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

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

The investigators recently reported the NADPARK study (ClinicalTrials.gov: NCT03816020), a phase I randomized, double-blinded trial, assessing the tolerability, cerebral bioavailability and molecular effects of NR therapy, 1000mg daily, in PD. The NADPARK study showed that NR 1000mg daily was well tolerated and led to a significant, but variable, increase in cerebral NAD (nicotinamide adenine dinucleotide) levels (measured by 31phosphorous magnetic resonance spectroscopy, 31P-MRS) and related metabolites in the cerebrospinal fluid (CSF). NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography (FDG-PET), and this was associated with mild clinical improvement. The results of the NADPARK trial nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials. The investigators recently conducted the NR-SAFE safety trial comparing 3000mg NR to placebo in 20 participants with PD over 4 weeks (NCT: NCT05344404) which showed no moderate or severe adverse events, and no signs of acute toxicity.

Due to the variability in response to NR in the NADPARK trial, the N-DOSE study will investigate the response to escalating doses of NR from 1000mg to 3000mg over 12 weeks, in order to ascertain the optimal biological dose of NR in PD.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease
• Intervention / Treatment: Other: Placebo; Dietary supplement: Nicotinamide Riboside

Detailed Description

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

Individuals with PD (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 increase in the NRRP (measured by FDG-PET), or maximal proportion of MRS-responders, in the absence of unacceptable toxicity.

Secondary Objectives:

• Determine the safety and tolerability of increasing NR doses in PD, measured by the frequency and severity of adverse events.
• Determine whether NR-therapy improves clinical motor and/or non-motor dysfunction in PD, and whether this effect is dose-dependent.
• Determine the effect of NR therapy on the NAD metabolome and related metabolites in peripheral blood cells and CSF, and whether this effect is dose-dependent.

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 whether NR-therapy decreases neuroinflammation and whether this effect is dose-dependent.
• Determine the effects of increasing NR-dose on gene and protein expression in PD.
• Determine whether NR-therapy influences histone acetylation status in PD, and whether this effect is dose-dependent.

• 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., 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 PD, and whether this effect is dose-dependent.

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 one of the neurologists involved in the study including MDS-UPDRS
• Clinical testing with MDS-NMS, MoCA, EQ-5L and modified GIDS-PD by one of the study nurses involved in the sudy
• 31P-MRS, 1H-MRS and FDG-PET scan.
• Physical examination and measurement of vital signs
• Routine blood tests
• Urine sample collection
• Fecal sample collection

Cerebrospinal fluid collection will be performed at Baseline and week 12

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Charalampos Tzoulis, PhD; Phone Number: +47 94392305; Email: charalampos.tzoulis@helse-bergen.no
• Study Contact Backup: Name: Haakon Berven, MD; Phone Number: +47 48495197; Email: haakonberven@outlook.com

Study Locations

• Norway
  • Vestland
    • Bergen, Vestland, Norway, 5021
      • Recruiting
      • Haukeland University Hospital
      • Contact: Charalampos Tzoulis, PhD; Phone Number: +47 94392305; Email: charalampos.tzoulis@helse-bergen.no
      • Contact: Haakon Berven, MD; Phone Number: +47 48495197; Email: haakonberven@outlook.com
      • Principal Investigator: Charalampos Tzoulis, PhD
      • Sub-Investigator: Haakon Berven, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 98 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Clinically established 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 enrolment.
• Age ≥ 40 years at the time of enrollment.
• Able to undergo lumbar punction.
• Able to undergo MRI.

Exclusion Criteria:

