NO-PARK

A PHASE II RANDOMIZED, DOUBLE-BLIND
CLINICAL TRIAL OF NICOTINAMIDE RIBOSIDE IN PD

Recruiting: NO
ClinicalTrials.gov ID: NCT03568968
Ethics approval body/ID: REK / 2017/2083
Type of study: phase II, randomized, double-blind clinical trial
Single/multi-center: multi-center
Participating countries: Norway

Access ClinicalTrials.gov

RATIONAL/HYPOTHESIS

To test the potential of NR as a neuroprotective therapy for PD, we will perform NO-PARK (ClinicalTrials.gov: NCT03568968), a multi-centre, phase II randomized double-blinded clinical trial, comparing NR to placebo in individuals with early-stage PD. The central hypothesis of NO-PARK is that oral administration of the NAD precursor NR can boost neuronal NAD levels, rectify neuronal metabolism and inhibit neurodegeneration, resulting in amelioration of clinical symptoms and delayed clinical disease progression in PD. To test the potential of NR as a neuroprotective therapy for PD, we will perform NO-PARK, a multi-centre, phase II randomized double-blinded clinical trial, comparing NR to placebo in individuals with early-stage PD.

INCLUSION CRITERIA

All of the following conditions must apply to the prospective
patient at screening prior to receiving study agent:

Have a clinical diagnosis of idiopathic PD according to the MDS clinical diagnostic criteria for Parkinson’s disease.

[¹²³I]FP-CIT single photon emission CT (DaTscan) confirming nigrostriatal degeneration.


Diagnosed with PD within 2 years from enrolment.


Hoehn and Yahr score
< 3 at enrolment.

Optimal symptomatic therapy, not requiring adjustments, for at least 1 month.


Age equal to or greater than 35 years at time of enrollment.

EXCLUSION CRITERIA

Patients will be excluded from the study if they meet any of the following 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

Any severe somatic illness that would make the individual unable to comply and participate in the study

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


Genetically confirmed mitochondrial disease

DESIGN

Individuals with PD (n = 400) will be recruited starting 01/10/2020 from eight centres across all four health regions of Norway: 1) Haukeland University Hospital (HUS, leading site), Bergen; 2) Akershus University Hospital (AHUS), Akershus, Oslo; 3) Ullevål University Hospital (UUH), Oslo; 4) Rikshospitalet (RH), Oslo; 5) Drammen Hospital (DH), Drammen; St. Olavs University Hospital (St. Olavs), Trondheim; 6) University Hospital of North Norway (UNN), Tromsø; 7) Dr Karen Herlofson Practice and Arendal Hospital (AH), Arendal; 8) Førde Central Hospital (FCH), Førde.


Eligible and consenting men and women with PD will be given dopaminergic therapy plus MAO-B inhibitor titrated to optimal clinical effect. The treatment regime will then be frozen and remain unchanged for the study period (52 weeks). If adverse effects occur due to the dopaminergic therapy after enrollment, the treatment will be adjusted according to good clinical practice. After the initial assessment, participants will be randomly assigned to either NR 500 mg x 2/day, or placebo and followed with regular clinical examination, brain imaging and blood tests for a total period of one year.

OBJECTIVES

PRIMARY OBJECTIVE: Determine whether NR delays disease progression in PD, as measured by the difference between the NR and placebo groups in total MDS-UPDRS (part I – IV) score change after 52 weeks of follow-up.

SECONDARY OBJECTIVES: Determine whether high dose oral NR:

1

Improves and/or prevents specific motor, non-motor and cognitive symptoms and/or improves patient quality of life in PD as measured by individual subsections of the MDS-UPDRS (e.g. MDS-UPDRS part 1, 2, 3 and 4), as well score difference measured by NMSQ, NMSS, Hoehn&Yahr, MoCA and EQ-5D.

2

Delays nigrostriatal degeneration, measured by DAT-scan and/or diffusion tensor imaging (DTI)

3

Delays brain atrophy (global or focal), measured by MRI volumetry

EXPLORATORY OBJECTIVES: include determining whether high dose oral NR:

1

improves brain spatiotemporal functional and structural connectivity measured by fMRI

2

Rectifies NAD metabolism and related metabolic and epigenetic effects, measured by brain [31P]-MRS, and multi-omics in patient biosamples

3

Ameliorates mitochondrial dysfunction, measured by qualitative and quantitative molecular tests in patient biosamples

4

Delays the progression of neuronal loss, measured by neurofilament light-chain in patient serum

OUTCOMES

PRIMARY OUTCOME:
The primary endpoint will be the between-group difference of change in total MDS-UPDRS (part I – IV) score after 52 weeks of treatment, comparing the active NR arm versus placebo arm.

SECONDARY OUTCOMES:Between-group (NR vs. placebo) differences in:
1. Individual subsections of the MDS-UPDRS (e.g., MDS-UPDRS part 1, 2, 3 and 4), and scores measured by NMSQ, NMSS, Hoehn&Yahr, MoCA and EQ-5D.
2. Clinical laboratory values
3. Dopamine transporter density as measured by DaTscan
4. Density of the nigrostriatal pathway, measured by DTI
5. Brain volume (total and area specific) measured using MRI.

EXPLORATORY OUTCOMES:
Between-group (NR vs. placebo) differences in:
1. Default brain fMRI resting state
2. Brain spatiotemporal functional and structural connectivity measures using MRI and fMRI.
3. Default resting state measured using fMRI.
4. In vivo levels of cerebral total NAD (i.e., the sum of NAD+ and NADH), and NAD+/NADH ratio (if feasible), ATP, phosphocreatine and other phosphorylated metabolites measured by 31P-MRS.
5. In vivo levels of cerebral neurotransmitters, lactate and phosphocreatine measured by 1H-MRS.
6. NAD metabolome in whole blood/PBMC/muscle, measured by mass spectrometry (LC-MS/MS Q-Exactive HF)
7. Transcriptome in whole blood/PBMC/muscle
8. Proteome in serum, whole blood/PBMC/muscle.
9. Histone acetylation profiles in PBMC/muscle.
10. Mitochondrial respiratory complex quantity and function in PBMC/muscle.
11. mtDNA quantitative and qualitative characteristics in PBMC/muscle
12. Neurofilament light-chain difference, measured in serum
13. Within-group (stratification) differences in treatment outcomes. Association between any clinical, imaging and/or molecular measures with clinical and/or biological outcomes.

START DATE

15th May 2020

END DATE (ESTIMATED)

31st December 2024