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

Haukeland University Hospital

Status and phase: Active, not recruiting; Phase 2

Conditions: Parkinson Disease

Treatments: Dietary Supplement: Nicotinamide Riboside; Other: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT05589766

2022/426716

Details and patient eligibility

About

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 1000 mg to 3000 mg over 12 weeks, in order to ascertain if NR dose escalation beyond 1000 mg per day is biologically meaningful in Parkinson's disease.

Full 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:

  -- The primary objective of the N-DOSE study is to determine if NR dose escalation beyond 1000 mg per day is biologically meaningful in Parkinson's disease, measured by cerebral NAD levels by 31P-MRS, in the absence of unacceptable toxicity.

• Secondary Objectives:

  • Determine the safety and tolerability of NR doses 2000 mg and 3000 mg daily in PD, measured by the frequency and severity of adverse events.
  • Determine whether NR-therapy augments NAD levels in the central nervous system (CNS) in a dose-responsive manner, as measured by LC-MS.

• Exploratory Objectives:

  • Determine whether NR-therapy affects increase in the NRRP in a dose-responsive manner.

  • Determine whether NR-therapy affects increase in the PDRP in a dose-responsive manner.

  • Determine whether NR-thearpy augments the NAD metabolome in the blood, urine and CSF in a dose-responsive manner.

  • Determine whether NR-therapy improves clinical motor dysfunction in PD in a dose-responsive manner.

  • Determine whether NR-therapy improves clinical non-motor dysfunction in PD in a dose-responsive manner.

  • Determine whether NR-therapy affects cognition in PD in a dose-responsive manner.

  • Determine whether NR-therapy affects quality of life in PD in a dose-responsive manner.

  • 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 PD.

  • Determine whether NR-therapy decreases inflammatory markers in a dose-responsive manner.

  • Determine whether NR-therapy influences histone acetylation status in PD 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:

    • 1. Decreased availability of methyl-donors (e.g., SAM).
    • 2. Decreased DNA methylation (globally or at specific sites).
    • 3. Decreased synthesis of neurotransmitters like dopamine and serotonin.
    • 4. Aberrant folate and one-carbon metabolism.

  • Explore the relationship between NR-therapy and the gut microbiome in PD, and whether this effect is dose-responsive.

  • Investigate whether NR-therapy affects the sense of smell.

• 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

Enrollment: 80 estimated patients

Sex: All

Ages: 40 to 100 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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80 participants in 3 patient groups, including a placebo group

Placebo

Placebo Comparator group

Description:

Placebo, no active ingredients. Administered in tablet form twice daily for the duration of the trial (12 weeks).

Treatment:

Other: Placebo

Dietary Supplement: NR 1000mg group

Experimental group

Description:

Nicotinamide Riboside 1000mg total daily. Administered in capsule form in doses of 500mg twice daily for the duration of the trial (12 weeks).

Treatment:

Dietary Supplement: Nicotinamide Riboside

Dietary Supplement: NR dose escalation group

Experimental group

Description:

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).

Treatment:

Dietary Supplement: Nicotinamide Riboside