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

Parkinson Disease Clinical Trial

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

Status Recruiting

Clinical Trial Summary

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.

Clinical Trial 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 ;

Related Conditions & MeSH terms

• Parkinson Disease

• NCT number: NCT05589766
• Study type: Interventional
• Source: Haukeland University Hospital
• Contact: Charalampos Tzoulis, PhD
• Phone: 94392305
• Email: charalampos.tzoulis@helse-bergen.no
• Status: Recruiting
• Phase: Phase 2
• Start date: January 23, 2023
• Completion date: December 31, 2024