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

Primary Purpose

Heart Failure, Left Ventricular Assist Device, Natriuretic Peptide

Status

Withdrawn

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

CD-NP

Placebo

About this trial

This is an interventional treatment trial for Heart Failure

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Study Drug (CD-NP)

Placebo (saline)

Arm Description

Participants will receive a single subcutaneous injection of CD-NP (5 ug/kg) for 3 days running

Participants will receive a single subcutaneous injection (~1 mL) of normal saline for 3 days running

Outcomes

Primary Outcome Measures

Hypotension

To assess safety and tolerability (without symptomatic hypotension or mean blood pressure <70 mmHg) of chronic continuous subcutaneous infusion administration of CD-NP.

Secondary Outcome Measures

Pharmacokinetic Outcome Characterization

Area under the plasma concentration versus time curve (AUC) assessed by plasma CD-NP and cGMP

Renal Function

Estimated GFR from creatinine clearance and

Endothelial function

Measurement by Reactive Hyperemia-peripheral arterial tonometry (RHI)

Full Information

NCT ID

NCT03091998

First Posted

March 9, 2017

Last Updated

July 25, 2017

Sponsor

Mayo Clinic

1. Study Identification

Unique Protocol Identification Number

NCT03091998

Brief Title

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

Acronym

CD-NP/LVAD

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2017

Overall Recruitment Status

Withdrawn

Why Stopped

No funding available

Study Start Date

September 30, 2017 (Anticipated)

Primary Completion Date

May 1, 2019 (Anticipated)

Study Completion Date

May 1, 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Mayo Clinic

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure, Left Ventricular Assist Device, Natriuretic Peptide

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Model Description

Injection of CD-NP vs Placebo

Masking

ParticipantCare ProviderInvestigator

Masking Description

The Research Pharmacists will manage the randomization of the study and release information at the conclusion, once all participants have been recruited and completed study measures.

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Study Drug (CD-NP)

Arm Type

Active Comparator

Arm Description

Participants will receive a single subcutaneous injection of CD-NP (5 ug/kg) for 3 days running

Arm Title

Placebo (saline)

Arm Type

Placebo Comparator

Arm Description

Participants will receive a single subcutaneous injection (~1 mL) of normal saline for 3 days running

Intervention Type

Drug

Intervention Name(s)

CD-NP

Other Intervention Name(s)

Cenderitide

Intervention Description

Participants will receive a subcutaneous injection of CD-NP (5 mcg / kg) daily for 3 days

Intervention Type

Other

Intervention Name(s)

Placebo

Other Intervention Name(s)

0.9% normal saline

Intervention Description

Participants will receive an ~ 1mL subcutaneous injection of normal saline, in lieu of Study Drug, for 3 days

Primary Outcome Measure Information:

Title

Hypotension

Description

To assess safety and tolerability (without symptomatic hypotension or mean blood pressure <70 mmHg) of chronic continuous subcutaneous infusion administration of CD-NP.

Time Frame

2 weeks

Secondary Outcome Measure Information:

Title

Pharmacokinetic Outcome Characterization

Description

Area under the plasma concentration versus time curve (AUC) assessed by plasma CD-NP and cGMP

Time Frame

2 weeks

Title

Renal Function

Description

Estimated GFR from creatinine clearance and

Time Frame

2 weeks

Title

Endothelial function

Description

Measurement by Reactive Hyperemia-peripheral arterial tonometry (RHI)

Time Frame

2 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

90 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Tomoko Ichiki, M.D.Ph.D.

Organizational Affiliation

Mayo Clinic

Official's Role

Principal Investigator

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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