Nitrite, Isoquercetin and Endothelial Dysfunction (NICE) Trial

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02552888

Acronym

NICE

Enrollment

Registered

2015-09-17

Start date

2016-03-31

Completion date

2017-06-30

Last updated

2021-04-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Kidney Disease

Keywords

Endothelial Dysfunction, Inflammation, Oxidative Stress, eGFR, Urine Albumin

Brief summary

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.

Interventions

DRUGImmediate release sodium nitrite

Immediate release sodium nitrite 40 mg by mouth twice per day

DIETARY_SUPPLEMENTIsoquercetin

Isoquercetin 225 mg by mouth once per day

OTHERplacebos

placebos

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

21 Years to 74 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Mean Percentage Change in Endothelium-dependent Flow-mediated Vasodilation (FMD) Over 12 Weeks	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

Measure	Time frame	Description
Mean Change in Endothelial Function Biomarker Asymmetrical DiMethylArginine (ADMA) Over 12 Weeks	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.
Mean Change in Endothelial Function Biomarker Endostatin Over 12 Weeks	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.
Mean Change in Endothelial Function Biomarker Urine Epidermal Growth Factor (UEGF) Over 12 Weeks	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.
Mean Change in Inflammatory Biomarker C-Reactive Protein (CRP) Over 12 Weeks	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.
Mean Change in Endothelial Function Biomarkers VCAM-1, ICAM-1, E-selectin and vWF Over 12 Weeks	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.
Mean Change in Inflammatory Biomarker Interleukin-6 (IL-6) Over 12 Weeks	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.
Mean Change in Oxidative Stress Biomarker Low-density Lipoprotein (LDL) Over 12 Weeks	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.
Mean Change in Oxidative Stress Biomarker Nitrotyrosine Over 12 Weeks	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.
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	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.

Other

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

Countries

United States

Participant flow

Participants by arm

Arm	Count
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	35
Placebos identical placebos. placebos: placebos	35
Total	70

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	1	1

Baseline characteristics

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

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 35	0 / 35
other Total, other adverse events	11 / 35	14 / 35
serious Total, serious adverse events	1 / 35	1 / 35

Outcome results

Primary

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.

Time frame: Baseline, 6 weeks, 12 weeks