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Nitrite, Isoquercetin and Endothelial Dysfunction (NICE) Trial (NICE)

Primary Purpose

Chronic Kidney Disease

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Immediate release sodium nitrite
Isoquercetin
placebos
Sponsored by
Tulane University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Kidney Disease focused on measuring Endothelial Dysfunction, Inflammation, Oxidative Stress, eGFR, Urine Albumin

Eligibility Criteria

21 Years - 74 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Men and women aged 21-74 years old with any race/ethnicity background
  • CKD as defined by an eGFR <60 ml/min/1.73 m2 or urinary albumin to creatinine ratio ≥ 30 mg/g or protein to creatinine ratio ≥150 mg/g.
  • Systolic BP≥120 and <180 mmHg and/or diastolic BP≥70 and <110 mmHg

Exclusion Criteria:

  • Allergic to organic nitrite, isoquercetin, niacin, or vitamin C
  • Institutionalized (e.g., prisoner, nursing home or skilled nursing facility resident)
  • Unable or unwilling to give consent
  • Known HIV infection and/or AIDS
  • Pregnant or lactating women
  • Currently on dialysis
  • Previous or current organ or bone marrow transplant
  • Receiving immunosuppressive treatment or other immunotherapy
  • Receiving chemotherapy or alkylating agents for systemic cancer
  • Recent acute myocardial infarction, cerebrovascular accidence or transient ischemic attack, or hospitalization in 3 months
  • Acute kidney injury within the previous 3 months
  • Currently taking a phosphodiesterase-5 enzyme inhibitor, such as Viagra
  • History of chronic headaches
  • Chronically receiving fluoroguinolones, cyclosporin (neural, sandimmune), nitrate drug, NSAIDS ( except aspirin ≤ 81 mg daily), allopurinol or uloric, meperidine and related central nervous system (CNS) depressants, oral glucocorticoids, and not willing or able to stop during study period.
  • Active infection (i.e. systemic or osteomyelitis)
  • Class III or IV heart failure
  • History of hemolytic anemia including sickle cell disease
  • Hemoglobin <10
  • History of chronic obstructive pulmonary disease (COPD)
  • Have a positive screen for glucose-6-phosphate dehydrogenase (G6PD) deficiency at screening
  • Involvement in other clinical trials
  • Current alcohol or other substance abuse
  • Current smokers
  • Unwillingness to stop flavonoid supplementation
  • Unwillingness to stop nitrate and/or nitrite supplementation

Sites / Locations

  • Tulane School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

treatment

Placebos

Arm Description

Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day.

identical placebos.

Outcomes

Primary Outcome Measures

Mean Percentage Change in Endothelium-dependent Flow-mediated Vasodilation (FMD) Over 12 Weeks
FMD was measured using high resolution ultrasound on the brachial artery. FMD was calculated as the maximal percentage change in vessel size during hyperemia . The mean changes between baseline, 6 weeks and 12 weeks in FMD with 95% CI were calculated using linear mixed effects model.

