Effects of Vitamin B3 Derivative Nicotinamide Riboside (NR) in Bone, Skeletal Muscle and Metabolic Functions in Aging

Study Overview
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Brief Summary
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Researchers are trying to determine if the vitamin B3 derivative Nicotinamide Riboside (NR) has any effects in bone, skeletal muscle, and metabolic functions and structure in aging.

Detailed Description
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Primary Objective: To assess the effect of NAD boosting through NR intake in skeletal muscle and bone metabolism function, and biochemical evidence of improvement of DNA damage repair in healthy elderly female patients with and without exercise. Secondary Objective: To assess the effect of NR in metabolic functions of glucose and lipid profile as well as to determine the safety of long term administration of NR in healthy elderly female patients with and without exercise.

Official Title
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A Randomized, Double-blinded, Placebo-controlled Study to Evaluate the Effects of Vitamin B3 Derivative Nicotinamide Riboside (NR) in Bone, Skeletal Muscle and Metabolic Functions in Aging

Conditions
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Healthy Elderly Volunteers

Intervention / Treatment
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* Dietary Supplement: Nicotinamide Riboside
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy elderly female subjects between 65 and 80 years of age Exclusion Criteria: General Exclusion Criteria Subjects who participate in regular structured exercise more than 2 hours and 30 min per week or 1hour and 15 min of vigorous exercise per week. Unwilling to comply with the follow-up schedule Inability or refusal to give informed consent by the patient Subject who takes multivitamins containing vitamin B3 derivatives in a dose > 200 mg/day Participation in another investigational drug study within 1 year of treatment Laboratory Exclusion Criteria Serum 25-hydroxyvitamin D < 15 ng/ml Serum phosphorus > 5 mg/dL Serum alkaline phosphatase 50% above normal limit Serum aspartate transaminase 50% above normal limit Serum calcium > 10.5 mg/dL Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min Creatinine Clearance < 50% Poorly controlled Diabetes Mellitus (HbA1c>8) Clinical History Exclusion Criteria Confirmed diagnosis of Diabetes Mellitus in use of insulin Subjects presenting systolic BP>180 mmHg or a diastolic BP>90 mmHg on initial evaluation Previous diagnosis of liver disease Previous chronic kidney disease stages III and IV Malignancy Malabsorption syndrome Hypo- or Hyperparathyroidism Acromegaly Cushing's syndrome Hypopituitarism Severe chronic obstructive pulmonary disease Congestive heart failure Musculoskeletal disorder History of rheumatoid arthritis Previous gastric bypass surgery Clinical history of osteoporotic fracture (spine, hip, or distal forearm) within past year Extreme of BMI (≤ 18.5 kg/m2 or ≥ 40 kg/m2) Medication Exclusion Criteria History of methotrexate therapy History of denosumab therapy History of oral or inhaled corticosteroid use > 3 months Current use of anticoagulants in general Anticonvulsant therapy (within previous year) Sodium fluoride (any history) Treatment within the past 3 years with bisphosphonates Treatment within the past 3 years with parathyroid hormone Treatment within the past 3 years with calcitonin Treatment within the past 3 years with estrogen Treatment within the past 3 years with selective estrogen receptor modulator

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The investigators will enroll 48 subjects (24 placebo vs. 24 NR) considering a dropout rate of 20%. Patients will be screened at outpatient clinic visit by the research team before the enrollment. For those subjects interested and qualified it will be offered participation in this trial. Once consent has been obtained baseline values will be established and subjects will begin treatment and followed for 4.5 months. After 4.5 months, a structured exercise regimen will be implemented in addition to the NR/placebo treatment and the patients will be followed for 6 weeks more, completing 6 months.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nicotinamide Riboside<br>NR is a single chemical moiety containing nicotinamide and ribose. The investigational product is a synthetic NR that is nature-identical to naturally-occurring NR, does not induce flushing or pruritus and has no effect on lipid levels. | Dietary Supplement: Nicotinamide Riboside<br>* It will be administered a total of 1000 mg/day of NR in a regimen of 500mg every 12 hours by mouth for 4.5 months. After 4.5 months, an advanced individual training (AIT) will be implemented in addition to administration of 1000mg/day (500mg every 12 hours) for 6 weeks more, completing total of 6 months.<br>|
| Placebo Comparator: Placebo<br>Correspondent placebo, a pill not containing the active component. | Dietary Supplement: Placebo<br>* It will be administered a correspondent placebo with the same shape and color as the active pill 12 hours by mouth for 4.5 months. After 4.5 months, an advanced individual training (AIT) will be implemented in addition to administration of correspondent placebo every 12 hours for 6 weeks more, completing total of 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal oxygen uptake (VO2 max) test | Maximal oxygen uptake (VO2 max) test measures the maximum rate of oxygen consumption during incremental exercise (exercise of increasing intensity) and reflects the cardiorespiratory fitness of an individual and is an important determinant of their endurance capacity during prolonged exercise. | 6 months | 
| Skeletal muscle function | The 6-minute walk test (6MWT) quantifies the distance a person can walk in six minutes and will be used to document the mobility/functional status of a patient. Originally developed to evaluate the physical capacity of patients with cardiopulmonary diseases, the test has been used to assess treatment effects, physical function status, and to predict morbidity and mortality in several patient populations including frail older adults. | 6 months | 
| Short Physical Performance Battery (SPPB) | The SPPB captures domains of strength, endurance, and balance and is highly predictive of subsequent disability. | 6 months | 
| Respiration rate on muscle biopsy samples | The samples will be analyzed for respiration rate in isolated mitochondria and permeabilized fibers | 6 months | 
| PCR on muscle biopsy samples | RT-PCR for gene expression | 6 months | 
| Immunoblot on muscle biopsy samples | Immunoblot in skeletal lysates for protein expression | 6 months | 
| Bone metabolism | Serum Carboxy-terminal Telopeptide (CTX), tartrate-resistant acid phosphatase isoform type 5b (TRAP5b), Amino-terminal Pro-peptide (P1NP), and osteocalcin will all be measured to monitor bone turnover markers. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose profile | Serum glucose measure | 6 months | 
| Insulin | Serum insulin measure | 6 months | 
| Lipid profile | Blood cholesterol measure | 6 months | 
| Hemoglobin A1C | Hb A1C measure in blood sample | 6 months | 
| Oral glucose tolerance test | An 18-gauge cannula will be inserted in a retrograde fashion into a dorsal hand vein of the non-dominant arm. The hand will be placed in a heated box (55°C) to enable sampling of arterialized venous blood. Blood will be drawn at 0 (baseline), 10, 20, 30, 60, 90, and 120 minutes for the measurement of glucose, insulin, and C-peptide concentrations. After the baseline blood draw, subjects will ingest 75 g of glucose over a period of 5 minutes. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAD boosting therapy, Nicotinamide Riboside, NAD precursors, Aging