N-DOSE

PHASE II RANDOMIZED, DOUBLE-BLIND DOSE OPTIMIZATION TRIAL OF NICOTINAMIDE RIBOSIDE IN PARKINSON’S DISEASE.

Recruiting: YES
ClinicalTrials.gov ID: NCT05589766
Ethics approval ID: (to be updated)
Type of study: phase II, randomized, double blind clinical trial
Single-center: Haukeland University Hospital
Participating countries: Norway

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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 unknown whether improved biological and clinical responses can be achieved by escalating the dose. Moreover, the NADPARK study showed that the NR-mediated increase in cerebral NAD levels, and accompanying metabolic and clinical response, are not universal and vary across individuals. The fact that all NR-recipients showed a robust metabolic response in blood, muscle and CSF, suggests that the variable cerebral NAD response may reflect interindividual variability in cerebral NAD metabolism (i.e., variation in the rate of NAD-synthesis or consumption). It is likely that such differences can be modulated by varying the substrate concentration (i.e., the intake dose of NR). 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 PD. 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 a PD-drug, so that we may harness its full therapeutic potential and maximize its clinical benefit and impact.

INCLUSION CRITERIA


Clinical diagnosis of idiopathic PD according to the MDS criteria

123I-Ioflupane dopamine transporter imaging (DAT-scan) confirming nigrostriatal degeneration


Hoehn and Yahr score
< 4 at enrollment


Age ≥ 40 years at the time of enrollment

EXCLUSION CRITERIA

Dementia or other neurodegenerative disorder at baseline visit.

Diagnosed with atypical parkinsonism (PSP, MSA, CBD) or vascular parkinsonism

Any psychiatric disorder that would interfere with compliance in the study

Metabolic, neoplastic, or other physically or mentally debilitating disorder at baseline visit.

Use of high dose vitamin B3 supplementation within 30 days of enrollment

DESIGN

A phase II, randomized, double-blind dose optimization trial of NR in PD will be conducted. A total of 80 patients with PD 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., UPDRS, MoCA, MMSE, 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 OBJECTIVES

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 PD, 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 PD, 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 PD, 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 PD.

10

Determine whether NR-therapy influences the gut microbiome in PD, 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 2000mg, 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 2000mg 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 total MDS-UPDDRS and individual subsections (part I-IV score) of MDS-UPDRS
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:
• Gene and protein expression levels of factors involved in lysosomal and proteasomal function.
• Levels of histone panacetylation, and levels and genomic distribution of H3K27 and H4K16 acetylation in PBMC, measured by immunoblotting and chromatin immunoprecipitation sequencing (ChIPseq).
• Levels of inflammatory cytokines in serum and CSF, measured using ELISA
• 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.
• Gene and protein expression levels in PBMC, measured by RNA sequencing (RNAseq) and proteomics (LC-MS), respectively.
• Gut microbiome, assessed by metagenomics in fecal samples.

START DATE

28 November 2022

END DATE (ESTIMATED)

31 December 2024