Secondary Outcome Measures

Mean Change in Endothelial Function Biomarkers VCAM-1, ICAM-1, E-selectin and vWF Over 12 Weeks
A blood sample was drawn for each participant to measure the levels of Vascular Adhesion Molecule-1(VCAM-1), Intercellular Adhesion Molecule-1 (ICAM-1), E-selectin, and von Willebrand Factor (vWF). The mean changes between baseline, 6 weeks and 12 weeks in VCAM-1, ICAM-1, E-selectin and vWF with 95% CI were calculated using linear mixed effects model.
Mean Change in Endothelial Function Biomarker Asymmetrical DiMethylArginine (ADMA) Over 12 Weeks
A blood sample was drawn for each participant to measure the levels of Asymmetrical DiMethylArginine (ADMA). The mean changes between baseline, 6 weeks and 12 weeks in ADMA with 95% CI were calculated using linear mixed effects model.
Mean Change in Endothelial Function Biomarker Endostatin Over 12 Weeks
A blood sample was drawn for each participant to measure the levels of endostatin. The mean changes between baseline, 6 weeks and 12 weeks in endostatin with 95% CI were calculated using linear mixed effects model, and the log transformed endostatin was calculated.
Mean Change in Endothelial Function Biomarker Urine Epidermal Growth Factor (UEGF) Over 12 Weeks
A urine sample was taken for each participant to measure the levels of Urine Epidermal Growth Factor (UEGF). The mean changes between baseline, 6 weeks and 12 weeks in UEGF with 95% CI were calculated using linear mixed effects model, and the log transformed Urine EGF/creatinine ratio was calculated.
Mean Change in Inflammatory Biomarker C-Reactive Protein (CRP) Over 12 Weeks
A blood sample was drawn for each participant to measure the levels of C-Reactive Protein (CRP). The mean changes between baseline, 6 weeks and 12 weeks in CRP with 95% CI were calculated using linear mixed effects model.
Mean Change in Inflammatory Biomarkers Tumor Necrosis Factor-α (TNF-a), Interleukin-17 (IL-17), Interleukin-1β (IL-1beta), and Monocyte Chemoattractant Protein-1 (MCP-1) Over 12 Weeks
A blood sample was drawn for each participant to measure the levels of Tumor Necrosis Factor-α (TNF-a), interleukin-17 (IL-17), interleukin-1β (IL-1beta), and Monocyte Chemoattractant Protein-1 (MCP-1). The mean changes between baseline, 6 weeks and 12 weeks in TNF-a, IL-17, IL-1beta, MCP-1 with 95% CI were calculated using linear mixed effects model.
Mean Change in Inflammatory Biomarker Interleukin-6 (IL-6) Over 12 Weeks
A blood sample was drawn for each participant to measure the levels of interleukin-6 (IL-6). The mean changes between baseline, 6 weeks and 12 weeks in interleukin-6 (IL-6) with 95% CI were calculated using linear mixed effects model, and the log transformed IL-6 was calculated.
Mean Change in Oxidative Stress Biomarker Low-density Lipoprotein (LDL) Over 12 Weeks
A blood sample was drawn for each participant to measure the levels of low-density lipoprotein (LDL). The mean changes between baseline, 6 weeks and 12 weeks in LDL with 95% CI were calculated using linear mixed effects model.
Mean Change in Oxidative Stress Biomarker Nitrotyrosine Over 12 Weeks
A blood sample was drawn for each participant to measure the levels of nitrotyrosine. The mean changes between baseline, 6 weeks and 12 weeks in nitrotyrosine with 95% CI were calculated using linear mixed effects model.

Full Information

First Posted
September 10, 2015
Last Updated
March 23, 2021
Sponsor
Tulane University
Collaborators
National Institute of General Medical Sciences (NIGMS)
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1. Study Identification

Unique Protocol Identification Number
NCT02552888
Brief Title
Nitrite, Isoquercetin and Endothelial Dysfunction (NICE) Trial
Acronym
NICE
Official Title
Nitrite, Isoquercetin and Endothelial Dysfunction (NICE) Trial
Study Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Completed
Study Start Date
March 2016 (undefined)
Primary Completion Date
June 2017 (Actual)
Study Completion Date
June 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Tulane University
Collaborators
National Institute of General Medical Sciences (NIGMS)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The proposed randomized controlled trial will test the safety and efficacy of combination therapy with sodium nitrite and isoquercetin on endothelial function and inflammation among patients with chronic kidney disease.
Detailed Description
The proposed randomized controlled trial will test the safety and efficacy of combination therapy with sodium nitrite and isoquercetin on endothelial function and inflammation among patients with chronic kidney disease. Investigators will recruit 70 albuminuric CKD patients and randomly assign participants to combination therapy with sodium nitrite and isoquercetin or placebo for three months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Kidney Disease
Keywords
Endothelial Dysfunction, Inflammation, Oxidative Stress, eGFR, Urine Albumin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
70 (Actual)

