Trial of Nicotinamide Riboside and Co-enzyme Q10 in Chronic Kidney Disease (CoNR)

Cross-over Randomized Controlled Trial of Coenzyme Q10 or Nicotinamide Riboside in Chronic Kidney Disease

Chronic kidney disease is associated with the loss of skeletal muscle mass and function. This process detrimentally impacts mobility, functional independence, and quality of life. Mounting evidence suggests that chronic kidney disease impairs skeletal muscle functioning by injuring mitochondria, the central energy producing units of cells.

Potential treatment options to restore mitochondrial function include aerobic and weight bearing exercise and medications that directly improve mitochondrial energetics. Unfortunately, exercise programs may be difficult to implement in people who have chronic diseases, such as kidney disease.. Coenzyme Q10 (coQ10) and nicotinamide riboside (NR) are naturally occurring supplements that can directly improve mitochondrial efficiency. Both compounds help mitochondria produce more energy while generating less waste.

The primary purpose of this study is to test whether coQ10 and NR can improve muscle function among people with chronic kidney disease. What we learn in this study may help us better understand the mechanisms of skeletal muscle impairment among people with kidney disease and ultimately improve their ability to be active and independent.

Study Overview

• Status: Completed
• Conditions: Frailty; Chronic Kidney Disease; Sarcopenia
• Intervention / Treatment: Dietary supplement: CoQ10; Dietary supplement: Nicotinamide riboside; Dietary supplement: Placebo

Detailed Description

Sarcopenia (decreased muscle mass or function) is common in patients with chronic kidney disease (CKD) patients with direct impacts on their metabolic and clinical outcomes. Existing evidence and the investigator's preliminary data suggest that mitochondrial dysfunction is a key underlying mechanism of sarcopenia in CKD. However, the ability of treatments to modify mitochondrial functioning in CKD patients is unknown. Coenzyme Q10 (coQ10) and nicotinamide riboside (NR) are naturally occurring supplements that reduce oxidative stress and restore substrate delivery to mitochondria, respectively.

Both processes have the potential to increase mitochondrial energy production with direct consequences for many metabolic and physical processes, including:

• aerobic capacity
• work efficiency
• mitochondrial energetics
• fatigue
• physical function
• inflammation
• oxidative stress
• heart failure symptoms
• metabolomics

These outcomes will assessed in all study participants who enroll in the trial. Addressing these knowledge gaps is necessary to shed new light on the pathophysiology of sarcopenia in CKD and suggest future interventions that reduce morbidity and mortality.

This is a randomized, placebo-controlled, double-blind crossover trial of coQ10 and NR treatments. Participants will receive coQ10 (1000 mg daily), NR (1200 mg daily), or placebo each for six-weeks in random order with a 7-day washout between treatment periods. The primary outcomes are aerobic capacity and muscle work efficiency, measured during cycle ergometry.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Chronic kidney disease, defined in this study as an estimated glomerular filtration rate (eGFR) of <50ml/min/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration equation

Exclusion Criteria:

