Subcu Administration of CD-NP in Heart Failure Patients With Left Ventricular Assist Device Support (CD-NP/LVAD)

A Phase I Trial to Determine Safety and Efficacy of Chronic Subcu Administration of CD-NP in Heart Failure Patients With Left Ventricular Assist Device Support

The worldwide use of left ventricular assist devices (LVAD), which is mechanical device to improve hemodynamic function, has improved the outcomes of severe heart failure (HF) patients leading to the continued annual increase in the number of LVAD implantations. However LVAD support still results in major complications such as renal failure or gastrointestinal bleeding. The investigators hypothesize that such major complications may be due to endothelial dysfunction induced by the lack of pulsatility, which may be improved by an innovative designer natriuretic peptide, CD-NP. They have demonstrated its favorable actions in animal models as well as humans, and tested its safety in LVAD patients. They hypothesize that CD-NP will have renal and endothelial protective actions through its receptor GC-A and GC-B. Thus, the investigators will test their hypothesis with a highly translational approach to examine CD-NP's role in endothelial and renal protection.

The aim is to determine safety and tolerability together with cGMP activating, neurohumoral modulating and renovascular protective properties of chronic subcutaneous delivery of CD-NP compared to placebo in stable LVAD patients for 3 days.

Study Overview

• Status: Withdrawn
• Conditions: Heart Failure; Left Ventricular Assist Device; Natriuretic Peptide
• Intervention / Treatment: Drug: CD-NP; Other: Placebo

Detailed Description

Stable patients with LVAD implantation (3 months s/p implantation) will undergo 3-day testing in the Mayo Clinic's Clinical Research and Trials Unit. They will undergo daily subcutaneous injection of CD-NP, or placebo, for 3 days with hemodynamic monitoring, ECHO, endothelial function assessment, and renal blood flow monitoring. Blood and urine samples will also be collected and assayed.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and non-pregnant/post-menopausal/sterile females, ages 18-90, in end-stage HF with LVAD support who are stable in the healed stage at least 3 months from the LVAD implant (Destination therapy only) (the post-menopausal state is defined as the absence of menses for ≥ 1 year or serum follicle-stimulating hormone ≥ 20 IU/L; sterilization in the female is defined as bilateral tubal occlusion for ≥ 6 months, bilateral oophorectomy, or complete hysterectomy)
• Be willing to provide informed consent.
• All cardiac medications must be at stable doses 4 weeks prior to enrollment.

Exclusion Criteria:

• Known allergy or other adverse reactions to exogenous natriuretic peptides (CD-NP or its components, nesiritide, other natriuretic peptides, or related compounds).
• Women who are pregnant, or breast-feeding.
• Having received nesiritide within 7 days prior to entry into the study.
• Having received any investigational drug or device within 30 days prior to entry into the study.
• Clinically unstable patients (e.g. mean blood pressure < 70 mmHg, ongoing requirement for vasopressors, or mechanical ventilation).
• Recent hospitalization for decompensated HF or recent defibrillation for cardiac resuscitation within 30 days prior to randomization.
• Patients with guarded prognosis who are unlikely to derive meaningful benefit from CD-NP.
• Presence of cardiac lesions or comorbidities that may contraindicate the use of natriuretic peptides, such as clinically significant cardiac valvular stenosis, hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, primary pulmonary hypertension, or uncorrected congenital heart disease that contraindicates the use of vasodilators.
• Symptomatic carotid artery disease, known critical carotid stenosis, or stroke within the past 3 months
• Requirement of pressors for maintenance of blood pressure.
• Intra-aortic blood pump use.
• Severe aortic or mitral stenosis or significant LV outflow tract obstruction.
• Clinically significant renal artery stenosis > 50%
• Baseline hemoglobin < 9.0 g/dl.
• Serum sodium < 130 mEq/L, potassium < 3.6 mEq/L, or magnesium < 1.5 mEq/L.
• Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at least 5 times the upper limit of normal or bilirubin at least 5 times the upper limit of normal
• Creatinine clearance (CrCl) < 30 ml.min-1.1.73m-2, as calculated by Cockcroft-Gault formula(67) and adjusted for body surface area within 3 months or requirement for dialysis.
• Written history of alcohol or drug abuse within the past 6 months.
• Inability to communicate effectively with study personnel.
• BMI >40

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Study Drug (CD-NP); Participants will receive a single subcutaneous injection of CD-NP (5 ug/kg) for 3 days running	Drug: CD-NP; Participants will receive a subcutaneous injection of CD-NP (5 mcg / kg) daily for 3 days; Other Names: Cenderitide
Placebo Comparator: Placebo (saline); Participants will receive a single subcutaneous injection (~1 mL) of normal saline for 3 days running	Other: Placebo; Participants will receive an ~ 1mL subcutaneous injection of normal saline, in lieu of Study Drug, for 3 days; Other Names: 0.9% normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hypotension	To assess safety and tolerability (without symptomatic hypotension or mean blood pressure <70 mmHg) of chronic continuous subcutaneous infusion administration of CD-NP.	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Outcome Characterization	Area under the plasma concentration versus time curve (AUC) assessed by plasma CD-NP and cGMP	2 weeks
Renal Function	Estimated GFR from creatinine clearance and	2 weeks
Endothelial function	Measurement by Reactive Hyperemia-peripheral arterial tonometry (RHI)	2 weeks

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Tomoko Ichiki, M.D.Ph.D., Mayo Clinic

Study record dates

Study Major Dates

• Study Start (Anticipated): September 30, 2017
• Primary Completion (Anticipated): May 1, 2019
• Study Completion (Anticipated): May 1, 2020

Study Registration Dates

• First Submitted: March 9, 2017
• First Submitted That Met QC Criteria: March 21, 2017
• First Posted (Actual): March 27, 2017

Study Record Updates

• Last Update Posted (Actual): July 28, 2017
• Last Update Submitted That Met QC Criteria: July 25, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: IRB # 16-004850

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No