Oral Nitrite for Older Heart Failure Patients

NCT02457260 | Completed Phase 2 Results

• 1 other identifier: PRO15020481
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

Studies have demonstrated nitrite therapy increases adenosine triphosphate (ATP) synthesis in skeletal muscle mitochondria concomitant with reduced whole-body oxygen cost during steady state exercise. Our own work has demonstrated safety and efficacy of an FDA investigational new drug (IND) approved sodium nitrite (10 milligram \[mg\]) capsule, and its utility to upregulate the sirtuin 3 adenosine monophosphate protein kinase (SIRT3-AMP) pathway of skeletal muscle of younger heart failure (HF) patients. It now seems exceptionally logical and opportune to apply these insights to older HF patients and to delineate mechanisms of disease and aging that respond to nitrite therapy.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (2)

• Skeletal Muscle Bioenergetics- Polymerase Chain Reaction (PCR)

  Obtained via analysis of skeletal muscle biopsy of the vastus lateralis, Polymerase chain reaction (PCR) to assess pertinent gene expression within the pathways of ubiquitin \[muscle ring finger protein 1 (MuRF), Atrogin1, Forkhead Box 03 (FoxO)\], additionally Fibronectin type III domain-containing protein 5, the precursor of irisin (FNDC5), Peroxisome proliferator-activated receptor gamma co activator 1-alpha (PGC1α), and Sirtuin 3 were assessed.

  Baseline; PRE and 4 weeks; POST

• Skeletal Muscle Bioenergetics - Mitochondrial Function

  Obtained via analysis of skeletal muscle biopsy of the vastus lateralis, Mitochondrial function was assessed using respirometry (State 3.12).

  Baseline; PRE and 4 weeks; POST

Secondary Outcomes (9)

• Serology-platelet Bioenergetics

  Baseline; PRE and 4 weeks; POST

• Measures of Physical Function- Cardiopulmonary Exercise Test (CPX)

  Baseline; PRE and 4 weeks; POST

• Measures of Physical Function- Gait Speed

  Baseline; PRE and 4 weeks; POST

• Measures of Physical Function- Handgrip

  Baseline; PRE and 4 weeks; POST

• Measures of Physical Function- Balance

  Baseline; PRE and 4 weeks; POST

Study Arms (3)

Healthy control

EXPERIMENTAL

10 healthy adults, age 70 or older to receive 14 Nitrogen (14N) sodium nitrite, 40 mg tid

Drug: 14 N Sodium Nitrite

HFpEF

EXPERIMENTAL

10 adults with heart failure and preserved ejection fraction age 70 or older to receive 14N sodium nitrite, 20 or 40 mg tid depending on dose stratification for safety

Drug: 14 N Sodium Nitrite

HFrEF

EXPERIMENTAL

10 adults with heart failure and reduced ejection fraction aged 70 or older to receive 14N sodium nitrite, 20 or 40 mg tid depending on dose stratification for safety

Drug: 14 N Sodium Nitrite

Interventions

14 N Sodium Nitrite DRUG

oral formulation of sodium nitrite 40 mg three times daily for 4 weeks

Also known as: sodium nitrite

HFpEF; HFrEF; Healthy control

Eligibility Criteria

• Age: 70 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Older Adult (65+)

You may qualify if:

• New York Heart Association (NYHA) class II or III for the previous three months despite a minimum of 6 weeks of treatment. Echo criteria will be confirmed as part of the initial study assessment.
• Age ≥70 years
• HFrEF patients left ventricular ejection fraction (LVEF) ≤40%
• HFpEF patients LVEF\>40%, may include E/E' \>8, left atrial size\>40 mL/m2
• Optimal therapy according to American Heart Association (AHA)/American College of Cardiology(ACC) and Heart Failure Society of America (HFSa) HFrEF guidelines, including treatment with angiotensin-converting enzyme inhibitor (ACEI) and beta-blocker therapy (for at least 6 weeks), or have documented reason for variation, including medication intolerance, contraindication, patient preference, or personal physician's judgment.
• Patients using aspirin (ASA) will be eligible, but asked to hold the medication for 48 hours prior to biopsy. This technique has previously been used with consistent safety. Patients will also be asked to avoid non-steroidal anti-inflammatory medications (NSAIDs) for 48 hours prior to the biopsy.
• Patients using anti-thrombin and anti-platelet therapy will plan to modify prior to muscle biopsies individually in coordination with the participant's primary cardiologist.
• Age ≥70 years
• Absence of any type of cardiovascular disease.
• Absence of diabetes or other chronic disease processes

You may not qualify if:

• Allergy to lidocaine
• Dementia
• End-stage malignancy
• Orthopedic exercise limitation
• Chronic use of oral corticosteroids or other medications that affect muscle function.
• Chronic ethyl alcohol (ETOH) or drug dependency.
• Any bleeding disorder that would contraindicate biopsy such as history of clinically significant bleeding diathesis (e.g., Hemophilia A or B, Von Willebrand's Disease or congenital Factor VII deficiency).
• Psychiatric hospitalization within the last 3 months
• Major cardiovascular event or procedure within the prior 6 weeks.
• HF secondary to significant uncorrected primary valvular disease (except mitral regurgitation secondary to left ventricular dysfunction). If valve replacement has been performed, patient may not be enrolled for 12 months after this procedure.
• Severe valvular heart disease
• Mechanical valve replacement requiring warfarin
• Currently taking clopidogrel for a recent stent placement and/or a complex atherosclerotic lesion such that holding clopidogrel creates disproportionate risk.
• ICD (Internal cardiodefibrillator) device with heart rate limits that prohibit exercise assessments. Referring physicians will be provided with an opportunity to reprogram devices so that patients can participate.

Sponsors & Collaborators

• Gladwin, Mark, MD: lead

Study Sites (1)

UPMC Montefiore Hospital

Pittsburgh, Pennsylvania, 15213, United States

Location

MeSH Terms

Conditions

Heart Failure

Interventions

Sodium Nitrite

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Nitrites; Nitrous Acid; Nitrogen Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Daniel E. Forman - Chief of a section of Geriatrics Cardiology
• Organization: University of Pittsburgh

formand@pitt.edu

412-864-2507

Study Officials

• Daniel Forman, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

• Mark Gladwin, MD

  University of Pittsburgh

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDIV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Healthy Controls vs Heart Failure with reduced Ejection Fraction (HFrEF) vs Heart Failure with preserved Ejection Fraction (HFpEF) on four weeks of nitrite treatment tid.

Study Record Dates

• First Submitted: May 12, 2015
• First Posted: May 29, 2015
• Study Start: January 8, 2016
• Primary Completion: March 6, 2017
• Study Completion: March 6, 2017
• Last Updated: September 18, 2018
• Results First Posted: July 17, 2018

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)