• 6-minute walking distance >500meters
• Pregnancy
• Receiving renal replacement therapy (dialysis or kidney transplantation)
• Expectation to start dialysis within 6 months
• Insulin dependent diabetes mellitus
• Severe anemia: hemoglobin <8 g/dL
• Hyperkalemia: K >5.7 mEq/L
• Weight >300 lbs
• HIV
• End stage liver disease with cirrhosis
• Oxygen-dependent Chronic Obstructive Pulmonary Disease (COPD)
• Unable to walk unassisted from room to room in own house
• Institutionalization, or inability to consent
• Use of immunosuppressive medications (i.e. steroids, calcineurin inhibitors)
• Malignancy requiring active treatment or currently under surveillance (at the discretion of the investigator)
• Cardiac pacemaker
• Current participation in another interventional trial
• Non-English speaking
• Hospitalization for heart attack, stroke, or unstable cardiac chest pain within the previous 3 months (e.g. myocardial infarction, unstable angina, cerebrovascular accident)
• Any medical condition that the investigator feels would prevent the participant from safely completing the exercise-based outcome measurements.
• Baseline systolic blood pressure >170 or diastolic blood pressure >100
• Persistent or permanent uncontrolled arrhythmia (at the discretion of the investigator)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CoQ10; Coenzyme Q10, 2 - 250 mg tablets twice a day (1000 mg total daily dose) for 6 weeks	Dietary supplement: CoQ10; CoQ10 tablet; Other Names: coenzyme Q10
Active Comparator: Nicotinamide riboside; Nicotinamide riboside, 1 - 600 mg tablet twice a day (1200 mg total daily dose) for 6 weeks	Dietary supplement: Nicotinamide riboside; NR tablet; Other Names: NR
Placebo Comparator: Placebo; Placebo, inactive sugar pill for 6 weeks	Dietary supplement: Placebo; Sugar pill designed to mimic coQ10 and NR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal Aerobic Capacity- CoQ10	The maximal aerobic capacity (oxygen uptake mL/min/kg body weight) during cycle ergometry at the end of each treatment period.	6 weeks
Work Efficiency	The work efficiency (oxygen uptake mL/min/kg body weight at a specified constant of 60 watts work rate for 3 minutes) during cycle ergometry at the end of each treatment period. This is reported as the work performed at 60 watts divided by the energy expended at 0 watts times 100, and reported on the percent scale..	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peripheral Blood Mononuclear Cell (PBMC) mitochondrial energetics- coQ10	Reserve capacity (pmol of oxygen consumed/min) at the end of the coenzyme Q10 treatment period,measured by the difference between basal oxygen consumption and maximal uncoupled oxygen consumption from isolated monocytes and lymphocytes.	6 weeks
PBMC mitochondrial energetics- NR	Reserve capacity (pmol of oxygen consumed/min) at the end of the nicotinamide riboside treatment period, measured by the difference between basal oxygen consumption and maximal uncoupled oxygen consumption from isolated monocytes and lymphocytes.	6 weeks
PBMC mitochondrial energetics- Placebo	Reserve capacity (pmol of oxygen consumed/min) at the end of the placebo treatment period, measured by the difference between basal oxygen consumption and maximal uncoupled oxygen consumption from isolated monocytes and lymphocytes.	6 weeks
Fatigue- CoQ10	Self-reported fatigue assessed by the score on the Patient-reported Outcomes Measurement Information System (PROMIS) Cancer Fatigue Short Form 17a at the end of the coenzyme Q10 treatment period. Each item is scaled from 1 to 5 (1='never' and 5='always'), yielding a total between 22 to 85.	6 weeks
Fatigue- NR	Self-reported fatigue assessed by the score on the PROMIS Cancer Fatigue Short Form 17a at the end of the nicotinamide riboside treatment period. Each item is scaled from 1 to 5 (1='never' and 5='always'), yielding a total between 22 to 85.	6 weeks
Fatigue- Placebo	Self-reported fatigue assessed by the score on the PROMIS Cancer Fatigue Short Form 17a at the end of the placebo treatment period. Each item is scaled from 1 to 5 (1='never' and 5='always'), yielding a total between 22 to 85.	6 weeks
Physical Function- CoQ10	Self-reported physical function abilities assessed by the score on the PROMIS Physical Function Short Form 20a at the end of the coQ10 treatment period. Each item is scaled from 1 to 5 (1='unable' and 5='without difficulty'), yielding a total between 20 to 100.	6 weeks
Physical Function- NR	Self-reported physical function abilities assessed by the score on the PROMIS Physical Function Short Form 20a at the end of the nicotinamide riboside treatment period. Each item is scaled from 1 to 5 (1='unable' and 5='without difficulty'), yielding a total between 20 to 100.	6 weeks
Physical Function- Placebo	Self-reported physical function abilities assessed by the score on the PROMIS Physical Function Short Form 20a at the end of the placebo treatment period. Each item is scaled from 1 to 5 (1='unable' and 5='without difficulty'), yielding a total between 20 to 100.	6 weeks
Heart Failure Symptoms- CoQ10	Self-reported symptoms of heart failure assessed by the score on the Kansas City Heart Failure Questionnaire at the end of the coenzyme Q10 treatment period. Each item is scaled from 1 to 5, or 1 to 6 (1 indicates highest level of symptoms and 5 or 6 indicates the least level of symptoms), yielding a total between 0 to 100.	6 weeks
