PHASE II RANDOMIZED, DOUBLE-BLIND DOSE OPTIMIZATION TRIAL OF NICOTINAMIDE RIBOSIDE IN ALZHEIMER’S DISEASE
Recruiting: From September 2022
ClinicalTrials.gov ID: NCT05617508
Ethics approval ID: (to be updated)
Type of study: phase II, randomized, double-blind clinical trial
Single-center: Haukeland University Hospital
Participating countries: Norway
RATIONAL/HYPOTHESIS
While the NADPARK study showed significant biological and clinical effects with 1000mg NR daily, higher doses have not been explored in PD. Therefore, it remains unknow whether improved biological and clinical responses can be achieved by escalating the dose. Moreover, it is not known whether similar dose-responses will be observed in other neurodegenerative disorders, like Alzheimer’s disease (AD). These questions are critical to address, so that NR-therapy can be correctly dosed and tailored to individual patients to achieve an optimal neurometabolic response.
The overarching objective of N-DOSE is to determine the Optimal Biological Dose (OBD) of NR in AD. We define the OBD of NR as the dose required to achieve: maximal cerebral NAD increase (measured by 31P-MRS or CSF metabolomics), or maximal expression increase in the NRRP (measured by FDG-PET), or maximal proportion of MRS-responders, in the absence of unacceptable toxicity.
The outcomes of this project will take us closer to developing NR into an AD-drug, so that we may harness its full therapeutic potential and maximize its clinical benefit and impact.
INCLUSION CRITERIA
Diagnosis of probable mild to moderate AD according to the core clinical criteria updated in the NIA and Alzheimer’s Association guidelines
Biomarker evidence consistent with AD neuropathologic change, defined by CSF markers
Diagnosed with AD within three years from enrolment
Mild to moderate dementia, i.e. CDR 0.5-2 (inclusive) at enrolment
Age 50 to 85 years (inclusive) at the time of enrollment
A study partner able to provide study data and assist the participant in the study drug administration.
Capacity to provide written informed consent for study participation, defined as Montreal Cognitive Assessment (MOCA) score > 16 (corresponding to Mini Mental State Evaluation (MMSE) score > 21.
Standard treatments for dementia, i.e. cholinesterase inhibitors and memantine can be used if stable for 12 weeks prior to screening and baseline visits.
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 enrolment
Metabolic, neoplastic, or other physically or mentally debilitating disorders at baseline visit
Inability to undergo neuroimaging with PET/MRI
DESIGN
A phase II, randomized, double-blind dose optimization trial of NR in AD will be conducted. A total of 80 patients with AD will be recruited and randomized to either placebo (n=20), 1000mg of NR daily for the entire duration of the study (n=20), or an escalating dose of NR from 1000, to 2000, to 3000mg daily with escalation happening every month (n=40). Patients will be followed for 3 months with the following measures taken at baseline and monthly:
1
Clinical assessment with appropriate standardized scales (e.g., ADAS-COG, MoCA, MMSE, IQ-CODE, MADRS, etc.)
2
Safety blood parameters
3
Screening for adverse events
4
Blood, serum, urine and CSF collection for metabolomics, proteomics, transcriptomics, epigenomics (as appropriate in each tissue). NADome will be analyzed using HPLC-MS in blood which has been snap-frozen in liquid nitrogen within 1min from collection, CSF, and potentially urine.
5
Feces collection for metagenomics
6
MRI and 31P-MRS for cerebral NAD measurements
7
FDG-PET
OBJECTIVES
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 increase in the NRRP (measured by FDG-PET), or maximal proportion of MRS-responders, in the absence of unacceptable toxicity.
SECONDARY OBJECTIVES:
1
Determine the safety and tolerability of increasing NR doses in AD, measured by the frequency and severity of adverse events, and changes in vital signs and clinical laboratory values
2
Determine whether NR-therapy improves clinical dysfunction in AD, and whether this effect is dose-dependent.
3
Determine the effect of NR therapy on the NAD metabolome and other metabolites in peripheral blood cells and CSF, and whether this effect is dose-dependent.
EXPERIMENTAL OBJECTIVES
1
Determine whether NR-therapy ameliorates proteostasis, via enhancing lysosomal and proteasomal function, and whether this effect is dose-dependent.
2
Determine whether NR-therapy influences histone acetylation status in AD, and whether this effect is dose-dependent.
3
Determine whether NR-therapy decreases neuroinflammation and whether this effect is dose-dependent.
4
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:
5
Decreased availability of methyl-donors (e.g., SAM).
6
Decreased DNA methylation (globally or at specific sites).
7
Decreased synthesis of neurotransmitters like dopamine and serotonin.
8
Aberrant folate and one-carbon metabolism
9
Determine the effects of increasing NR-dose on gene and protein expression in AD.
10
Determine whether NR-therapy influences the gut microbiome in AD, and whether this effect is dose-dependent.
OUTCOMES
PRIMARY OUTCOME:
The between-visit difference in the dose-escalation group (i.e., baseline vs NR 1000mg, NR 1000mg vs NR 1500mg, NR 2000mg vs NR 3000mg) in:
1. Cerebral NAD levels (measured by 31P-MRS)
2. CSF NAD and related metabolite levels (measured by HPLC-MS metabolomics)
3. NRRP expression (measured by FDG-PET)
The between-visit difference in the placebo group (i.e., V1 vs V2, V2 vs V3, V3 vs V4) will be assessed to determine the specificity of the findings to the NR-therapy. The between visit difference in the 1000mg NR group will be assessed to identify any time effects and differentiate those from dose-effects.
SECONDARY OUTCOMES:
The between-visit difference in the dose-escalation group (baseline vs NR 1000mg, NR 1000mg vs NR 2000mg, NR 200mg vs NR 3000mg) in:
1. Frequency and severity of adverse events, and changes in vital signs and clinical laboratory values.
2. Disease severity, measured by ADAS-COG score, CDR sum of boxes and individual psychometric scores
3. Levels of metabolites in PBMC and CSF, measured by HPLC-MS and the NADmed method.
EXPERIMENTAL OUTCOMES:
The pairwise between-dose difference in the dose-escalation group (baseline vs NR 1000mg, NR 1000mg vs NR 2000mg, NR 2000mg vs NR 3000mg) in:
1. Gene and protein expression levels of factors involved in lysosomal and proteasomal function.
2. Levels of histone panacetylation, and levels and genomic distribution of H3K27 and H4K16 acetylation in PBMC, measured by immunoblotting and chromatin immunoprecipitation sequencing (ChIPseq).
3. Levels of inflammatory cytokines in serum and CSF, measured using ELISA
4. Levels of one carbon metabolism metabolites, measured by HPLC-MS metabolomics in PBMC and CSF; levels of monoamine neurotransmitters in CSF; levels and genomic distribution of DNA methylation, measured by Illumina Infinium MethylationEPIC Kit.
5. Gene and protein expression levels in PBMC, measured by RNA sequencing (RNAseq) and proteomics (LC-MS), respectively.
6. Gut microbiome, assessed by metagenomics in faecal samples.
START DATE
22nd November 2022