Clinical trial NCT05617508: N-DOSE AD: a Dose Optimization Trial of Nicotinamide Riboside in Alzheimer's Disease
Official title: N-DOSE AD: a Dose Optimization Trial of Nicotinamide Riboside in Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Alzheimer Disease
Dementia
Keywords: NAD metabolism
Mitochondria
Nicotinamide Riboside
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
Collaborators: name: Haraldsplass Deaconess Hospital
First posted: 2022-11-15
Enrollment: 80
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized double-blinded placebo-controlled study. 80 participants randomized in 1:1:2 ratio to either: 1. Placebo (n=20), 2. NR 1000mg for 3 months (n=20), 3. Dose escalation group: NR 1000mg 1st month, NR 2000mg 2nd month, NR 3000mg 3rd month (n=40).
Primary purpose: TREATMENT

Brief summary: The goal of this double-blinded placebo-controlled randomized trial is to determine the optimal dose of nicotinamide riboside (NR), in individuals with Alzheimer's disease (AD).

The main questions the N-DOSE AD trial aims to answer are:

What dose of nicotinamide riboside (NR) is required to achieve maximal cerebral nicotinamide adenine dinucleotide (NAD) increase, measured by 31P-magnetic resonance spectroscopy (MRS) or cerebrospinal fluid (CSF) metabolomics)?

What dose of nicotinamide riboside (NR) is required to achieve maximal alteration in the cerebral metabolism patterns, measured by fluorodeoxyglucose-positron emission tomography (FDG-PET)?

What dose of nicotinamide riboside (NR) will have optimal effect in the absence of unacceptable toxicity?

Participants will be asked to do participate in:

Clinical examinations

Cognitive assessments

Lumbar puncture

Magnetic resonance imaging - positron emission tomography (MRI-PET) scannings

Biosampling

They'll be given placebo, 1000 mg NR or escalating doses of NR (1000 mg - 2000 mg - 3000 mg) over 12 weeks.

Detailed description: N-DOSE AD is a double-blinded placebo-controlled randomized trial aiming to determine the optimal biological dose (OBD) of nicotinamide riboside (NR), in individuals with Alzheimer's disease (AD).

Individuals with AD (n = 80) will be recruited starting November 2022. Participants will be randomized 1:1:2 to either placebo group (n = 20) or NR 1000mg daily (n = 20) for 12 weeks or to a dose-escalation group where NR 1000mg daily will be administered week 1-4, NR 2000mg daily week 5-8 and NR 3000mg daily week 9-12 (n =40). Both the participants and the investigators will be blinded.

Primary Objective:

To determine the Optimal Biological Dose (OBD) for NR, defined as the dose required to achieve: maximal cerebral NAD increase (measured by 31P-MRS or CSF metabolomics), or maximal expression alteration (measured by FDG-PET), or maximal proportion of MRS-responders, in the absence of unacceptable toxicity.

Secondary Objectives:

* Determine the safety and tolerability of NR doses 2000 mg and 3000 mg daily in AD, measured by the frequency and severity of adverse events.
* Determine if NR improves cognitive dysfunction in AD and determine the dose-response of this effect.
* Determine if NR improves cognitive dysfunction in AD and determine the dose-response of this effect.

Experimental objectives:

* Determine whether NR-therapy ameliorates proteostasis, by upregulating the expression of lysosomal and proteasomal pathways, and whether this effect is dose-dependent.
* Determine the dose-responsive effects of NR on gene and protein expression in AD.
* Determine whether NR-therapy decreases inflammatory markers in a dose-responsive manner.
* Determine whether NR-therapy influences histone acetylation status in AD in a dose-responsive manner.
* Determine whether NR-therapy, in any of the tested doses, affects methylation metabolism. Specifically, whether NR-therapy, in any of the tested doses, leads to decreased availability of methylation substrates and, as a result, any of the following:

  * Decreased availability of methyl-donors, e.g. S-adenosyl methionine (SAM).
  * Decreased DNA methylation (globally or at specific sites).
  * Decreased synthesis of neurotransmitters like dopamine and serotonin.
  * Aberrant folate and one-carbon metabolism
* Explore the relationship between NR-therapy and the gut microbiome in AD, and whether this effect is dose-responsive.

Procedures:

All participants will attend study visits at Baseline, week 4, week 8 and week 12. The study visits will consist of the following:

Assessment by physician and study nurse involved in the study including The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Clinical Dementia Rating (CDR), Montreal Cognitive Assessment Test (MoCA), Trail Making Test (TMT), The Lawton Instrumental Activities of Daily Living Scale (IADL), The Physical Self-Maintenance Scale (PSMS), Montgomery-Asberg Depression Rating Scale (MADRS), the The Neuropsychiatric Inventory Questionnaire (NPI-Q)

A 31P-magnetic resonance spectroscopy (MRS), 1H-magnetic resonance spectroscopy (MRS) and fluorodeoxyglucose-positron emission tomography (FDG-PET) scan.

