: Placebo for CXL-1020 Cohort 1
* Drug: Placebo for CXL-1020 Cohort 2
* Drug: CXL-1020 Dose for Echo Cohort A
* Drug: CXL-1020 Doses for Echo Cohort B


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: In order to be eligible for randomization, a patient MUST: Be a male or post menopausal or surgically sterile female outpatient between 18 and 85 years of age Have chronic Systolic HF due to primary/idiopathic dilated cardiomyopathy, coronary artery disease or hypertension, and stable for at least 30 days prior to screening Have a core echo lab confirmed left ventricular ejection fraction ≤ 40% in a baseline 2D-Echocardiogram prior to and within 60 days of the first dose of study medication with evidence of at least minimal LV dilation on the basis of an observed LV-EDV index that is above normal Have a baseline NT-Pro-BNP of greater than or equal to the top of the normal reference range (124pg/ml) prior to and within 60 days of the first dose of study medication Be on unchanging doses of HF medications (with exception of diuretic dosage) for 2 weeks prior to randomization without planned initiation of new hemodynamically active therapy during the conduct of the study 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 study protocol requirements for the duration of the study, including pharmacokinetic sampling 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 prior to enrollment and urine pregnancy tests prior to each dosing) If a fertile male, must be using 2 approved contraceptive methods (a condom and a spermicidal agent, even if the partner is using birth control) for the duration of the study and for 3 months following participation in the study and further agree to not donate sperm for 3 months after participation in the study. Must have a negative urine test for drugs of abuse and a negative ethanol breath test at screening and before each dosing period Have required local lab data within non-exclusionary ranges before each dosing Exclusion Criteria: In order to be eligible for randomization, a patient MUST NOT: Have participated in any investigational drug study within 30 days preceding randomization or have previously received therapy with CXL-1020 Have a heart rate <50 or ≥ 90 BPM at baseline prior to randomization. Have a blood pressure >150 Systolic and/or >90 diastolic mmHg at baseline prior to randomization Have a systolic blood pressure of less than 100 mmHg at baseline prior to randomization Have QT/QTc prolongation > 460 msec or > 500msec in patients with preexisting bundle branch block (only applies to non-paced patients in sinus rhythm) Have experienced a documented symptomatic or electrocardiographically recorded episode of atrial fibrillation/flutter within 60 days before screening and be in normal sinus rhythm at each baseline before study drug is administered Have a history of sustained or hemodynamically significant VT or VF requiring cardioversion, or self-terminating VT associated with hypotension Have non-sustained VT (HR > 120 bpm) of 10 beats or more during monitoring in the baseline monitoring period prior to each dose of study medication, or in any Holter or EKG recording within 1 year of first dose of study medication. Have a weight or height that exceeds the specifications for the ICG Device of (greater than 341 pounds or taller than 7 feet 2 inches.) Be post-successful cardiac resuscitation Have a history of worsening HF within 30 days prior to screening as defined by: Unscheduled ER or clinic visits relating to HF or hospital admission for management of HF Treatment with intravenous inotropic or vasodilator drugs Be diagnosed with acute coronary syndrome or acute myocardial infarction within three months prior to screening Have a history of stroke (CVA) or transient ischemic attack (TIA) within six months prior to screening Have a 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 therapy with any antiarrhythmic drugs other than amiodarone Have experienced the firing of an implantable ICD for documented ventricular ectopy within three months prior to screening Have a known allergy to the ICG Device sensor gel or adhesive Have unsuitable Echocardiographic Windows for the comprehensive Echo assessments required in the Echo cohorts (exclusion for echo cohorts only) Have a skin lesion at the site of the ICG Device sensor placement. Have a screening or baseline serum Na < 130 mEq/l or > 145 mEq/l; a serum K < 3.5 mEq/l or > 5.0 mEq/l; a serum Ca < 7.5 mg/dl or > 10 mg/dl; or a serum Mg < 1.6 mEq/l or > 3.0 mEq/l., or a digoxin level above 1ng/ml Have