Clinical research

NO-PARK: a phase II randomized, double-blind clinical trial of nicotinamide riboside in PD 

Recruiting: YES 

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 

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: 

1. Have a clinical diagnosis of idiopathic PD according to the MDS clinical diagnostic criteria for Parkinson’s disease 
2.  [¹²³I]FP-CIT single photon emission CT (DaTscan) confirming nigrostriatal degeneration  
3. Diagnosed with PD within 2 years from enrolment 
4. Hoehn and Yahr score < 3 at enrolment  
5. Optimal symptomatic therapy, not requiring adjustments, for at least 1 month. 
6. 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: 

1. Dementia or other neurodegenerative disorder at baseline visit 
2. Diagnosed with atypical parkinsonism (PSP, MSA, CBD) or vascular parkinsonism 
3. Any psychiatric disorder that would interfere with compliance in the study. 
4. Any severe somatic illness that would make the individual unable to comply and participate in the study.  
5. Use of high dose vitamin B3 supplementation within 30 days of enrollment 
6. Metabolic, neoplastic, or other physically or mentally debilitating disorder at baseline visit.  
7. 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 are: 

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 for enrolment: 01 June 2020 

Expected end date: 31 December 2024 

NR-SAFE: a phase I safety and tolerability study of high-dose nicotinamide riboside in PD 

Recruiting: YES 

ClinicalTrials.gov ID: (to be updated) 

Ethics approval body/ID: REK / 379218 

Type of study: phase I, randomized, double-blind safety trial 

Single/multi-center: single-center (Haukeland University Hospital) 

Participating countries: Norway 

Rational/hypothesis 

It is plausible that the beneficial effects of NR in PD, observed in the NADPARK study, are dose-dependent and more prominent at higher doses. NR doses of up to 2000mg per day have been tested in healthy humans with no signs of toxicity. However, the safety and tolerability of even higher doses is untested. Here, we will assess the safety and tolerability of an oral dose of 3000 mg NR daily. 

Inclusion criteria 

1. Age equal to or greater than 35 years and lower than 100 years at time of enrollment.  
2. Clinical diagnosis of idiopathic PD according to the MDS criteria1,2. 
3. Hoehn and Yahr score < 4 at enrolment.  

Exclusion criteria 

1. Dementia or other neurodegenerative disorder at baseline visit. 
2. Any psychiatric disorder that would interfere with compliance in the study. 
3. Any severe somatic illness that would make the individual unable to comply and participate in the study.  
4. Use of high dose vitamin B3 supplementation within 30 days of enrollment 
5. Metabolic, neoplastic, or other physically or mentally debilitating disorder at baseline visit.  

Design 

We are performing a phase I, randomized, double-blind trial. A total of 20 patients with PD will be recruited and randomized (1:1) to either NR 1500mg x 2 daily or placebo. Patients will be followed for 4 weeks with the following measures: 

1. Clinical assessment (clinical examination, vital signs, ECG) at baseline and every week  
2. Safety blood parameters at baseline, days 3, 5, 7, and then every week 
3. Screening for adverse events at baseline, days 3, 7, and then every week  
4. Blood and urine for metabolomics collected at baseline and day 28 

Objectives 

Primary Objective 

To determine the safety of oral NR dose of 3000mg daily for a period of 4 weeks in individuals with Parkinson’s disease (PD). Safety is defined as:  

1. The absence of moderate or severe, acute or subacute adverse effects associated with an oral NR dose of 3000mg daily. 
2. No significant change in clinical laboratory values associated with an oral NR dose of 3000mg daily.  
3. No significant change in vital parameters associated with an oral NR dose of 3000mg daily. 