• Dementia or other neurodegenerative disorder at baseline visit.
• Diagnosed with atypical parkinsonism (progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo, no active ingredients. Administered in tablet form twice daily for the duration of the trial (12 weeks).	Other: Placebo; Placebo tablet identical in taste, form and appearance to NR tablets, administered twice daily for a total of 12 weeks.
Experimental: Dietary Supplement: NR 1000mg group; Nicotinamide Riboside 1000mg total daily. Administered in capsule form in doses of 500mg twice daily for the duration of the trial (12 weeks).	Dietary supplement: Nicotinamide Riboside; Nicotinamide Riboside supplementation up to 3000mg daily in total.; Other Names: Niagen; NR
Experimental: Dietary Supplement: NR dose escalation group; Nicotinamide Riboside dose escalation group: 1000mg NR daily in doses of 500mg twice daily (week 1 - week 4), 2000mg NR daily in doses of 1000mg twice daily (week 5 - week 8), 3000mg NR daily in doses of 1500mg twice daily (week 9 - week 12).	Dietary supplement: Nicotinamide Riboside; Nicotinamide Riboside supplementation up to 3000mg daily in total.; Other Names: Niagen; NR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The between-visit difference in cerebral NAD levels.	Measured by 31P-Magnetic resonance spectroscopy (31P-MRS)	12 weeks
The between-visit difference in CSF NAD and related metabolite levels.	Measured by HPLC-MS metabolomics, or the NADmed method.	12 weeks
The between-visit difference in expression of the Nicotinamide Riboside Related Pattern (NRRP).	Measured by FDG-PET.	12 weeks
The between-visit difference in the proportion of MRS responders	Defined as participants displaying significant increase in the Nicotinamide Riboside Related Pattern (NRRP) on FDG-PET.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency and severity of adverse events	The between-visit difference in incidence of treatment-associated adverse events (AEs).	12 weeks
Change in health-related quality of life	The between-visit difference in health-related quality of life, measured by the EuroQol 5L - health-related quality of life (EQ-5L) scale.	12 weeks
Change in NAD-metabolites in whole blood and CSF	The between-visit difference in levels of NAD-metabolites in whole blood and CSF, measured by HPLC-MS and the NADmed method.	12 weeks
Change in MDS-NMS	The between-visit difference in the International Parkinson and Movement Disorder Society Non-Motor Rating Scale (MDS-NMS). The scale ranges from 0 - 832 points. A higher score indicates a worse outcome.	12 weeks
Change in MoCA	The between-visit difference in Montreal Cognitive Assessment (MoCA) scores. The scale ranges from 0-30 points. A lower score indicates a worse outcome.	12 weeks
Change in modified GIDS-PD	The between-visit difference in a modified version of the Gastrointestinal Dysfunction Scale (GIDS-PD). The scale ranges from 1-108 points. A higher score indicates a worse outcome. We will employ a modified version of this score where we will be scoring participants on a monthly basis and not over 6 months as in the non-modified score.	12 weeks.
Change in MDS-UPDRS	The between-visit difference in the International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The scale ranges from 0-199. A higher score indicates a worse outcome.	12 weeks.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Change in levels of monoamine neurotransmitters in CSF	The between-visit difference in levels of monoamine neurotransmitters in CSF.	12 weeks
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
Change in levels of DNA methylation	The between-visit difference in levels of DNA methylation, measured by the Illumina Infinium MethylationEPIC Kit.	12 weeks
Change in gut microbiome composition	The between-visit difference in gut microbiome composition, assessed by metagenomics in fecal samples.	12 weeks
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
Change in levels of histone acetylation	The between-visit difference in levels of histone panacetylation, and levels of H3K27 and H4K16 acetylation in whole blood, measured by immunoblotting and chromatin immunoprecipitation sequencing (ChIPseq).	12 weeks
Change in genomic distribution of histone acetylation	The between-visit difference in genomic distribution of H3K27 and H4K16 acetylation in whole blood, measured by immunoblotting and chromatin immunoprecipitation sequencing (ChIPseq).	12 weeks
Change in fecal metabolomics	The between-visit difference in fecal metabolomics, including fatty acid profiling.	12 weeks

Collaborators and Investigators

• Sponsor: Haukeland University Hospital
• Investigators: Principal Investigator: Charalampos Tzoulis, PhD, Neuro-Sysmed, Haukeland University Hospital and University of Bergen

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2023
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: October 13, 2022
• First Submitted That Met QC Criteria: October 18, 2022
• First Posted (Actual): October 21, 2022

Study Record Updates

• Last Update Posted (Actual): November 28, 2023
• Last Update Submitted That Met QC Criteria: November 22, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Parkinson's disease; Mitochondria; Nicotinamide Riboside; NAD metabolism
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: 2022/426716

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No