Nicotinamide Riboside Supplementation for Treating Arterial Stiffness and Elevated Systolic Blood Pressure in Patients With Moderate to Severe CKD
Primary Purpose
Vascular Diseases, Kidney Disease, Blood Pressure
Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Nicotinamide riboside
Sponsored by
About this trial
This is an interventional treatment trial for Vascular Diseases focused on measuring stiffness, chronic kidney disease, Hypertension
Eligibility Criteria
Inclusion Criteria:
- Age 35-80 years;
- Ability to provide informed consent;
- Willing to accept random assignment to condition;
- CKD stage III or IV (eGFR with the 4-variable MDRD prediction equation: 20-60 mL/min/1.73m2; stable renal function in the past 3 months);
- Blood pressure controlled to <140/90 mmHg for the past 3 months;
- Body mass index <40 kg/m2;
- Weight stable in the prior 3 months (<2 kg weight change) and willing to remain weight stable throughout the study
Exclusion Criteria:
- Patients with advanced CKD requiring chronic dialysis;
- Significant co-morbid conditions that lead the investigator to conclude that life expectancy < 1 year;
- History of severe congestive heart failure (i.e., ejection fraction < 35%);
- Hospitalization in the past month;
- Proteinuria > 5 g/day;
- Immunosuppressant agents such as cyclosporine, tacrolimus, azathioprine, etanercept, infliximab, adalimumab, anakinra or long-term oral glucocorticoids taken in past 12 months;
- Known malignancy;
- Woman who are pregnant, nursing or planning to become pregnant;
- Special classes of subjects considered vulnerable populations will not be included in the study.
Sites / Locations
- UColoradoRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Nicotinamide Riboside
Placebo
Arm Description
Each nicotinamide riboside capsule contains 250 mg of nicotinamide riboside chloride mixed with microcrystalline cellulose. Dosage: 500 mg by mouth twice a day for 3 months.
Matched placebo capsules.
Outcomes
Primary Outcome Measures
carotid-femoral pulse wave velocity
change in carotid-femoral pulse wave velocity
Secondary Outcome Measures
Systolic blood pressure
Casual blood pressure
Systolic blood pressure
24h ambulatory blood pressure
Full Information
NCT ID
NCT04040959
First Posted
July 26, 2019
Last Updated
March 13, 2023
Sponsor
University of Colorado, Denver
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
1. Study Identification
Unique Protocol Identification Number
NCT04040959
Brief Title
Nicotinamide Riboside Supplementation for Treating Arterial Stiffness and Elevated Systolic Blood Pressure in Patients With Moderate to Severe CKD
Official Title
Nicotinamide Riboside Supplementation for Treating Arterial Stiffness and Elevated Systolic Blood Pressure in Patients With Moderate to Severe CKD
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 19, 2019 (Actual)
Primary Completion Date
May 15, 2024 (Anticipated)
Study Completion Date
September 15, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Risk of cardiovascular diseases (CVD) is significantly elevated in patients with chronic kidney disease (CKD); however, this increased risk is only partially explained by traditional CV risk factors. Arterial dysfunction is an important nontraditional CV risk factor gaining increased recognition in the field of nephrology. This process is best represented, both physiologically and pathophysiologically, by increases in the gold standard measure of arterial stiffening, carotid to femoral artery pulse wave velocity (CFPWV), which reflects, in particular, increases in aortic stiffness. Aortic stiffening with CKD is mediated by structural and functional (increased vascular smooth muscle tone) changes in the arterial wall stimulated by oxidative stress and chronic low-grade inflammation. Caloric restriction (CR) is a promising strategy for prevention of CKD-associated arterial dysfunction and CVD. However, long-term adherence to chronic CR regimens with optimal nutrition is very difficult to achieve. Research has shown that boosting NAD+ bioavailability to stimulate SIRT-1, a "CR mimetic" approach, reduces CFPW and oxidative stress in old mice, and this lab recently took the first step in translating these findings in a study of adults with normal kidney function and elevated systolic blood pressure (SBP). The data found that supplementation with nicotinamide riboside, a natural, commercially available precursor of NAD+ and novel CR mimetic, increased NAD+ bioavailability and reduced CFPWV and SBP. A randomized, placebo-controlled, double-blind, single-site phase IIa clinical trial to assess the safety and efficacy of oral nicotinamide riboside (500 mg capsules 2x/day; NIAGEN®; ChromaDex Inc.) for 3 months vs. placebo for decreasing aortic stiffness and SBP in patients (35-80 years) with stage III and IV CKD is being proposed. It is hypothesized that treatment will reduce CFPWV and SBP, as related to increases in systemic NAD+ bioavailability and reductions in oxidative stress, and inflammation.