 

Secondary objectives: 

To assess the following in relation to an oral NR dose of 3000mg daily: 

1. Tolerability defined as self-reported mild adverse effects by subjects. 
2. Changes in the NAD metabolome and related metabolites 

 

Primary outcome  

Between-group (NR vs. placebo) difference in 

1. Reported moderate/severe acute and subacute adverse effects at the end of study 
2. Safety laboratory values: CRP, ALAT, ASAT, GT, bilirubin, ALP, creatinine, urea, RBC, Hb, WBC with differential, platelets, CK, FT4, TSH, B12, folic acid, homocysteine, methylmalonic acid, sodium, potassium, calcium, fasting glucose, insulin) 
3. Vital parameters: (Blood pressure, pulse, EKG).  

 

Secondary outcomes  

1. Self-reported mild adverse effects after 4 weeks of follow up. 
2. NAD metabolome in whole blood/PBMC measured by mass spectrometry (LC-MS/MS Q-Exactive HF). 

 

Expected start date for enrolment: 07 March 2022 

Expected end date: 06 May 2022 

N-DOSE: a phase II randomized, double-blind dose optimization trial of nicotinamide riboside in Parkinson’s disease.  

Recruiting: From September 2022 

ClinicalTrials.gov ID: (to be updated) 

Ethics approval ID: (to be updated) 

Type of study: phase II, randomized, double blind clinical trial 

Single/multi-center: single-center, Haukeland University Hospital 

Participating countries: Norway 

Rational/hypothesis 

While the NADPARK study showed significant biological and clinical effects with 1000mg NR daily, higher doses have not been explored in PD. Therefore, it remains unknown whether improved biological and clinical responses can be achieved by escalating the dose. Moreover, the NADPARK study showed that the NR-mediated increase in cerebral NAD levels, and accompanying metabolic and clinical response, are not universal and vary across individuals. The fact that all NR-recipients showed a robust metabolic response in blood, muscle and CSF, suggests that the variable cerebral NAD response may reflect interindividual variability in cerebral NAD metabolism (i.e., variation in the rate of NAD-synthesis or consumption). It is likely that such differences can be modulated by varying the substrate concentration (i.e., the intake dose of NR). These questions are critical to address so that NR-therapy can be correctly dosed and tailored to individual patients to achieve an optimal neurometabolic response.  

The overarching objective of N-DOSE is to determine the Optimal Biological Dose (OBD) of NR in PD. We define the OBD of NR 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.  

The outcomes of this project will take us closer to developing NR into a PD-drug, so that we may harness its full therapeutic potential and maximize its clinical benefit and impact. 

Inclusion criteria for

1. Clinical diagnosis of idiopathic PD according to the MDS criteria. 
2. 123I-Ioflupane dopamine transporter imaging (DAT-scan) confirming nigrostriatal degeneration. 
3. Hoehn and Yahr score < 4 at enrollment. 
4. Age ≥ 40 years at the time of enrollment. 

Exclusion criteria 

1. Dementia or other neurodegenerative disorder at baseline visit. 
2. Diagnosed with atypical parkinsonism (PSP, MSA, CBD) or vascular parkinsonism. 
3. Any psychiatric disorder that would interfere with compliance in the study. 
4. Metabolic, neoplastic, or other physically or mentally debilitating disorder at baseline visit.  
5. Use of high dose vitamin B3 supplementation within 30 days of enrollment 

Design 

A phase II, randomized, double-blind dose optimization trial of NR in PD will be conducted. A total of 80 patients with PD will be recruited and randomized to either placebo (n=20), 1000mg of NR daily for the entire duration of the study (n=20), or an escalating dose of NR from 1000, to 2000, to 3000mg daily with escalation happening every month (n=40). Patients will be followed for 3 months with the following measures taken at baseline and monthly:

1. Clinical assessment with appropriate standardized scales (e.g., UPDRS, MoCA, MMSE, etc) 
2. Safety blood parameters 
3. Screening for adverse events 
4. Blood, serum, urine and CSF collection for metabolomics, proteomics, transcriptomics, epigenomics (as appropriate in each tissue). NADome will be analyzed using HPLC-MS in blood which has been snap-frozen in liquid nitrogen within 1min from collection, CSF, and potentially urine. 
5. Feces collection for metagenomics 
6. MRI and 31P-MRS for cerebral NAD measurements 
7. FDG-PET 

Objectives

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:

1. Determine the safety and tolerability of increasing NR doses in PD, measured by the frequency and severity of adverse events, and changes in vital signs and clinical laboratory values. 
2. Determine whether NR-therapy improves clinical dysfunction in PD, and whether this effect is dose-dependent.  
3. Determine the effect of NR therapy on the NAD metabolome and other metabolites in peripheral blood cells and CSF, and whether this effect is dose-dependent.  

