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

Sponsor

University of Washington (Other)

Overall Status

Completed

CT.gov ID

NCT03579693

Collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

Enrollment

Location

Arms

29.4

Actual Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Kidney Disease Sarcopenia Frailty	Dietary Supplement: CoQ10 Dietary Supplement: Nicotinamide riboside Dietary Supplement: Placebo	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

25 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Randomized, placebo-controlled, cross-over trialRandomized, placebo-controlled, cross-over trial

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 14, 2018

Actual Primary Completion Date :

Apr 26, 2021

Actual Study Completion Date :

Apr 26, 2021

Arms and Interventions

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

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:

Placebo Comparator: Placebo

Placebo, inactive sugar pill for 6 weeks

Dietary Supplement: Placebo

Sugar pill designed to mimic coQ10 and NR

Outcome Measures

Primary Outcome Measures

Maximal Aerobic Capacity- CoQ10 [6 weeks]
The maximal aerobic capacity (oxygen update mL/min/kg body weight) during cycle ergometry at the end of the coenzyme Q10 treatment period.
Maximal Aerobic Capacity- NR [6 weeks]
The maximal aerobic capacity (oxygen update mL/min/kg body weight) during cycle ergometry at the end of the nicotinamide riboside treatment period.
Maximal Aerobic Capacity- Placebo [6 weeks]
The maximal aerobic capacity (oxygen update mL/min/kg body weight) during cycle ergometry at the end of the placebo treatment period.
Work Efficiency- CoQ10 [6 weeks]
The work efficiency (oxygen update mL/min/kg body weight at a specified constant work rate for 3 minutes) during cycle ergometry at the end of the coenzyme Q10 treatment period.
Work Efficiency- NR [6 weeks]
The work efficiency (oxygen update mL/min/kg body weight at a specified constant work rate for 3 minutes) during cycle ergometry at the end of the nicotinamide riboside treatment period.
Work Efficiency- Placebo [6 weeks]
The work efficiency (oxygen update mL/min/kg body weight at a specified constant work rate for 3 minutes) during cycle ergometry at the end of the placebo treatment period.

Secondary Outcome Measures

Peripheral Blood Mononuclear Cell (PBMC) mitochondrial energetics- coQ10 [6 weeks]
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.
PBMC mitochondrial energetics- NR [6 weeks]
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.
PBMC mitochondrial energetics- Placebo [6 weeks]
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.
Fatigue- CoQ10 [6 weeks]
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.
Fatigue- NR [6 weeks]
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.
Fatigue- Placebo [6 weeks]
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.
Physical Function- CoQ10 [6 weeks]
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.
Physical Function- NR [6 weeks]
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.
Physical Function- Placebo [6 weeks]
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.
Heart Failure Symptoms- CoQ10 [6 weeks]
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.
Heart Failure Symptoms- NR [6 weeks]
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.
Heart Failure Symptoms- Placebo [6 weeks]
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.
Oxidative Stress: F2-isoprostanes- CoQ10 [6 weeks]
Level of serum F2-isoprostanes at the end of the coenzyme Q10 treatment period. Measured in pg/mL of serum.
Oxidative Stress: F2-isoprostanes- NR [6 weeks]
Level of serum F2-isoprostanes at the end of the nicotinamide riboside treatment period. Measured in pg/mL of serum.
Oxidative Stress: F2-isoprostanes- Placebo [6 weeks]
Level of serum F2-isoprostanes at the end of the placebo treatment period. Measured in pg/mL of serum.
Oxidative Stress: Isofurans- CoQ10 [6 weeks]
Level of serum isofurans at the end of the coenzyme Q10 treatment period. Measured in pg/mL of serum.
Oxidative Stress: Isofurans- NR [6 weeks]
Level of serum isofurans at the end of the nicotinamide riboside treatment period. Measured in pg/mL of serum.
Oxidative Stress: Isofurans- Placebo [6 weeks]
Level of serum isofurans at the end of the placebo treatment period. Measured in pg/mL of serum.
Inflammation: Interleukin (IL)-6- CoQ10 [6 weeks]
Level of serum IL-6 at the end of the coenzyme Q10 treatment period. Measured in pg/mL of serum.
Inflammation: IL-6- NR [6 weeks]
Level of serum IL-6 at the end of the nicotinamide riboside treatment period. Measured in pg/mL of serum.
Inflammation: IL-6- Placebo [6 weeks]
Level of serum IL-6 at the end of the placebo treatment period. Measured in pg/mL of serum.
Inflammation: C-reactive Protein (CRP)- CoQ10 [6 weeks]
Level of serum C-reactive protein at the end of the coenzyme Q10 treatment period. Measured in pg/mL of serum.
Inflammation: CRP- NR [6 weeks]
Level of serum C-reactive protein at the end of the nicotinamide riboside treatment period. Measured in pg/mL of serum.
Inflammation: CRP- Placebo [6 weeks]
Level of serum C-reactive protein at the end of the placebo treatment period. Measured in pg/mL of serum.
Metabolomics Plasma Profile- CoQ10 [6 weeks]
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.
Metabolomics Plasma Profile- NR [6 weeks]
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.
Metabolomics Plasma Profile- Placebo [6 weeks]
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.
Metabolomics Urine Profile- CoQ10 [6 weeks]
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.
Metabolomics Urine Profile- NR [6 weeks]
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.
Metabolomics Urine Profile- Placebo [6 weeks]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years to 79 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)