Trial Outcomes & Findings for Nitrite, Isoquercetin and Endothelial Dysfunction (NICE) Trial (NCT NCT02552888)

NCT ID: NCT02552888

Last Updated: 2021-04-20

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 70 participants
• Primary outcome timeframe: Baseline, 6 weeks, 12 weeks
• Results posted on: 2021-04-20

Participant Flow

Participant milestones

Measure	Treatment Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos identical placebos. placebos: placebos
Overall Study STARTED	35	35
Overall Study COMPLETED	34	34
Overall Study NOT COMPLETED	1	1

Reasons for withdrawal

Measure	Treatment Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos identical placebos. placebos: placebos
Overall Study Lost to Follow-up	1	1

Baseline Characteristics

Nitrite, Isoquercetin and Endothelial Dysfunction (NICE) Trial

Baseline characteristics by cohort

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos	Total n=70 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	19 Participants n=5 Participants	19 Participants n=7 Participants	38 Participants n=5 Participants
Age, Categorical >=65 years	16 Participants n=5 Participants	16 Participants n=7 Participants	32 Participants n=5 Participants
Age, Continuous	61.3 years STANDARD_DEVIATION 10.4 • n=5 Participants	62.2 years STANDARD_DEVIATION 10.2 • n=7 Participants	61.8 years STANDARD_DEVIATION 10.3 • n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	13 Participants n=7 Participants	26 Participants n=5 Participants
Sex: Female, Male Male	22 Participants n=5 Participants	22 Participants n=7 Participants	44 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	17 Participants n=5 Participants	15 Participants n=7 Participants	32 Participants n=5 Participants
Race (NIH/OMB) White	16 Participants n=5 Participants	20 Participants n=7 Participants	36 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	35 participants n=5 Participants	35 participants n=7 Participants	70 participants n=5 Participants
Baseline Metabolic Panel of Study Participants by Treatment Allocation Fasting plasma glucose, mean, mg/dL	119 mg/dL STANDARD_DEVIATION 44 • n=5 Participants	124 mg/dL STANDARD_DEVIATION 70 • n=7 Participants	121.5 mg/dL STANDARD_DEVIATION 57 • n=5 Participants
Baseline Metabolic Panel of Study Participants by Treatment Allocation Total cholesterol, mean, mg/dL	178 mg/dL STANDARD_DEVIATION 43 • n=5 Participants	171 mg/dL STANDARD_DEVIATION 50 • n=7 Participants	174.5 mg/dL STANDARD_DEVIATION 46.5 • n=5 Participants
Baseline Metabolic Panel of Study Participants by Treatment Allocation HDL-cholesterol, mean, mg/dL	48 mg/dL STANDARD_DEVIATION 13 • n=5 Participants	47 mg/dL STANDARD_DEVIATION 14 • n=7 Participants	47.5 mg/dL STANDARD_DEVIATION 13.5 • n=5 Participants
Baseline Metabolic Panel of Study Participants by Treatment Allocation LDL-cholesterol, mean, mg/dL	107 mg/dL STANDARD_DEVIATION 34 • n=5 Participants	100 mg/dL STANDARD_DEVIATION 37 • n=7 Participants	103.5 mg/dL STANDARD_DEVIATION 35.5 • n=5 Participants
Baseline Blood Pressure of Study Participants by Treatment Allocation Systolic blood pressure, mean, mmHg	129 mmHg STANDARD_DEVIATION 15 • n=5 Participants	129 mmHg STANDARD_DEVIATION 15 • n=7 Participants	129 mmHg STANDARD_DEVIATION 15 • n=5 Participants
Baseline Blood Pressure of Study Participants by Treatment Allocation Diastolic blood pressure, mean, mmHg	73 mmHg STANDARD_DEVIATION 7 • n=5 Participants	75 mmHg STANDARD_DEVIATION 11 • n=7 Participants	74 mmHg STANDARD_DEVIATION 9 • n=5 Participants
Baseline Body Mass Index of Study Participants by Treatment Allocation	30.9 kg/m^2 STANDARD_DEVIATION 5.6 • n=5 Participants	32.5 kg/m^2 STANDARD_DEVIATION 5.7 • n=7 Participants	31.7 kg/m^2 STANDARD_DEVIATION 5.65 • n=5 Participants
Baseline Estimated Glomerular Filtration Rate of Study Participants by Treatment Allocation	51 ml/min/1.73m^2 STANDARD_DEVIATION 22 • n=5 Participants	45 ml/min/1.73m^2 STANDARD_DEVIATION 16 • n=7 Participants	48 ml/min/1.73m^2 STANDARD_DEVIATION 19 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Percentage Change in Endothelium-dependent Flow-mediated Vasodilation (FMD) Over 12 Weeks	1.1 Percentage change Interval -0.1 to 2.3	0.3 Percentage change Interval -0.9 to 1.5

