N-DOSE AD: A Dose Optimization Trial of Nicotinamide Riboside in Alzheimer's Disease

Alzheimer Disease Clinical Trial

Official title:

N-DOSE AD: A Dose Optimization Trial of Nicotinamide Riboside in Alzheimer's Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05617508
• Other study ID #: 428878
• Status: Recruiting
• Phase: Phase 2
• Start date: November 22, 2022
• Est. completion date: March 31, 2025

Study information

• Verified date: February 2024
• Source: Haukeland University Hospital
• Contact: Kristoffer Haugarvoll, MD, PhD
• Phone: +4798266741
• Email: kristoffer.haugarvoll[@]helse-bergen.no
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: March 31, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Dementia

Intervention

Other:
• Placebo
Placebo capsules administered twice daily for a total of 12 weeks.

Dietary Supplement:
• Nicotinamide Riboside supplementation 1000mg daily in total
Nicotinamide Riboside supplementation 1000mg daily in total
• Nicotinamide Riboside dose escalation (up to 3000 mg daily in total)
Nicotinamide Riboside supplementation up to 3000mg daily in total

Locations

Country	Name	City	State
Norway	Haraldsplass Deaconess Hospital	Bergen	Vestland
Norway	Haukeland University Hospital	Bergen	Vestland

Sponsors (2)

Lead Sponsor	Collaborator
Haukeland University Hospital	Haraldsplass Deaconess Hospital

Country where clinical trial is conducted

Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in gene and protein expression levels related to lysosomal and proteasomal function	The between-visit change in gene and protein expression levels related to lysosomal and proteasomal function in whole blood, measured by RNA sequencing (RNAseq) and proteomics (LC-MS), respectively.	12 weeks
Other	Change in levels of one carbon metabolism metabolites	The between-visit change in one carbon metabolism/methylation pathway metabolites. Measured by HPLC-MS metabolomics in whole blood and CSF.	12 weeks
Other	Change in levels of monoamine neurotransmitters in CSF	The between-visit difference in levels of monoamine neurotransmitters in CSF.	12 weeks
Other	Change in genomic distribution of DNA methylation	The between-visit difference in genomic distribution of DNA methylation, measured by the Illumina Infinium MethylationEPIC Kit.	12 weeks
Other	Change in levels of DNA methylation	The between-visit difference in levels of DNA methylation, measured by the Illumina Infinium MethylationEPIC Kit.	12 weeks
Other	Change in levels of histone acetylation	The between-visit difference in levels of histone panacetylation, and levels of site specific histone acetylation in whole blood, measured by immunoblotting and chromatin immunoprecipitation sequencing (ChIPseq).	12 weeks
Other	Change in genomic distribution of histone acetylation	The between-visit difference in genomic distribution of histone acetylation in whole blood, measured by immunoblotting and chromatin immunoprecipitation sequencing (ChIPseq).	12 weeks
Other	Change in gut microbiome composition	The between-visit difference in gut microbiome composition, assessed by metagenomics in fecal samples.	12 weeks
Other	Change in faecal metabolomics	The between-visit difference in fecal metabolomics, including fatty acid profiling	12 weeks
Other	Change in levels of inflammatory cytokines in serum and CSF	The between-visit difference in levels of inflammatory cytokines in serum and CSF, measured using the ELISA method.	12 weeks
Primary	The between-visit difference in cerebral nicotinamide adenine dinucleotide (NAD) levels. Measured by 31P-Magnetic resonance spectroscopy (31P-MRS)	Measured by 31P-Magnetic resonance spectroscopy (31P-MRS)	12 weeks
Primary	The between-visit difference in cerebrospinal fluid (CSF) NAD and related metabolite levels.	Measured by High-Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS) metabolomics, or the NADMED® method.	12 weeks
Primary	The between-visit difference in cerebral metabolism patterns maximal alteration in the cerebral metabolism patterns	Measured by fluorodeoxyglucose-positron emission tomography (FDG-PET)	12 weeks
Primary	The between-visit difference in the proportion of MRS responders	Measured by 31P-Magnetic resonance spectroscopy (31P-MRS)	12 weeks
Secondary	Frequency and severity of adverse events	The between-visit difference in incidence of treatment-associated mild/moderate/severe adverse events (AEs)	12 weeks
Secondary	Determining the between-visit change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13)	The ADAS-Cog 13 is a psychometric instrument that evaluates memory, attention, reasoning, language, concentration, planning, executive function, and praxis using an 13-point AD Assessment Scale. It has a minimum score of 0 and a maximum severity score of 85, and a higher score indicates more impairment. A reduction in between-visit scores indicates an improvement in cognitive functions.	12 weeks
Secondary	The between-visit chang in Clinical Dementia Rating scale sum of boxes (CDR-SB)	The CDR integrates assessments from 3 domains of cognition (memory, orientation, judgment/problem-solving) and 3 domains of function (community affairs, home/hobbies, personal care). Following caregiver interview and systematic participant examination, the rater assigns a score describing the participant's current performance level in each of these domains of life functioning. The "Sum of boxes" scoring methodology (CDR-SB) sums the score for each of the 6 domains and provides a value ranging from 0 to 18 with higher scores indicating greater impairment. Positive change from baseline indicates greater impairment.	12 weeks
Secondary	Between-visit change cognitive function measured by the Montreal Cognitive Assessment (MoCA) scale	MoCA scale (minimum score = 0, maximum score = 30) and a dichotomized cut-off score for normality of 26 or over. High scores indicate less cognitive impairment than low scores.	12 weeks
Secondary	The between-visit change in executive functioning measured by the Trail Making Test (TMT)	The TMT is a timed test and the goal is to complete the test as accurately and as quickly as possible. Raw scores are reported in seconds to complete the test. For Part B, an average score is 75 seconds and a deficient score is greater than 273 seconds.	12 weeks
Secondary	Between-visit change in the Lawton Instrumental Activities of Daily Living (IADL) Scale	The IADL scale consists of 8 items providing information about telephone use, preparing food, shopping, doing daily household chores, doing laundry, using transport, medication managing, and managing money. Scores range from 0 (dependent) to 8 (independent).	12 weeks
Secondary	Between-visit change in the Physical Self-Maintenance Scale (PSMS)	The PSMS includes 6 items, testing the following areas: toilet use, eating, dressing, physical appearance, deambulation and bath. The PSMS ranges from 1 to 30, with higher scores indicating WORSE functioning.	12 weeks
Secondary	Between-visit change in neuropsychiatric symptoms, measured by Change in Neuropsychiatric Inventory brief questionnaire form (NPI-Q)	The NPI-Q measures the burden of 12 neuropsychiatric symptoms of dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, and appetite/eating. Symptom severity is rated on a 3-point scale with higher scores indicating worse symptoms. Minimum score would be 0 and maximum score would be 36.	12 Weeks
Secondary	Between-change in depressive symptoms, measured by Montgomery-Asberg Depression Rating Scale (MADRS)	MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.	12 weeks