Heart Failure Symptoms- NR	Self-reported symptoms of heart failure assessed by the score on the Kansas City Heart Failure Questionnaire at the end of the nicotinamide riboside treatment period. Each item is scaled from 1 to 5, or 1 to 6 (1 indicates highest level of symptoms and 5 or 6 indicates the least level of symptoms), yielding a total between 0 to 100.	6 weeks
Heart Failure Symptoms- Placebo	Self-reported symptoms of heart failure assessed by the score on the Kansas City Heart Failure Questionnaire at the end of the placebo treatment period. Each item is scaled from 1 to 5, or 1 to 6 (1 indicates highest level of symptoms and 5 or 6 indicates the least level of symptoms), yielding a total between 0 to 100.	6 weeks
Oxidative Stress: F2-isoprostanes- CoQ10	Level of serum F2-isoprostanes at the end of the coenzyme Q10 treatment period. Measured in pg/mL of serum.	6 weeks
Oxidative Stress: F2-isoprostanes- NR	Level of serum F2-isoprostanes at the end of the nicotinamide riboside treatment period. Measured in pg/mL of serum.	6 weeks
Oxidative Stress: F2-isoprostanes- Placebo	Level of serum F2-isoprostanes at the end of the placebo treatment period. Measured in pg/mL of serum.	6 weeks
Oxidative Stress: Isofurans- CoQ10	Level of serum isofurans at the end of the coenzyme Q10 treatment period. Measured in pg/mL of serum.	6 weeks
Oxidative Stress: Isofurans- NR	Level of serum isofurans at the end of the nicotinamide riboside treatment period. Measured in pg/mL of serum.	6 weeks
Oxidative Stress: Isofurans- Placebo	Level of serum isofurans at the end of the placebo treatment period. Measured in pg/mL of serum.	6 weeks
Inflammation: Interleukin (IL)-6- CoQ10	Level of serum IL-6 at the end of the coenzyme Q10 treatment period. Measured in pg/mL of serum.	6 weeks
Inflammation: IL-6- NR	Level of serum IL-6 at the end of the nicotinamide riboside treatment period. Measured in pg/mL of serum.	6 weeks
Inflammation: IL-6- Placebo	Level of serum IL-6 at the end of the placebo treatment period. Measured in pg/mL of serum.	6 weeks
Inflammation: C-reactive Protein (CRP)- CoQ10	Level of serum C-reactive protein at the end of the coenzyme Q10 treatment period. Measured in pg/mL of serum.	6 weeks
Inflammation: CRP- NR	Level of serum C-reactive protein at the end of the nicotinamide riboside treatment period. Measured in pg/mL of serum.	6 weeks
Inflammation: CRP- Placebo	Level of serum C-reactive protein at the end of the placebo treatment period. Measured in pg/mL of serum.	6 weeks
Metabolomics Plasma Profile- CoQ10	Targeted metabolomics profile of plasma, using liquid chromatography and high resolution mass spectroscopy, investigating fold changes in log-transformed metabolites (unitless), at the end of the coenzyme Q10 treatment period.	6 weeks
Metabolomics Plasma Profile- NR	Targeted metabolomics profile of plasma, using liquid chromatography and high resolution mass spectroscopy, investigating fold changes in log-transformed metabolites (unitless), at the end of the nicotinamide riboside treatment period.	6 weeks
Metabolomics Plasma Profile- Placebo	Targeted metabolomics profile of plasma, using liquid chromatography and high resolution mass spectroscopy, investigating fold changes in log-transformed metabolites (unitless), at the end of the placebo treatment period.	6 weeks
Metabolomics Urine Profile- CoQ10	Targeted metabolomics profile of urine, using liquid chromatography and high resolution mass spectroscopy, investigating fold changes in log-transformed metabolites (unitless), at the end of the coenzyme Q10 treatment period.	6 weeks
Metabolomics Urine Profile- NR	Targeted metabolomics profile of urine, using liquid chromatography and high resolution mass spectroscopy, investigating fold changes in log-transformed metabolites (unitless), at the end of the nicotinamide riboside treatment period.	6 weeks
Metabolomics Urine Profile- Placebo	Targeted metabolomics profile of urine, using liquid chromatography and high resolution mass spectroscopy, investigating fold changes in log-transformed metabolites (unitless), at the end of the placebo treatment period.	6 weeks

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Bryan Kestenbaum, MD, University of Washington; Principal Investigator: Baback Roshanravan, MD, University of Washington

Publications and helpful links

Helpful Links

• Website for the Kidney Research Institute at the University of Washington

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2018
• Primary Completion (Actual): April 26, 2021
• Study Completion (Actual): April 26, 2021

Study Registration Dates

• First Submitted: June 25, 2018
• First Submitted That Met QC Criteria: July 5, 2018
• First Posted (Actual): July 6, 2018

Study Record Updates

• Last Update Posted (Estimate): January 10, 2023
• Last Update Submitted That Met QC Criteria: December 13, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Antioxidants; Fatigue; CoQ10; Aerobic capacity; Mitochondria; Ergometry; Nicotinamide riboside
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Urologic Diseases; Neurologic Manifestations; Renal Insufficiency; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Muscular Atrophy; Atrophy; Kidney Diseases; Renal Insufficiency, Chronic; Frailty; Sarcopenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin; Coenzyme Q10
• Other Study ID Numbers: STUDY00004998; R01DK101509 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No