Nitrite, Isoquercetin and Endothelial Dysfunction (NICE) Trial

Study Overview
=================
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.

Official Title
-----------------
Nitrite, Isoquercetin and Endothelial Dysfunction (NICE) Trial

Conditions
-----------------
Chronic Kidney Disease

Intervention / Treatment
-----------------
* Drug: Immediate release sodium nitrite
* Dietary Supplement: Isoquercetin
* Other: placebos


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 74 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment<br>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<br>* Immediate release sodium nitrite 40 mg by mouth twice per day<br>* Other names: TV1001;Dietary Supplement: Isoquercetin<br>* Isoquercetin 225 mg by mouth once per day<br>* Other names: 3-O-glucoside;|
| Placebo Comparator: Placebos<br>identical placebos. | Other: placebos<br>* placebos<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
eGFR, Endothelial Dysfunction, Inflammation, Oxidative Stress, Urine Albumin