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Completed

NCT Number: NCT02552888

Nitrite, Isoquercetin and Endothelial Dysfunction (NICE) Trial

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.

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Key information

Conditions

Chronic Kidney Disease Chronic Disease Disease Attributes Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Inflammation Kidney Diseases Male Urogenital Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Renal Insufficiency Renal Insufficiency, Chronic Urogenital Diseases Urologic Diseases

Age range

21 year–74 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Tulane School of Medicine

New Orleans, Louisiana, 70112, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Immediate release sodium nitrite

Drug

Immediate release sodium nitrite 40 mg by mouth twice per day

Other names: TV1001

Isoquercetin

Dietary Supplement

Isoquercetin 225 mg by mouth once per day

Other names: 3-O-glucoside

placebos

Other

placebos

Primary outcomes

  1. Mean Percentage Change in Endothelium-dependent Flow-mediated Vasodilation (FMD) Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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 outcomes

  1. Mean Change in Endothelial Function Biomarkers VCAM-1, ICAM-1, E-selectin and vWF Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  2. Mean Change in Endothelial Function Biomarker Asymmetrical DiMethylArginine (ADMA) Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  3. Mean Change in Endothelial Function Biomarker Endostatin Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  4. Mean Change in Endothelial Function Biomarker Urine Epidermal Growth Factor (UEGF) Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  5. Mean Change in Inflammatory Biomarker C-Reactive Protein (CRP) Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  6. 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

    Time frame: Baseline, 6 weeks, 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.

  7. Mean Change in Inflammatory Biomarker Interleukin-6 (IL-6) Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  8. Mean Change in Oxidative Stress Biomarker Low-density Lipoprotein (LDL) Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  9. Mean Change in Oxidative Stress Biomarker Nitrotyrosine Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

Other outcomes

  1. Mean Percentage Change in Methemoglobin Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  2. Mean Change in Isoquercetin Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  3. Mean Change in Plasma Nitrite Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  4. Mean Change in Estimated-Glomerular Filtration Rate (eGFR) Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  5. Mean Change in Lipid Profile Biomarkers Total Cholesterol, Low Density Lipoprotein (LDL)-Cholesterol and High Density Lipoprotein (HDL)-Cholesterol Over 12 Weeks

    Time frame: Baseline,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.

  6. Mean Change in Lipid Profile Biomarker Triglycerides Over 12 Weeks

    Time frame: Baseline,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.

  7. Mean Change in Hemoglobin Over 12 Weeks

    Time frame: baseline, 6 weeks, 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.

  8. Mean Change in Plasma Nitrate Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  9. Mean Change in Urinary Albumin-to-creatinine Ratios Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  10. Mean Change in Blood Pressure Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

  11. Mean Change in Pulse Over 12 Weeks

    Time frame: Baseline, 6 weeks, 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.

Sponsors and collaborators

Lead sponsor

Tulane University

Other

Collaborators

  • National Institute of General Medical Sciences (NIGMS)

Registry information

Acronym: NICE

Important dates

Study start
2016
Primary completion
2017
Study completion
2017
First posted
Sep 17, 2015
Registry last updated
Apr 20, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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