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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Kidney Disease
• Intervention / Treatment: Drug: Immediate release sodium nitrite; Dietary supplement: Isoquercetin; Other: placebos

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.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane School Of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 74 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: treatment; Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day.	Drug: Immediate release sodium nitrite; Immediate release sodium nitrite 40 mg by mouth twice per day; Other Names: TV1001; Dietary supplement: Isoquercetin; Isoquercetin 225 mg by mouth once per day; Other Names: 3-O-glucoside
Placebo Comparator: Placebos; identical placebos.	Other: placebos; placebos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 6 weeks, 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 6 weeks, 12 weeks
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.	Baseline, 6 weeks, 12 weeks
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.	Baseline, 6 weeks, 12 weeks
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.	Baseline, 6 weeks, 12 weeks
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.	Baseline, 6 weeks, 12 weeks
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.	Baseline, 6 weeks, 12 weeks
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.	Baseline, 6 weeks, 12 weeks
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.	Baseline, 6 weeks, 12 weeks
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.	Baseline, 6 weeks, 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Percentage Change in Methemoglobin Over 12 Weeks	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.	Baseline, 6 weeks, 12 weeks
Mean Change in Isoquercetin Over 12 Weeks	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.	Baseline, 6 weeks, 12 weeks
Mean Change in Plasma Nitrite Over 12 Weeks	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.	Baseline, 6 weeks, 12 weeks
Mean Change in Estimated-Glomerular Filtration Rate (eGFR) Over 12 Weeks	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.	Baseline, 6 weeks, 12 weeks
Mean Change in Lipid Profile Biomarkers Total Cholesterol, Low Density Lipoprotein (LDL)-Cholesterol and High Density Lipoprotein (HDL)-Cholesterol Over 12 Weeks	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.	Baseline,12 weeks
Mean Change in Lipid Profile Biomarker Triglycerides Over 12 Weeks	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.	Baseline,12 weeks
Mean Change in Hemoglobin Over 12 Weeks	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.	baseline, 6 weeks, 12 weeks
Mean Change in Plasma Nitrate Over 12 Weeks	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.	Baseline, 6 weeks, 12 weeks
Mean Change in Urinary Albumin-to-creatinine Ratios Over 12 Weeks	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.	Baseline, 6 weeks, 12 weeks
Mean Change in Blood Pressure Over 12 Weeks	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.	Baseline, 6 weeks, 12 weeks
Mean Change in Pulse Over 12 Weeks	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.	Baseline, 6 weeks, 12 weeks

Collaborators and Investigators

• Sponsor: Tulane University
• Collaborators: National Institute of General Medical Sciences (NIGMS)
• Investigators: Principal Investigator: Jing Chen, MD, Tulane University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: September 10, 2015
• First Submitted That Met QC Criteria: September 16, 2015
• First Posted (Estimate): September 17, 2015

Study Record Updates

• Last Update Posted (Actual): April 20, 2021
• Last Update Submitted That Met QC Criteria: March 23, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Inflammation; Oxidative Stress; eGFR; Endothelial Dysfunction; Urine Albumin
• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic
• Other Study ID Numbers: TulaneU; 1U54GM104940 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No