SECONDARY outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Endothelial Function Biomarkers VCAM-1, ICAM-1, E-selectin and vWF Over 12 Weeks vWF, ng/mL	-683 ng/mL Interval -3784.0 to 2419.0	2744 ng/mL Interval -328.0 to 5815.0
Mean Change in Endothelial Function Biomarkers VCAM-1, ICAM-1, E-selectin and vWF Over 12 Weeks ICAM, ng/mL	-16.1 ng/mL Interval -41.5 to 9.3	-4.0 ng/mL Interval -29.0 to 21.0
Mean Change in Endothelial Function Biomarkers VCAM-1, ICAM-1, E-selectin and vWF Over 12 Weeks VCAM-1, ng/mL	-22.2 ng/mL Interval -49.3 to 5.0	-10.8 ng/mL Interval -37.5 to 15.9
Mean Change in Endothelial Function Biomarkers VCAM-1, ICAM-1, E-selectin and vWF Over 12 Weeks E-Selecint, ng/mL	-0.32 ng/mL Interval -3.14 to 2.5	1.06 ng/mL Interval -1.73 to 3.84

SECONDARY outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Endothelial Function Biomarker Asymmetrical DiMethylArginine (ADMA) Over 12 Weeks	0.03 umol/mL Interval -0.02 to 0.08	0.02 umol/mL Interval -0.03 to 0.07

SECONDARY outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Endothelial Function Biomarker Endostatin Over 12 Weeks	-0.02 log (ng/mL) Interval -0.08 to 0.05	-0.01 log (ng/mL) Interval -0.08 to 0.05

SECONDARY outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Endothelial Function Biomarker Urine Epidermal Growth Factor (UEGF) Over 12 Weeks	-0.01 log (pg/g) Interval -0.39 to 0.37	0.23 log (pg/g) Interval -0.14 to 0.61

SECONDARY outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Inflammatory Biomarker C-Reactive Protein (CRP) Over 12 Weeks	0.05 mg/mL Interval -0.31 to 0.42	-0.02 mg/mL Interval -0.38 to 0.33

SECONDARY outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
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 IL-17, pg/mL	-0.72 pg/mL Interval -1.8 to 0.36	0.01 pg/mL Interval -1.05 to 1.08
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 IL-1 beta, pg/mL	-17.1 pg/mL Interval -77.5 to 43.4	-30.5 pg/mL Interval -90.0 to 29.0
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 TNF-a, pg/mL	-0.04 pg/mL Interval -0.2 to 0.12	-0.04 pg/mL Interval -0.2 to 0.12
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 MCP-1, pg/mL	-6.0 pg/mL Interval -25.0 to 13.0	0.6 pg/mL Interval -18.0 to 19.3

SECONDARY outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Inflammatory Biomarker Interleukin-6 (IL-6) Over 12 Weeks	0.07 log (pg/mL) Interval -0.06 to 0.2	-0.17 log (pg/mL) Interval -0.3 to -0.04

SECONDARY outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Oxidative Stress Biomarker Low-density Lipoprotein (LDL) Over 12 Weeks	-1.7 ng/mL Interval -3.9 to 0.5	-0.3 ng/mL Interval -2.4 to 1.9

SECONDARY outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Oxidative Stress Biomarker Nitrotyrosine Over 12 Weeks	-10.9 pg/mL Interval -96.9 to 75.2	62.2 pg/mL Interval -22.6 to 147.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Percentage Change in Methemoglobin Over 12 Weeks	-0.06 Percentage change Interval -0.11 to -0.01	-0.05 Percentage change Interval -0.11 to -0.01

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Isoquercetin Over 12 Weeks	166 ug/L Interval 102.0 to 230.0	11.7 ug/L Interval -51.1 to 74.5