Aim 1: To measure CFPWV (primary outcome) before/after nicotinamide riboside vs. placebo treatment; Aim 2: To measure casual and 24h-ambulatory SBP (secondary outcome) before and after treatment; Aim 3: To determine the safety and tolerability of treatment with nicotinamide riboside vs. placebo; Aim 4: To measure systemic NAD+ and NAD+-related metabolite concentrations, as well as circulating markers of oxidative stress, inflammation, and vasoconstriction factors before and after treatment.
Detailed Description
Background: Risk of cardiovascular diseases (CVD) is significantly elevated in patients with chronic kidney disease (CKD). Arterial dysfunction is an important nontraditional CV risk factor gaining increased recognition in the field of nephrology. While many changes likely contribute to the development of arterial dysfunction in patients with CKD, among those of greatest concern is the development of stiffening of the large elastic arteries. Caloric restriction (CR) is a promising strategy for prevention of CKD-associated arterial dysfunction and CVD; however, adherence to CR is poor and may be detrimental in CKD patients due to reduced skeletal muscle and bone mass. Therefore, identification of more practical interventions that mimic the beneficial effects of CR, with stronger adherence and less risk of adverse consequences, is of significant biomedical importance.
Nicotinamide riboside is a naturally occurring precursor of nicotinamide adenine dinucleotide (NAD+), a critical mediator of the beneficial effects of CR, and therefore, a novel CR mimetic compound. We recently completed a study of nicotinamide riboside supplementation in healthy middle-age and older adults and demonstrated that 6 weeks of supplementation with nicotinamide riboside lowered carotid-femoral pulse wave velocity (CFPWV), the gold-standard clinical measure of aortic stiffness and a strong independent predictor of CVD and related morbidity and mortality in patients with and without kidney disease. In addition, treatment with nicotinamide riboside decreased systolic blood pressure (SBP) by 8 mmHg compared with placebo.
As a next translational step, we propose to conduct a randomized, placebo-controlled, double-blind, single site phase IIa clinical trial to further assess the safety and efficacy of oral nicotinamide riboside (3 months vs. placebo) for decreasing aortic stiffness and SBP in patients with stage III and IV CKD. We hypothesize that nicotinamide riboside will lower aortic stiffness and SBP and that these improvements will be related to increases in systemic NAD+ bioavailability, selective influences on vascular smooth muscle tone, and reductions in markers of systemic oxidative stress and/or inflammation.
Primary Outcome Measure (Aim 1): Aortic stiffness will be evaluated as CFPWV, the gold-standard measurement technique and clinically relevant marker of vascular function. CFPWV will be measured before and after 3 months of treatment with nicotinamide riboside or placebo.
Secondary Outcome Measures (Aim 2): Casual and ambulatory SBP will be the main secondary outcomes measures: (a) Casual (resting) SBP will be measured according to American Heart Association/American College of Cardiology guidelines, with an automated oscillometric sphygmomanometer. Casual SBP will be measured before and after 3 months of treatment with nicotinamide riboside or placebo; (b) Ambulatory SBP is an independent risk factor for CVD and a predictor of target organ damage. Ambulatory SBP (24-hour, daytime, nighttime mean pressures) will be measured before and after 3 months of treatment with nicotinamide riboside or placebo.
Other Outcome Measures (Aims 3 and 4): To evaluate the safety of nicotinamide riboside, we will monitor treatment-emergent adverse events at each visit (once every 2 weeks). The most common adverse events associated with nicotinamide riboside include mild-to-moderate headache, feelings of warmth, hot flushing sensations, gastrointestinal discomfort, and fatigue. We will also evaluate safety before and after 3 months of treatment with nicotinamide riboside or placebo by measuring the following clinical markers: standard blood hematology, standard clinical chemistry profiles, and standard urinalysis.
Tolerability will be assessed as subject dropout due to treatment-emergent adverse events.