a screening TSH < 0.1 mcU/ml or > 5.0 mcU/ml Have a screening or 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 or a PDE5 inhibitor within 96 hours of study admission Have other clinically significant laboratory or medical conditions that, in the opinion of the Investigator, make the patient unsuitable for evaluation in the study Have a generalized atopic state or a history of a mild to moderate documented drug allergy Be receiving a drug which is expected to possess the potential for a clinically significant pharmacokinetic interaction with CXL-1020, as defined in the IDB. Note: Patients receiving cardiac resynchronization therapy for HF are eligible provided that the device has been placed for greater than 30 days and pacemaker settings can be left unchanged for the study period.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 CXL-1020<br>An intravenous infusion of CXL-1020 administered for a total of 4 hours over a total of 3 occasions separated by at least one week. Each of the 3 doses of CXL-1020 are different, starting with the lowest dose and increasing to the highest dose. | Drug: CXL-1020<br>* Intravenous infusion of one of 3 active dosages of CXL-1020<br>|
| Placebo Comparator: Cohort 1 Placebo<br>A 4 hour infusion of Placebo administered one time randomly among the 3 active doses of CXL-1020 in cohort 1 | Drug: Placebo for CXL-1020 Cohort 1<br>* A 4 hour infusion of a IV solution containing 5% Dextrose in water (Sugar Water)<br>|
| Experimental: Cohort 2 CXL-1020<br>An intravenous infusion of CXL-1020 administered for a total of 4 hours over a total of 3 occasions separated by at least one week. Each of the 3 doses of CXL-1020 are different, starting with the lowest dose and increasing to the highest dose. | Drug: CXL-1020<br>* Intravenous infusion of one of 3 active dosages of CXL-1020 at dosages higher than in Cohort 1<br>|
| Placebo Comparator: Cohort 2 Placebo<br>A 4 hour infusion of Placebo administered one time randomly among the 3 active doses of CXL-1020 in cohort 1 | Drug: Placebo for CXL-1020 Cohort 2<br>* A 4 hour infusion of a IV solution containing 5% Dextrose in water (Sugar Water)<br>|
| Active Comparator: Echo Cohort A CXL-1020<br>A 4 hour infusion of a fixed dose of CXL-1020 which was studied in Cohort 1 or Cohort 2 which is expected to be well tolerated and have hemodynamic effect | Drug: CXL-1020 Dose for Echo Cohort A<br>* A 4 hour fixed dose of CXL-1020 which was studied in Cohort 1 or 2 which was demonstrated to be safe and well tolerated and have some anticipated hemodynamic effect<br>|
| Active Comparator: Echo Cohort B CXL-1020<br>CXL-1020 administered at a fixed rate for the initial 2 hours and at a higher fixed rate for the last 2 hours of a 4 hour infusion at doses which were studied in Cohort 1 or Cohort 2 and expected to be well tolerated and have hemodynamic effects | Drug: CXL-1020 Doses for Echo Cohort B<br>* A 2 hour dose level of CXL-1020 which was studied in Cohort 1 or 2 which was demonstrated to be safe and well tolerated and have some anticipated hemodynamic effect followed by another higher 2 hour dose level of CXL-1020 which was studied in Cohort 1 or 2 which was demonstrated to be safe and well tolerated and have some anticipated hemodynamic effect<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | Safety is measured by assessment of multiple parameters including standard laboratory safety, changes in blood pressure and heart rate, changes in electrocardiogram, monitoring of heart rhythm via holter monitor, measurement of cardiac safety biomarkers such as plasma troponin as well as treatment emergent adverse events | From initial exposure to 30 days following exposure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamic Effects as Measured by Impedance Cardiography and Echocardiography | Standard measurement of impedance cardiography parameters will be made non invasively in all study cohorts. Echocardiography will be evaluated in parallel with Impedance cardiography in the Echo Cohorts | before during and following the infusion of study medication | 
| Plasma and Urinary Pharmacokinetics | Measurement of plasma samples and urine collections for CXL-1020 and metabolites. Samples are collected approximately 19 times from a intravenous catheter, before during and following infusion. In addition 4 collections of all freely voided urine will be collected from before infusion until 18 hours following infusion. | From start of infusion until 18 hours post infusion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Heart Failure