8. Arms, Groups, and Interventions

Arm Title
treatment
Arm Type
Experimental
Arm Description
Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day.
Arm Title
Placebos
Arm Type
Placebo Comparator
Arm Description
identical placebos.
Intervention Type
Drug
Intervention Name(s)
Immediate release sodium nitrite
Other Intervention Name(s)
TV1001
Intervention Description
Immediate release sodium nitrite 40 mg by mouth twice per day
Intervention Type
Dietary Supplement
Intervention Name(s)
Isoquercetin
Other Intervention Name(s)
3-O-glucoside
Intervention Description
Isoquercetin 225 mg by mouth once per day
Intervention Type
Other
Intervention Name(s)
placebos
Intervention Description
placebos
Primary Outcome Measure Information:
Title
Mean Percentage Change in Endothelium-dependent Flow-mediated Vasodilation (FMD) Over 12 Weeks
Description
FMD was measured using high resolution ultrasound on the brachial artery. FMD was calculated as the maximal percentage change in vessel size during hyperemia . The mean changes between baseline, 6 weeks and 12 weeks in FMD with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Secondary Outcome Measure Information:
Title
Mean Change in Endothelial Function Biomarkers VCAM-1, ICAM-1, E-selectin and vWF Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of Vascular Adhesion Molecule-1(VCAM-1), Intercellular Adhesion Molecule-1 (ICAM-1), E-selectin, and von Willebrand Factor (vWF). The mean changes between baseline, 6 weeks and 12 weeks in VCAM-1, ICAM-1, E-selectin and vWF with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Endothelial Function Biomarker Asymmetrical DiMethylArginine (ADMA) Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of Asymmetrical DiMethylArginine (ADMA). The mean changes between baseline, 6 weeks and 12 weeks in ADMA with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Endothelial Function Biomarker Endostatin Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of endostatin. The mean changes between baseline, 6 weeks and 12 weeks in endostatin with 95% CI were calculated using linear mixed effects model, and the log transformed endostatin was calculated.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Endothelial Function Biomarker Urine Epidermal Growth Factor (UEGF) Over 12 Weeks
Description
A urine sample was taken for each participant to measure the levels of Urine Epidermal Growth Factor (UEGF). The mean changes between baseline, 6 weeks and 12 weeks in UEGF with 95% CI were calculated using linear mixed effects model, and the log transformed Urine EGF/creatinine ratio was calculated.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Inflammatory Biomarker C-Reactive Protein (CRP) Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of C-Reactive Protein (CRP). The mean changes between baseline, 6 weeks and 12 weeks in CRP with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Inflammatory Biomarkers Tumor Necrosis Factor-α (TNF-a), Interleukin-17 (IL-17), Interleukin-1β (IL-1beta), and Monocyte Chemoattractant Protein-1 (MCP-1) Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of Tumor Necrosis Factor-α (TNF-a), interleukin-17 (IL-17), interleukin-1β (IL-1beta), and Monocyte Chemoattractant Protein-1 (MCP-1). The mean changes between baseline, 6 weeks and 12 weeks in TNF-a, IL-17, IL-1beta, MCP-1 with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Inflammatory Biomarker Interleukin-6 (IL-6) Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of interleukin-6 (IL-6). The mean changes between baseline, 6 weeks and 12 weeks in interleukin-6 (IL-6) with 95% CI were calculated using linear mixed effects model, and the log transformed IL-6 was calculated.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Oxidative Stress Biomarker Low-density Lipoprotein (LDL) Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of low-density lipoprotein (LDL). The mean changes between baseline, 6 weeks and 12 weeks in LDL with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Oxidative Stress Biomarker Nitrotyrosine Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of nitrotyrosine. The mean changes between baseline, 6 weeks and 12 weeks in nitrotyrosine with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Other Pre-specified Outcome Measures:
Title
Mean Percentage Change in Methemoglobin Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of methemoglobin. The mean percentage change between baseline, 6 weeks and 12 weeks in methemoglobin with 95% CI was calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Isoquercetin Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of isoquercetin. The mean changes between baseline, 6 weeks and 12 weeks in isoquercetin with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Plasma Nitrite Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of plasma nitrite. The mean changes between baseline, 6 weeks and 12 weeks in plasma nitrite with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Estimated-Glomerular Filtration Rate (eGFR) Over 12 Weeks
Description
Estimated-Glomerular Filtration Rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. The equation is GFR = 141 * min(Scr/κ,1)α * max(Scr/κ, 1)-1.209 * 0.993Age * 1.018 [if female] * 1.159 [if black]. Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. The mean changes between baseline, 6 weeks and 12 weeks in eGFR with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Lipid Profile Biomarkers Total Cholesterol, Low Density Lipoprotein (LDL)-Cholesterol and High Density Lipoprotein (HDL)-Cholesterol Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of total cholesterol, Low Density Lipoprotein (LDL)-cholesterol and High Density Lipoprotein (HDL)-cholesterol. The mean changes between baseline and 12 weeks in total cholesterol, Low Density Lipoprotein (LDL)-cholesterol and High Density Lipoprotein (HDL)-cholesterol with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline,12 weeks
Title
Mean Change in Lipid Profile Biomarker Triglycerides Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of triglycerides. The mean changes between baseline and 12 weeks in triglycerides with 95% CI were calculated using linear mixed effects model, and the log transformed triglyceride was calculated.
Time Frame
Baseline,12 weeks
Title
Mean Change in Hemoglobin Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of hemoglobin. The mean changes between baseline, 6 weeks and 12 weeks in hemoglobin with 95% CI were calculated using linear mixed effects model.
Time Frame
baseline, 6 weeks, 12 weeks
Title
Mean Change in Plasma Nitrate Over 12 Weeks
Description
A blood sample was drawn for each participant to measure the levels of plasma nitrate. The mean changes between baseline, 6 weeks and 12 weeks in plasma nitrate with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Urinary Albumin-to-creatinine Ratios Over 12 Weeks
Description
A urine sample was taken for each participant to measure the levels of urinary albumin-to-creatinine ratios. The mean changes between baseline, 6 weeks and 12 weeks in urinary albumin-to-creatinine ratios with 95% CI were calculated using linear mixed effects model, and the log transformed urinary albumin-to-creatinine ratios was calculated.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Blood Pressure Over 12 Weeks
Description
Blood pressure was measured using the OMRON HEM-907 XL BP Monitor per standard protocol by trained and certified research staff. The mean changes between baseline, 6 weeks and 12 weeks in blood pressure with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks
Title
Mean Change in Pulse Over 12 Weeks
Description
Pulse was measured at the brachial artery per standard protocol by trained and certified research staff. The mean changes between baseline, 6 weeks and 12 weeks in pulse with 95% CI were calculated using linear mixed effects model.
Time Frame
Baseline, 6 weeks, 12 weeks

