Clinical trial NCT05589766: N-DOSE: A Dose Optimization Trial of Nicotinamide Riboside in Parkinson's Disease
Official title: N-DOSE: A Dose Optimization Trial of Nicotinamide Riboside in Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Parkinson Disease
Keywords: Parkinson's disease
NAD metabolism
Mitochondria
Nicotinamide Riboside
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
Collaborators: name: University of Bergen
First posted: 2022-10-21
Enrollment: 80
Sex: ALL
Minimum age (years): 40
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized double-blinded placebo-controlled study. 80 participants randomized in 1:1:2 ratio to either: 1. Placebo (n=20), 2. NR 1000mg for 3 months (n=20), 3. Dose escalation group: NR 1000mg 1st month, NR 2000mg 2nd month, NR 3000mg 3rd month (n=40).
Primary purpose: TREATMENT

Brief 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 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.

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:

  -- 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

Eligibility criteria: 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.

Primary outcomes:
measure: The between-visit difference in cerebral NAD levels.
timeFrame: 12 weeks
Secondary outcomes:
measure: Frequency and severity of adverse events
timeFrame: 12 weeks
measure: The between-visit difference in CSF NAD and related metabolite levels.
timeFrame: 12 weeks
Other outcomes:
measure: The between-visit difference in expression of the Nicotinamide Riboside Related Pattern (NRRP).
timeFrame: 12 weeks
measure: The between-visit difference in expression of the Parkinsons Disease Related Pattern (PDRP).
timeFrame: 12 weeks
measure: Change in NAD-metabolites in whole blood and CSF
timeFrame: 12 weeks
measure: Change in MDS-UPDRS
timeFrame: 12 weeks
measure: Change in MDS-NMS
timeFrame: 12 weeks
measure: Change in MoCA
timeFrame: 12 weeks
measure: Change in health-related quality of life
timeFrame: 12 weeks
measure: Change in modified GIDS-PD
timeFrame: 12 weeks
measure: Change in gene and protein expression levels related to lysosomal and proteasomal function
timeFrame: 12 weeks
measure: Change in levels of one carbon metabolism metabolites
timeFrame: 12 weeks
measure: Change in levels of monoamine neurotransmitters in CSF
timeFrame: 12 weeks
measure: Change in levels of DNA methylation
timeFrame: 12 weeks
measure: Change in genomic distribution of DNA methylation
timeFrame: 12 weeks
measure: Change in levels of histone acetylation
timeFrame: 12 weeks
measure: Change in genomic distribution of histone acetylation
timeFrame: 12 weeks
measure: Change in gut microbiome composition
timeFrame: 12 weeks
measure: Change in fecal metabolomics
timeFrame: 12 weeks
measure: Change in levels of inflammatory cytokines in serum and CSF
timeFrame: 12 weeks
Locations:
city: Bergen
country: Norway
facility: Haukeland University Hospital
state: Vestland
Study officials:
affiliation: Neuro-Sysmed, Haukeland University Hospital and University of Bergen
name: Charalampos Tzoulis, PhD
role: PRINCIPAL_INVESTIGATOR
References: