A PHASE II RANDOMIZED, DOUBLE-BLIND
CLINICAL TRIAL OF NICOTINAMIDE RIBOSIDE IN PD
Recruiting: YES
ClinicalTrials.gov ID: NCT06208527
Ethics approval body/ID: 680827¨
Type of study: phase II, randomized, double-blind clinical trial
Single/multi-center: single-center
Participating countries: Norway
RATIONAL/HYPOTHESIS
This clinical study, designed as a double-blind, randomized, placebo-controlled trial, aims to investigate the potential of nicotinamide riboside (NR) to decelerate functional decline in the elderly frail population. In animal studies, NR, which is converted to nicotinamide adenine dinucleotide (NAD), has shown potential as a neuroprotective agent, with indications of protection against amyotrophic lateral sclerosis (ALS), Alzheimer’s dementia, and Parkinson’s disease. Furthermore, aging is commonly associated with decreased tissue NAD levels, a phenomenon linked to premature aging and a spectrum of age-related disorders, including cardiovascular diseases and cancers. Existing preclinical and clinical research highlights the promise of NAD replenishment through enhanced DNA repair, sirtuin activity, and improved mitochondrial function. The research center has conducted two phase II clinical trials on NR for Parkinson’s disease (NAD-PARK and NR-SAFE), administering up to 3000 mg of NR daily. These trials have shown promising results, indicating NR’s potential as a treatment that may alter the course of the disease and possibly as neuroprotective treatment in Parkinson’s disease.
The NAD age trial primarily aims to determine:
• The efficacy of NAD therapy in improving clinical symptoms of frailty, evaluated through standardized physical and cognitive function tests.
• The safety of administering 2000 mg NR daily in an elderly frail population.
The study will include 100 individuals, classified as frail based on the Fried Frailty Phenotype. Participants will be randomly assigned to receive either 2000 mg of NR daily or a placebo. Over a 52-week period, participants will undergo:
• Clinical evaluations, including actigraphy and questionnaires.
• Cognitive assessments.
• Bio sampling
• Magnetic resonance imaging (MRI).
• Positron emission tomography (FDG-PET) scanning.
INCLUSION CRITERIA
Participant must understand the nature of the study and be able to provide written and informed consent
Male or female aged≥ 75years at baseline
Frailty Phenotype score ≥3 to identify frail individuals
Montreal Cognitive Assessment (MoCA) at screening >1.5
EXCLUSION CRITERIA
Inability toprovide informed consent.
Permanent resident in a nursing home
Advanced disability, end-stage disease, presence of severe chronic illness and/or life expectancy of less than a year
Inability to complete a 6-minute walk test (6MWT) and/or contraindications to the procedure (history of unstable angina or myocardial infarction within 30 days prior to the test)
Diagnosis of active malignancy in the last 2 years at baseline (exceptions include non-metastatic skin conditions and non-metastatic and/or treated prostate cancer with stable PSA levels in six months prior to baseline). Specific considerations may apply depending on the type of cancer.
Significant neurological disorders, including but not limited to multiple sclerosis, uncontrolledseizure conditions, andneurodegenerative disorder
Significant psychiatric disorders, including but not limited topsychotic disorders, severe bipolar orunipolar depression
A history of cerebrovascular events, including TIA that occurs less than 3 months prior to baseline.
Hospitalization or major surgery within 3 months prior to baseline
Significant changes in medications or treatment plans made less than one month prior to baseline, judged by the site investigator to interfere with the subject’s participation in the study
Consumption of high dose NAD precursor supplements (e.g., Nicotinamide riboside, nicotinamidemononucleotide or Vitamin B3), or related supplements within 6 months prior to baseline
Elective surgeries scheduled during the study duration
Concurrent participation in other clinical trials with interventions that could affect frailty measures
Any medical history, at the discretion of the investigator, might hinder compliance with study procedures or increase risk to the participant
DESIGN
The NADage study is a phase II, randomized, double-blind trial. Participants will be recruited at HelseBergen in Norway. At baseline, participants will be randomized into one of two groups: NR 2000 mg daily(n = 50) or Placebo (n = 50). Individuals who are identified as frail will be eligible for screening. Following screening, eligible participants will be enrolled and randomly assigned (1:1) to NR 2000 mg daily (1000 mg x 2) or Placebo for a 52-week period. During the study period, the participants will:
1
be assessed in three in-clinic visits (at week 0, 26, and 52)
2
assessed through decentralized remote visits in the study period, where self-reported outcomes will be registered using a digital platform (Viedoc Me)
3
wearable sensor-based data will be collected for 1 week x3 (1-week pre-baseline, at 3 month-visit and 6-month visit)
4
sleep monitoring using Somnofy will be collected for 1 week x2 (1 week pre-baseline and 1 week pre-12 month visit)
OBJECTIVES
PRIMARY OBJECTIVE:
To assess the efficacy of nicotinamide riboside (NR) inimproving motor function in older, community-dwelling individuals living with frailty, using the 6-minute walk test (6MWT)
SECONDARY OBJECTIVES:
The secondary objectives are to determine whether treatment with NR, in an older, community-dwelling population living with frailty:
1
Is safe and well tolerated.
2
Improves physical frailty, assessed by grip strength measured on dominant hand with a hydraulic hand-held dynamometer.
3
Influences cognitive function, measured by the Repeatable Battery for the Assessment of Neuropsychological Status(RBANS; test battery onimmediateand delay edmemory, visuospatial/constructional abilities, language, and attention).