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Plasma Nitrite Over 12 Weeks	-0.07 micromol/L Interval -0.2 to 0.05	-0.11 micromol/L Interval -0.23 to 0.01

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Estimated-Glomerular Filtration Rate (eGFR) Over 12 Weeks	0.1 mL/min/1.73 m^2 Interval -2.3 to 2.5	0.2 mL/min/1.73 m^2 Interval -2.2 to 2.6

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline,12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Lipid Profile Biomarkers Total Cholesterol, Low Density Lipoprotein (LDL)-Cholesterol and High Density Lipoprotein (HDL)-Cholesterol Over 12 Weeks Total Cholesterol, mg/dL	-1.6 mg/dL Interval -10.5 to 7.2	3.9 mg/dL Interval -4.9 to 12.8
Mean Change in Lipid Profile Biomarkers Total Cholesterol, Low Density Lipoprotein (LDL)-Cholesterol and High Density Lipoprotein (HDL)-Cholesterol Over 12 Weeks LDL-cholesterol, mg/dL	-1.9 mg/dL Interval -7.4 to 3.7	0.9 mg/dL Interval -7.4 to 3.7
Mean Change in Lipid Profile Biomarkers Total Cholesterol, Low Density Lipoprotein (LDL)-Cholesterol and High Density Lipoprotein (HDL)-Cholesterol Over 12 Weeks HDL-cholesterol, mg/dL	0.9 mg/dL Interval -1.7 to 3.4	2.2 mg/dL Interval -0.4 to 4.7

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline,12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Lipid Profile Biomarker Triglycerides Over 12 Weeks	-0.09 log (mg/dL) Interval -0.4 to 4.7	-0.01 log (mg/dL) Interval -0.14 to 0.11

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Hemoglobin Over 12 Weeks	-0.25 g/dL Interval -0.46 to -0.04	-0.13 g/dL Interval -0.34 to 0.07

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Plasma Nitrate Over 12 Weeks	15.4 umol/L Interval 5.9 to 25.0	-6.3 umol/L Interval -15.7 to 3.1

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Urinary Albumin-to-creatinine Ratios Over 12 Weeks	0.04 log (mg/g) Interval -0.27 to 0.36	0.02 log (mg/g) Interval -0.29 to 0.33

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Blood Pressure Over 12 Weeks Systolic blood pressure, mmHg	-2.2 mm Hg Interval -6.8 to 2.4	-0.7 mm Hg Interval -5.3 to 3.8
Mean Change in Blood Pressure Over 12 Weeks Diastolic blood pressure, mmHg	-2.5 mm Hg Interval -5.0 to -0.1	0.1 mm Hg Interval -2.3 to 2.6

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, 6 weeks, 12 weeks

Population: Mean Changes Over 12 Weeks (95% CI)

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.

Outcome measures

Measure	Treatment n=35 Participants Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 Participants identical placebos. placebos: placebos
Mean Change in Pulse Over 12 Weeks	0.6 beat/minute Interval -1.7 to 2.3	-0.5 beat/minute Interval -2.8 to 1.9

Adverse Events

Treatment

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

Placebos

Serious events: 1 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Measure	Treatment n=35 participants at risk Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 participants at risk identical placebos. placebos: placebos
Cardiac disorders Serious Adverse Event - Inpatient hospitalization	2.9% 1/35 • Number of events 1 • Each participant was assessed for adverse events in the duration of 3 months.	2.9% 1/35 • Number of events 1 • Each participant was assessed for adverse events in the duration of 3 months.

Other adverse events

Measure	Treatment n=35 participants at risk Immediate release sodium nitrite 40 mg by mouth twice per day and Isoquercetin 225 mg by mouth once per day. Immediate release sodium nitrite: Immediate release sodium nitrite 40 mg by mouth twice per day Isoquercetin: Isoquercetin 225 mg by mouth once per day	Placebos n=35 participants at risk identical placebos. placebos: placebos
Cardiac disorders Adverse Events	31.4% 11/35 • Number of events 55 • Each participant was assessed for adverse events in the duration of 3 months.	40.0% 14/35 • Number of events 63 • Each participant was assessed for adverse events in the duration of 3 months.

Additional Information

Dr. Jing Chen

Tulane School of Medicine

Phone: 5049886110

Email: jchen@tulane.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place