10. Eligibility

Sex
All
Gender Based
Yes
Gender Eligibility Description
participant eligibility is based on self-representation of gender identity.
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
74 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men and women aged 21-74 years old with any race/ethnicity background CKD as defined by an eGFR <60 ml/min/1.73 m2 or urinary albumin to creatinine ratio ≥ 30 mg/g or protein to creatinine ratio ≥150 mg/g. Systolic BP≥120 and <180 mmHg and/or diastolic BP≥70 and <110 mmHg Exclusion Criteria: Allergic to organic nitrite, isoquercetin, niacin, or vitamin C Institutionalized (e.g., prisoner, nursing home or skilled nursing facility resident) Unable or unwilling to give consent Known HIV infection and/or AIDS Pregnant or lactating women Currently on dialysis Previous or current organ or bone marrow transplant Receiving immunosuppressive treatment or other immunotherapy Receiving chemotherapy or alkylating agents for systemic cancer Recent acute myocardial infarction, cerebrovascular accidence or transient ischemic attack, or hospitalization in 3 months Acute kidney injury within the previous 3 months Currently taking a phosphodiesterase-5 enzyme inhibitor, such as Viagra History of chronic headaches Chronically receiving fluoroguinolones, cyclosporin (neural, sandimmune), nitrate drug, NSAIDS ( except aspirin ≤ 81 mg daily), allopurinol or uloric, meperidine and related central nervous system (CNS) depressants, oral glucocorticoids, and not willing or able to stop during study period. Active infection (i.e. systemic or osteomyelitis) Class III or IV heart failure History of hemolytic anemia including sickle cell disease Hemoglobin <10 History of chronic obstructive pulmonary disease (COPD) Have a positive screen for glucose-6-phosphate dehydrogenase (G6PD) deficiency at screening Involvement in other clinical trials Current alcohol or other substance abuse Current smokers Unwillingness to stop flavonoid supplementation Unwillingness to stop nitrate and/or nitrite supplementation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jing Chen, MD
Organizational Affiliation
Tulane University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Tulane School of Medicine
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
deidentified data sets may be available to other researchers.
IPD Sharing Time Frame
no end date.
IPD Sharing Access Criteria
The de-identified patient level data will be provided directly to the researcher in a secure manner, and the researcher is responsible for protecting the confidentiality and integrity of the data while the research is conducted.
Citations:
PubMed Identifier
33023894
Citation
Chen J, Hamm LL, Bundy JD, Kumbala DR, Bodana S, Chandra S, Chen CS, Starcke CC, Guo Y, Schaefer CM, Lustigova E, Mahone E, Vadalia AM, Livingston T, Obst K, Hernandez J, Bokhari SR, Kleinpeter M, Alper AB, Lukitsch I, He H, Nieman DC, He J. Combination Treatment with Sodium Nitrite and Isoquercetin on Endothelial Dysfunction among Patients with CKD: A Randomized Phase 2 Pilot Trial. Clin J Am Soc Nephrol. 2020 Nov 6;15(11):1566-1575. doi: 10.2215/CJN.02020220. Epub 2020 Oct 6.
Results Reference
derived

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Nitrite, Isoquercetin and Endothelial Dysfunction (NICE) Trial

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