EXPLORATORY OBJECTIVES
To determine whether treatment with NR, in an older, community-dwelling older population living with frailty:
1. Augments NAD metabolism in blood, measured by LC-MS metabolomics and/or NADMED assay
2. Augments NAD metabolism in the brain, measured by 31P-magnetic resonance spectroscopy (31P-MRS)
3. Influences brain metabolic networks, measured by Fluorodeoxyglucose-positron emission tomography (FDG-PET)
4. Influences blood biomarkers of aging, including gene and protein expression (blood biochemistry encompassing cardiovascular, metabolic, renal and hepatic markers, immune- and inflammatory profiles and DNA methylation age)
5. Improves physical frailty, assessed by the short physical performance battery (SPPB)
6. Influences step count, measured in number of steps using Axivity wearable sensors. Counts the total number of steps taken by an individual over a specified period
7. Influences overall activity level, measured using Axivity’s accelerometer data. Quantifies the total amount of physical activity based on intensity and duration
8. Influences speed of movements, measured in meters per second (m/s) using Axivity’s accelerometer and gyroscope data. Calculates the average or peak speed of movements during different activities
9. Influences acceleration, measured in meters per second squared (m/s2) using Axivity’s accelerometer data. Measures the rate of change of speed, indicating how quickly an individual is increasing or decreasing their speed during activities
10. Influences angular velocity, measured in radians per second (rad/s) using Axivity’s gyroscope data. Measures the rate of rotation around an axis, assessing movement dynamics
11. Influences quality of life, assessed by EQ-5D-5L
12. Influences sleep, assessed by the Pittsburgh Sleep Quality Index (PSQI)
13. Influences sleep, assessed by Somnofy monitor
14. Influences auditory capacity, assessed by Audiometry
15. Influences smell, assessed by Brief Smell Identification Test (BSIT)
16. Influences self reported cognitive function (CFI)
17. Influences the Grooved Pegboard test for assessment of motor coordination
18. Influences cognitive function assessed by subtests of psychomotor tempo/attention, memory, and executive function from the Cambridge Neuropsychological Test Automated Battery (CANTAB)
19. To determine genetic factors influencing the blood and/or brain bioavailability of NAD following the oral consumption of NR
20. Influences omics biomarkers assessed by blood transcriptome, proteome, metabolome and gut microbiome
21. To determine genetic factors influencing the metabolic response to NR treatment
OUTCOMES
PRIMARY OUTCOME:
The difference in gait speed (NR vs. Placebo) from baseline to week 52 as assessed by the 6MWT (and sensor-based gait speed) in a community-dwelling older population living with frailty.
SECONDARY OUTCOMES:
1. Safety and tolerability, assessed by the frequency and severity of adverse effects (AE).
2. Physical strength assessed by hand grip strength (measured on the dominant hand with a hydraulic hand-held dynamometer).
3. Cognitive function using the RBANS test battery (test on immediate memory, visuospatial/constructional abilities, language, attention, and delayed memory).
EXPLORATORY OUTCOMES:
1. Physical performance assessed by the SPPB (objective measurements on balance, lower extremity strength, and functional capacity through walking and sit to stand test)
2. Step count measured in number of steps using Axivity wearable sensors. Counts the total number of steps taken by an individual over a specified period
3. Overall activity level measured using Axivity’s accelerometer data. Quantifies the total amount of physical acitivity based on intensity and duration
4. Speed of movements measured in meters per second (m/s) using Axivity’s accelerometer and gyroscope data. Calculates the average or peak speed of movements during different activites
5. Acceleration measured in meters per second squared (m/s2) using Axivity’s accelerometer data. Measures the rate of change of speed, indicating how quickly an individual is increasing or decreasing their speed during activities
6. Angular velocity measured in radians per second (rad/s) using Axivity’s gyroscope data. Measures the rate of rotation around an axis, assessing movement dynamics
7. Activities of daily living assessed by the Barthel Index Activities of Daily Living (ADL) scale
8. Independent living skills assessed by the Nottingham Instrumental Activities of Daily Living (IADL) scale
9. Mood assessment as assessed by the Geriatric depression scale (GDS)
10. Self-assessment of perceived health using the Short form 36 scale (RAND-36)
11. Sleep assessment using the Pittsburgh Sleep Quality Index (PSQI)
12. Sleep assessment using the Somnofy monitor
13. Auditory capacity using audiometry
14. Smell identification test using the Brief Smell Identification Test (BSIT)
15. Nutrition assessment: using the Mini Nutritional Assessment (MNA)
16. Quality of life assessment (EQ-5D-5L)
17. Self reported cognitive function (cognitive function instrument (CFI)
18. Cognitive assessment using the Grooved Pegboard test (motor coordination)
19. Cognitive assessment using the Cambridge Neuropsychological Test Automated Battery (CANTAB)
20. Comorbidity examined using the Cumulative Illness Rating Scale-Geriatric (CIRS-G)
21. Brain NAD metabolism using 31P-MRS as a measurement of NAD levels in the brain parenchyma
22. Brain metabolic networks using FDG-PET to assess NR-related pattern (NRRP)
23. Blood NAD-metabolome measured by liquid chromatography-mass spectrometry (LC-MS)
24. Blood-based ageing biomarkers assessed by blood routine biochemistry encompassing cardiovascular-, metabolic-, renal- and hepatic markers and immune- and inflammatory profiles and DNA methylation age
25. Omics biomarkers assessed by blood transcriptome, proteome, metabolome, and gut microbiome
26. Genomic profile assessed by sequencing and/or SNP-chip. We will assess genome-wide associations with the blood and/or brain bioavailability of NAD following the oral consumption of NR, and the general metabolic response to NR treatment, assessed by metabolomics