Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF

NCT02256345 | Completed Phase 2 Results

• 1 other identifier: 01340
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

This study will be performed to determine the safety, tolerability, and dose-response to inorganic nitrate on exercise capacity in HFpEF. There are two primary goals for this study:

1. 1.Determine the population-specific pharmacokinetics and dose of KNO3 that can be safely given to subjects with HFpEF.
2. 2.Determine if there is a dose-response effect of nitrate supplementation on exercise capacity, evidenced by peak oxygen consumption (peak VO2), and physiologic adaptations to exercise.

Conditions

Heart Failure; Diastolic Heart Failure

Outcome Measures

Primary Outcomes (1)

• Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose

  Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise.

  Baseline, end of week 1, end of week 2

Secondary Outcomes (3)

• Change in Vasodilatory Reserve for Each Dose

  Baseline, end of week 1, end of week 2

• Change in Mitochondrial Oxidative Capacity for Each Dose

  Baseline, end of week 1, end of week 2

• Change in Aortic Augmentation Index

  Baseline, end of week 1, end of week 2

Study Arms (2)

KNO3 active comparator

ACTIVE COMPARATOR

KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated

Drug: KNO3

KCl placebo comparator

PLACEBO COMPARATOR

KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated

Drug: KCl

Interventions

KNO3 DRUG

Active Comparator

Also known as: Potassium Nitrate

KNO3 active comparator

KCl DRUG

Placebo Comparator

Also known as: Potassium Chloride

KCl placebo comparator

Eligibility Criteria

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

You may qualify if:

• NYHA Class II-III symptoms.
• LV EF \> 50%.
• Stable medical therapy for at least 1 month.
• Evidence of significant diastolic dysfunction, meeting the European Society of Echocardiography criteria for HFpEF.

You may not qualify if:

• Any rhythm other than sinus with native conduction.
• Inability to exercise.
• Moderate or greater valvular disease.
• Hypertrophic, infiltrative, or inflammatory cardiomyopathy.
• Pericardial disease.
• Current angina.
• Acute coronary syndrome or coronary intervention within the past 2 months.
• Primary pulmonary arteriopathy.
• Clinically significant lung disease.
• Ischemia on stress testing without subsequent revascularization.
• Treatment with phosphodiesterase inhibitors that cannot be withheld.
• Treatment with organic nitrates or allopurinol.
• Significant liver disease impacting synthetic function or volume control.
• Poor echocardiographic windows.
• eGFR \< 30 mL/min/m2 or Cr \>2.5.

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (1)

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (1)

• Zamani P, Tan V, Soto-Calderon H, Beraun M, Brandimarto JA, Trieu L, Varakantam S, Doulias PT, Townsend RR, Chittams J, Margulies KB, Cappola TP, Poole DC, Ischiropoulos H, Chirinos JA. Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction. Circ Res. 2017 Mar 31;120(7):1151-1161. doi: 10.1161/CIRCRESAHA.116.309832. Epub 2016 Dec 7.

  PMID: 27927683 DERIVED

MeSH Terms

Conditions

Heart Failure; Heart Failure, Diastolic

Interventions

potassium nitrate; Potassium Chloride

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Potassium Compounds

Limitations and Caveats

* Small sample size * Serial blood draws, which caused a decrease in hemoglobin concentration, which may have constrained the increase in VO2,peak and reduced the magnitude of the improvement in exercise capacity and quality of life.

Results Point of Contact

• Title: Julio Chirinos
• Organization: UPenn

julio.chirinos@uphs.upenn.edu

2158235800

Study Officials

• Julio A Chirinos, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2014
• First Posted: October 3, 2014
• Study Start: January 1, 2015
• Primary Completion: June 1, 2016
• Study Completion: June 1, 2016
• Last Updated: October 3, 2017
• Results First Posted: October 3, 2017

Record last verified: 2017-08

Locations

US (1)