Physical examination and measurement of vital signs. Routine blood tests. Urine sample collection. Faecal sample collection at Baseline and week 12. Cerebrospinal fluid (CSF) collection will be performed at Baseline and week 12.

Eligibility criteria: Inclusion Criteria:

* The following condition must apply to the prospective patient at screening prior to receiving study agent:

  * Diagnosis of probable Alzheimer Disease (AD) according to the core clinical criteria updated in the National Institute on Aging (NIA) and Alzheimer's Association guidelines.
  * Biomarker evidence consistent with AD neuropathologic change, defined by cerebrospinal fluid (CSF) markers.
  * Diagnosed with AD within two years from enrollment.
  * Clinical Dementia Rating (CDR) 0.5-1 (inclusive) at enrollment.
  * Age 50 to 85 years (inclusive) at the time of enrollment.
  * A study partner (i.e. a family member or a friend) able to provide study data and assist the participant in the study drug administration, i.e. contact ≥ 3 times weekly.
  * Capacity to provide written informed consent for study participation defined as Montreal Cognitive Assessment (MoCA) score ≥ 16 or Mini Mental State Evaluation (MMSE) score ≥ 20. MMSE or MoCA must have been performed within 6 months prior to baseline. If there is any doubt regarding the participants capacity to give informed consent we will ask for an independent evaluation by a consultant clinician who is not associated with the N-DOSE AD study.
  * Cholinesterase inhibitors and memantine can be used if stable for 8 weeks prior to baseline visit.
  * Able to undergo lumbar puncture.
  * Able to undergo magnetic resonance imaging (MRI)

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

* Diagnosis of dementia other than probable AD.
* Comorbidity that precludes study participation or data interpretation.
* Any psychiatric disorder that would interfere with compliance in the study.
* Any severe somatic illness that would interfere with compliance and participation in the study.
* Use of high dose vitamin B3 supplementation within 30 days of enrollment.
* Metabolic, neoplastic, or other physically or mentally debilitating disorder at baseline visit.
* Current treatment with Oral Anti-coagulation Therapies
* Implants that preclude MRI examinations, e.g. DBS, pacemaker

Primary outcomes:
measure: The between-visit difference in cerebral nicotinamide adenine dinucleotide (NAD) levels. Measured by 31P-Magnetic resonance spectroscopy (31P-MRS)
timeFrame: 12 weeks
measure: The between-visit difference in cerebrospinal fluid (CSF) NAD and related metabolite levels.
timeFrame: 12 weeks
measure: The between-visit difference in cerebral metabolism patterns maximal alteration in the cerebral metabolism patterns
timeFrame: 12 weeks
measure: The between-visit difference in the proportion of MRS responders
timeFrame: 12 weeks
Secondary outcomes:
measure: Frequency and severity of adverse events
timeFrame: 12 weeks
measure: Determining the between-visit change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13)
timeFrame: 12 weeks
measure: The between-visit chang in Clinical Dementia Rating scale sum of boxes (CDR-SB)
timeFrame: 12 weeks
measure: Between-visit change cognitive function measured by the Montreal Cognitive Assessment (MoCA) scale
timeFrame: 12 weeks
measure: The between-visit change in executive functioning measured by the Trail Making Test (TMT)
timeFrame: 12 weeks
measure: Between-visit change in the Lawton Instrumental Activities of Daily Living (IADL) Scale
timeFrame: 12 weeks
measure: Between-visit change in the Physical Self-Maintenance Scale (PSMS)
timeFrame: 12 weeks
measure: Between-visit change in neuropsychiatric symptoms, measured by Change in Neuropsychiatric Inventory brief questionnaire form (NPI-Q)
timeFrame: 12 Weeks
measure: Between-change in depressive symptoms, measured by Montgomery-Asberg Depression Rating Scale (MADRS)
timeFrame: 12 weeks
Other outcomes:
measure: Change in gene and protein expression levels related to lysosomal and proteasomal function
timeFrame: 12 weeks
measure: Change in levels of one carbon metabolism metabolites
timeFrame: 12 weeks
measure: Change in levels of monoamine neurotransmitters in CSF
timeFrame: 12 weeks
measure: Change in genomic distribution of DNA methylation
timeFrame: 12 weeks
measure: Change in levels of DNA methylation
timeFrame: 12 weeks
measure: Change in levels of histone acetylation
timeFrame: 12 weeks
measure: Change in genomic distribution of histone acetylation
timeFrame: 12 weeks
measure: Change in gut microbiome composition
timeFrame: 12 weeks
measure: Change in faecal metabolomics
timeFrame: 12 weeks
measure: Change in levels of inflammatory cytokines in serum and CSF
timeFrame: 12 weeks
Locations:
city: Bergen
country: Norway
facility: Haraldsplass Deaconess Hospital
state: Vestland
city: Bergen
country: Norway
facility: Haukeland University Hospital
state: Vestland
Study officials:
affiliation: Haukeland University Hospital
name: Kristoffer Haugarvoll, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: