Clinical trial NCT06208527: The NADage Study: Nicotinamide Riboside Replenishment Therapy Against Functional Decline in Aging
Official title: The NADage Study: a Randomized Double-blind Trial of NAD Replenishment Therapy on Aging
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Frailty
Frail Elderly Syndrome
Frailty Syndrome
Aging
Keywords: Frailty
Nicotinamide Riboside
NR
Nicotinamide adenine dinucleotide
NAD
Frail
Aging
Functional decline
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
First posted: 2024-01-17
Enrollment: 100
Sex: ALL
Minimum age (years): 75
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized double-blinded placebo-controlled study with a duration of 1 year. 100 participants randomized to either Placebo (n=50) or NR 2000 mg (n=50).
Primary purpose: TREATMENT

Brief summary: 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.

The outcomes of this study could potentially demonstrate that NR effectively reduces signs of frailty, offering considerable advantages to the individuals affected, their families, and society as a whole.

Detailed description: This study aims to administer 2000 mg of nicotinamide riboside (NR) daily to explore its effects on brain and body metabolism in an elderly, frail population. The research design is a single-center, double-blind, randomized, placebo-controlled approach. Participants will be evenly randomized into two groups in a 1:1 ratio: one to receive a placebo and the other to receive 2000 mg of NR daily. The intervention will last for 52 weeks, during which primary and secondary outcomes will be assessed across and within both groups.

The primary objective is to evaluate the impact of NR on gait speed by comparing the treatment group with the placebo group. Secondary objectives include assessing the safety and tolerability of NR, as well as its clinical effects on physical and cognitive functions, using standardized tests. Furthermore, exploratory objectives will be pursued using various methods such as questionnaires, biosampling, actigraphy, and brain scans. These scans will include 31P-MR-spectrometry to analyze NAD levels in the brain and FDG-PET to assess metabolic network activity. The study will include 100 frail individuals who have provided informed consent. Biological samples to be collected include blood/serum, blood cells, urine, and fecal samples.

Given the previously demonstrated potential of NR in reducing symptoms of Parkinson's disease, this study seeks to expand knowledge of its effects on an elderly, frail population without neurodegenerative disorders. If NR is found to be effective in improving measures of frailty, it could significantly impact societal health and economy, especially considering the extensive socio-economic challenges associated with frailty.

Eligibility criteria: Inclusion Criteria:

* Participant must understand the nature of the study and be able to provide written, informed consent.
* Male or female aged ≥ 75 years at baseline.
* Fried Frailty Phenotype score ≥ 3 to identify frail individuals.
* Montreal Cognitive Assessment (MoCA) at screening adjusted to age, gender, and educational level, with a threshold set at the 10th percentile (z-score ≤ -1.28).

Exclusion Criteria:

* Inability to provide informed consent.
* Does not reside in a facility or institution.
* 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 prostate-specific antigen (PSA) levels in six months prior to baseline). Specific considerations may apply depending on the type of cancer.
* Significant neurological or psychiatric disorders, including but not limited to psychotic disorders, severe bipolar or unipolar depression, multiple sclerosis, uncontrolled seizure conditions, and neurodegenerative disorder.
* A history of cerebrovascular events, excluding transient ischemic attack (TIA) that occurs more 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 NAD precursor supplements (e.g., Nicotinamide riboside, nicotinamide mononucleotide 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.

Primary outcomes:
measure: The between-group (NR vs. Placebo) difference in the change in gait speed.
timeFrame: 52 weeks
Secondary outcomes:
measure: Incidence of treatment-emergent adverse events (safety and tolerability).
timeFrame: 52 weeks
measure: Change in physical performance assessed by the Short Physical Performance Battery (SPPB).
timeFrame: 52 weeks
measure: Change in physical performance assessed by hand grip strength.
timeFrame: 52 weeks
measure: Change in cognitive function assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) test battery.
timeFrame: 52 weeks
Other outcomes:
measure: Change in daily step count.
timeFrame: 52 weeks
measure: Change in overall activity level.
timeFrame: 52 weeks
measure: Change in speed of movements.
timeFrame: 52 weeks
measure: Change in acceleration of movements.
timeFrame: 52 weeks
measure: Change in angular velocity of movements.
timeFrame: 52 weeks
measure: Change in Activities of Daily Living (ADL) score.
timeFrame: 52 weeks
measure: Change in Independent living skills (IADL) score.
timeFrame: 52 weeks
measure: Change in mobility assessed by the Life Space Questionnaire (LSQ).
timeFrame: 52 weeks
measure: Change in mood assessed by the Montgomery Aasberg Depression Rating Scale (MADRS).
timeFrame: 52 weeks
measure: Change in self-reported mood assessed by the Geriatric depression scale (GDS).
timeFrame: 52 weeks
measure: Change in self-assessment of perceived health assessed by the Short form 36 (RAND-36).
timeFrame: 52 weeks
measure: Change in sleep assessed by the Pittsburgh Sleep Quality Index (PSQI) global score.
timeFrame: 52 weeks
measure: Change in smell identification capacity assessed using the Brief Smell Identification Test (BSIT).
timeFrame: 52 weeks
measure: Change in nutritional status assessed using the Mini Nutritional Assessment (MNA) form.
timeFrame: 52 weeks
measure: Change in sarcopenia assessment.
timeFrame: 52 weeks
measure: Change in health-related quality of life assessed by a standardized measure of quality of life (the EQ-5D-5L questionnaire).
timeFrame: 52 weeks
measure: Change in cognitive function using the Grooved Pegboard test.
timeFrame: 52 weeks
measure: Change in cumulative illness / comorbidity examined using the Cumulative Illness Rating Scale-Geriatric (CIRS-G).
timeFrame: 52 weeks
measure: Change in social support assessed using the Multidimensional scale of perceived social support (MSPSS).
timeFrame: 52 weeks
measure: The between-visit difference in cerebral NAD levels.
timeFrame: 52 weeks
measure: The between-visit difference in expression of the Nicotinamide Riboside Related Pattern (NRRP).
timeFrame: 52 weeks
measure: The between-visit difference in levels of NAD-metabolites in whole blood.
timeFrame: 52 weeks
measure: Change in blood-based biomarkers.
timeFrame: 52 weeks
measure: Change in gene and protein expression levels related to lysosomal and proteasomal function.
timeFrame: 52 weeks
measure: Change in genomic distribution of DNA methylation.
timeFrame: 52 weeks
measure: Change in levels of DNA methylation.
timeFrame: 52 weeks
measure: Change in gut microbiome composition.
timeFrame: 52 weeks
measure: Change in fecal metabolomics.
timeFrame: 52 weeks
measure: Change in levels of inflammatory cytokines in serum.
timeFrame: 52 weeks
Locations:
city: Bergen
country: Norway
facility: Haukeland University Hospital
state: Vestland
city: Bergen
country: Norway
facility: Haukeland University Hospital
Study officials:
affiliation: Haukeland University Hospital
name: Charalampos Tzoulis, PhD
role: STUDY_DIRECTOR
References: