Heart FailurePhase 2NCT02256345
Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF
A Phase 2 study testing KNO3 and KCl in people with Heart Failure and Diastolic Heart Failure, run by University of Pennsylvania at 1 site in United States.
Trial 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. Determine the population-specific pharmacokinetics and dose of KNO3 that can be safely given to subjects with HFpEF. 2. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure, Diastolic Heart Failure
- What is being tested?
- KNO3 and KCl
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2015to Jun 2016
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 20Show fewer
- 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.
- Current smoking.
- Alcohol dependency.
- History of Barret's esophagus.
- G6PD deficiency
- Methemoglobinemia - baseline methemoglobin level >3% prior to any study medication.
Trial locations and contacts
1 site in 1 country.
United States1 site
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, 19104
About this study
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:
- Determine the population-specific pharmacokinetics and dose of KNO3 that can be safely given to subjects with HFpEF.
- 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.
Read the detailed description
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
- Heart Failure, Diastolic Heart Failure
- Being tested
- KNO3, KCl
- Medical subject headings
- Heart Failure, Heart Failure, Diastolic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
KNO3Drug
Also called Potassium Nitrate
Active Comparator
KClDrug
Also called Potassium Chloride
Placebo Comparator
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: Drug: KCl |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline, end of week 1, end of week 2
Secondary outcomes (3)
Change in Vasodilatory Reserve for Each Dose
Percent change in peak vascular resistance from rest to peak exercise
Measured: Baseline, end of week 1, end of week 2
Change in Mitochondrial Oxidative Capacity for Each Dose
Percent change in oxidative capacity (oxyhemoglobin levels) before and after occlusion
Measured: Baseline, end of week 1, end of week 2
Change in Aortic Augmentation Index
Percent change in augmentation index, whereas augmentation index at each time point (visit) is defined as the amplitude of the second peak to the first peak of the aortic pulse wave form multiplied by 100: augmentation index = (P2/P1)×100.
Measured: Baseline, end of week 1, end of week 2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Oct 2014 (estimated)
- Study startJan 2015
- Primary completionJun 2016
- Study completionJun 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- More trials run by University of PennsylvaniaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pennsylvania
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Julio A Chirinos, MD, Principal investigator, University of Pennsylvania
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02256345
- Sponsor's protocol ID
- 01340
- Status last verified
- Aug 2017
- First submitted
- 30 Sep 2014
- Last updated
- 3 Oct 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
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.
PubMed 27927683
Study at a glance
From the registry record, last updated by the sponsor on 3 Oct 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF
- ClinicalTrials.gov ID
- NCT02256345
- Acronym / sponsor ID
- 01340
- Conditions
- Heart Failure, Diastolic Heart Failure
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- University of PennsylvaniaUniversity, hospital or other
- Study start
- Jan 2015
- Primary completion
- Jun 2016 (actual)
- Study completion
- Jun 2016 (actual)
- First posted
- 3 Oct 2014 (estimated)
- Results
- Posted 3 Oct 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Determine the population-specific pharmacokinetics and dose of KNO3 that can be safely given to subjects with HFpEF.
- 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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| KNO3 active comparator | Active comparator | Drug: KNO3KNO3 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 |
| KCl placebo comparator | Placebo comparator | Drug: KClKCl 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (20 listed)
- Any rhythm other than sinus with native conduction.
- Inability to exercise.
- Moderate or greater valvular disease.
- Hypertrophic, infiltrative, or inflammatory cardiomyopathy.
- Pericardial disease.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| KNO3Also: Potassium NitrateActive Comparator | Drug | KNO3 active comparator |
| KClAlso: Potassium ChloridePlacebo Comparator | Drug | KCl placebo comparator |
Primary outcome
Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose
Time frame: Baseline, end of week 1, end of week 2
Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise.
3 secondary outcomes
Change in Vasodilatory Reserve for Each Dose
Time frame: Baseline, end of week 1, end of week 2
Change in Mitochondrial Oxidative Capacity for Each Dose
Time frame: Baseline, end of week 1, end of week 2
Change in Aortic Augmentation Index
Time frame: Baseline, end of week 1, end of week 2
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Oct 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 27927683Zamani 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Julio A Chirinos, MD principal investigator
University of Pennsylvania
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing KNO3 and KCl in people with Heart Failure and Diastolic Heart Failure, run by University of Pennsylvania at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Oct 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose (time frame: Baseline, end of week 1, end of week 2). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02256345, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Oct 2017.