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

NCT ID: NCT02256345

Last Updated: 2017-10-03

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

12 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-01-31

Study Completion Date

2016-06-30

Brief Summary

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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. Determine the population-specific pharmacokinetics and dose of KNO3 that can be safely given to subjects with HFpEF.
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.

Detailed Description

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This study randomized subjects to either placebo (n=3) or KNO3 (n=9) given a sequential dosing regimen: 6 mmol twice daily for 1 week followed by dose escalation to 6 mmol thrice daily for 1 week). Although a primary goal of the study was to assess the safety of KNO3 and within-group changes in various end points in KNO3-treated subjects, a small number of placebo-treated (PB, n=3) subjects were included only to assess for any potential training effect on repeated exercise and Kansas City Cardiomyopathy Questionnaire (KCCQ) measurements. Potassium chloride, given in equivalent doses, was used as the PB to account for differences in blood pressure or flow that could be attributed to potassium.

The study was initially designed to be single-blinded to allow the principal investigator to be aware of arm allocation because of potential concerns for methemoglobinemia with drug administration. One investigator, who was the primary investigator responsible for supervising all visits and measurements during the study, remained blinded to treatment allocation throughout the entirety of the study. All physiological and imaging data were analyzed in a double-blind manner.

Conditions

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Heart Failure Diastolic Heart Failure

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Participants

Study Groups

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KNO3 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

Group Type ACTIVE_COMPARATOR

KNO3

Intervention Type DRUG

Active Comparator

KCl 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

Group Type PLACEBO_COMPARATOR

KCl

Intervention Type DRUG

Placebo Comparator

Interventions

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KNO3

Active Comparator

Intervention Type DRUG

KCl

Placebo Comparator

Intervention Type DRUG

Other Intervention Names

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Potassium Nitrate Potassium Chloride

Eligibility Criteria

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Inclusion Criteria

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

Exclusion Criteria

1. Any rhythm other than sinus with native conduction.
2. Inability to exercise.
3. Moderate or greater valvular disease.
4. Hypertrophic, infiltrative, or inflammatory cardiomyopathy.
5. Pericardial disease.
6. Current angina.
7. Acute coronary syndrome or coronary intervention within the past 2 months.
8. Primary pulmonary arteriopathy.
9. Clinically significant lung disease.
10. Ischemia on stress testing without subsequent revascularization.
11. Treatment with phosphodiesterase inhibitors that cannot be withheld.
12. Treatment with organic nitrates or allopurinol.
13. Significant liver disease impacting synthetic function or volume control.
14. Poor echocardiographic windows.
15. eGFR \< 30 mL/min/m2 or Cr \>2.5.
16. Current smoking.
17. Alcohol dependency.
18. History of Barret's esophagus.
19. G6PD deficiency
20. Methemoglobinemia - baseline methemoglobin level \>3% prior to any study medication.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Pennsylvania

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Julio A Chirinos, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Locations

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Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Site Status

Countries

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United States

References

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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.

Reference Type DERIVED
PMID: 27927683 (View on PubMed)

Other Identifiers

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01340

Identifier Type: -

Identifier Source: org_study_id