Adherence to the intervention will be assessed by pill count performed once every 2 weeks.
Concentrations of NAD+ and associated metabolites will be evaluated to determine whether oral supplementation with nicotinamide riboside increases systemic NAD+ bioavailability. Peripheral blood mononuclear cells will be isolated and quantitative targeted metabolomics will be employed to evaluate concentrations of associated metabolites.
CKD and aortic stiffness and increased blood pressure are associated with increased systemic oxidative stress, inflammation, and pro-vasoconstriction factors. Nicotinamide riboside may reduce vascular stiffness by acting on one or more of these pathways. Circulating biomarkers of potential mechanisms of action (norepinephrine, endothelin-1, C-reactive protein, oxidized low density lipoprotein, total antioxidant status, tumor necrosis factor-alpha, interleukin-6, interleukin-1 beta and interleukin-10) will be evaluated to provide mechanistic insight. All of the discussed other outcome measures will be evaluated before and after 3 months of supplementation with nicotinamide riboside or placebo.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Vascular Diseases, Kidney Disease, Blood Pressure, Oxidative Stress
Keywords
stiffness, chronic kidney disease, Hypertension
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
118 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Nicotinamide Riboside
Arm Type
Experimental
Arm Description
Each nicotinamide riboside capsule contains 250 mg of nicotinamide riboside chloride mixed with microcrystalline cellulose. Dosage: 500 mg by mouth twice a day for 3 months.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Matched placebo capsules.
Intervention Type
Drug
Intervention Name(s)
Nicotinamide riboside
Intervention Description
Nicotinamide riboside is a naturally occurring vitamin B3 derivative found in yeast, bacteria, and mammalian tissues, and also has been detected in cows' milk.
Primary Outcome Measure Information:
Title
carotid-femoral pulse wave velocity
Description
change in carotid-femoral pulse wave velocity
Time Frame
Baseline and 3 months
Secondary Outcome Measure Information:
Title
Systolic blood pressure
Description
Casual blood pressure
Time Frame
Baseline and 3 months
Title
Systolic blood pressure
Description
24h ambulatory blood pressure
Time Frame
Baseline and 3 months
Other Pre-specified Outcome Measures:
Title
Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Events v4.0
Description
Safety and tolerability of the intervention
Time Frame
weeks 2, 4, 6, 8, 10, and 12
Title
Change in blood cellular NAD+ metabolism
Description
Assessment of the "NAD+ metabolome" in circulating PBMCs
Time Frame
baseline and 3 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age 35-80 years;
Ability to provide informed consent;
Willing to accept random assignment to condition;
CKD stage III or IV (eGFR with the 4-variable MDRD prediction equation: 20-60 mL/min/1.73m2; stable renal function in the past 3 months);
Blood pressure controlled to <140/90 mmHg for the past 3 months;
Body mass index <40 kg/m2;
Weight stable in the prior 3 months (<2 kg weight change) and willing to remain weight stable throughout the study
Exclusion Criteria:
Patients with advanced CKD requiring chronic dialysis;
Significant co-morbid conditions that lead the investigator to conclude that life expectancy < 1 year;
History of severe congestive heart failure (i.e., ejection fraction < 35%);
Hospitalization in the past month;
Proteinuria > 5 g/day;
Immunosuppressant agents such as cyclosporine, tacrolimus, azathioprine, etanercept, infliximab, adalimumab, anakinra or long-term oral glucocorticoids taken in past 12 months;
Known malignancy;
Woman who are pregnant, nursing or planning to become pregnant;
Special classes of subjects considered vulnerable populations will not be included in the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michel Chonchol, MD
Phone
303-724-7796
Email
Michel.Chonchol@ucdenver.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Beverly Farmer, RN
Phone
303-724-7797
Email
Beverly.Farmer@ucdenver.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michel Chonchol, MD
Organizational Affiliation
University of Colorado, Denver
Official's Role
Principal Investigator
Facility Information:
Facility Name
UColorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michel B Chonchol, MD
Phone
303-715-8423
Email
Michel.Chonchol@ucdenver.edu
First Name & Middle Initial & Last Name & Degree
Michel B Chonchol, MD
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Nicotinamide Riboside Supplementation for Treating Arterial Stiffness and Elevated Systolic Blood Pressure in Patients With Moderate to Severe CKD
We'll reach out to this number within 24 hrs