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

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ClinicalTrials.gov Identifier: NCT02552888
Recruitment Status : Completed
First Posted : September 17, 2015
Results First Posted : April 20, 2021
Last Update Posted : April 20, 2021
Sponsor:
Collaborator:
National Institute of General Medical Sciences (NIGMS)
Information provided by (Responsible Party):
Tulane University

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.

Condition or disease Intervention/treatment Phase
Chronic Kidney Disease Drug: Immediate release sodium nitrite Dietary Supplement: Isoquercetin Other: placebos Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Nitrite, Isoquercetin and Endothelial Dysfunction (NICE) Trial
Study Start Date : March 2016
Actual Primary Completion Date : June 2017
Actual Study Completion Date : June 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

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 Name: TV1001

Dietary Supplement: Isoquercetin
Isoquercetin 225 mg by mouth once per day
Other Name: 3-O-glucoside

Placebo Comparator: Placebos
identical placebos.
Other: placebos
placebos




Primary Outcome Measures :
  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 Outcome Measures :
  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 Outcome Measures:
  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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years to 74 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Gender Eligibility Description:   participant eligibility is based on self-representation of gender identity.
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02552888


Locations
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United States, Louisiana
Tulane School of Medicine
New Orleans, Louisiana, United States, 70112
Sponsors and Collaborators
Tulane University
National Institute of General Medical Sciences (NIGMS)
Investigators
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Principal Investigator: Jing Chen, MD Tulane University
  Study Documents (Full-Text)

Documents provided by Tulane University:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Tulane University
ClinicalTrials.gov Identifier: NCT02552888    
Other Study ID Numbers: TulaneU
1U54GM104940 ( U.S. NIH Grant/Contract )
First Posted: September 17, 2015    Key Record Dates
Results First Posted: April 20, 2021
Last Update Posted: April 20, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: deidentified data sets may be available to other researchers.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: no end date.
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Tulane University:
Endothelial Dysfunction
Inflammation
Oxidative Stress
eGFR
Urine Albumin
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Urologic Diseases
Renal Insufficiency