Experimental objectives:

1. Determine whether NR-therapy ameliorates proteostasis, via enhancing lysosomal and proteasomal function, and whether this effect is dose-dependent.  
2. Determine whether NR-therapy influences histone acetylation status in PD, and whether this effect is dose-dependent.  
3. Determine whether NR-therapy decreases neuroinflammation and whether this effect is dose-dependent.  
4. 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: 
5. Decreased availability of methyl-donors (e.g., SAM). 
6. Decreased DNA methylation (globally or at specific sites). 
7. Decreased synthesis of neurotransmitters like dopamine and serotonin. 
8. Aberrant folate and one-carbon metabolism 
9. Determine the effects of increasing NR-dose on gene and protein expression in PD.  
10. Determine whether NR-therapy influences the gut microbiome in PD, and whether this effect is dose-dependent.  

Outcomes

Primary Outcome:

The between-visit difference in the dose-escalation group (i.e., baseline vs NR 1000mg, NR 1000mg vs NR 2000mg, NR 2000mg vs NR 3000mg) in:  

1. Cerebral NAD levels (measured by 31P-MRS) 
2. CSF NAD and related metabolite levels (measured by HPLC-MS metabolomics) 
3. NRRP expression (measured by FDG-PET) 

The between-visit difference in the placebo group (i.e., V1 vs V2, V2 vs V3, V3 vs V4) will be assessed to determine the specificity of the findings to the NR-therapy. The between visit difference in the 1000mg NR group will be assessed to identify any time effects and differentiate those from dose-effects.  

Secondary outcomes: 

The between-visit difference in the dose-escalation group (baseline vs NR 1000mg, NR 1000mg vs NR 2000mg, NR 2000mg vs NR 3000mg) in:  

1. Frequency and severity of adverse events, and changes in vital signs and clinical laboratory values. 
2. Disease severity, measured by total MDS-UPDDRS and individual subsections (part I-IV score) of MDS-UPDRS 
3. Levels of metabolites in PBMC and CSF, measured by HPLC-MS and the NADmed method. 

Experimental outcomes:

The pairwise between-dose difference in the dose-escalation group (baseline vs NR 1000mg, NR 1000mg vs NR 2000mg, NR 2000mg vs NR 3000mg) in:  

• Gene and protein expression levels of factors involved in lysosomal and proteasomal function.  
• Levels of histone panacetylation, and levels and genomic distribution of H3K27 and H4K16 acetylation in PBMC, measured by immunoblotting and chromatin immunoprecipitation sequencing (ChIPseq). 
• Levels of inflammatory cytokines in serum and CSF, measured using ELISA 
• Levels of one carbon metabolism metabolites, measured by HPLC-MS metabolomics in PBMC and CSF; levels of monoamine neurotransmitters in CSF; levels and genomic distribution of DNA methylation, measured by Illumina Infinium MethylationEPIC Kit.   
• Gene and protein expression levels in PBMC, measured by RNA sequencing (RNAseq) and proteomics (LC-MS), respectively.  
• Gut microbiome, assessed by metagenomics in fecal samples.  

 

Start date for enrolment: 01 September 2022 

Expected end date: 31 May 2022 

N-DOSE-AD: a phase II randomized, double-blind dose optimization trial of nicotinamide riboside in Alzheimer’s disease

Recruiting: From September 2022 

ClinicalTrials.gov ID: (to be updated) 

Ethics approval ID: (to be updated) 

Type of study: phase II, randomized, double-blind clinical trial 

Single/multi-center: single-center, Haukeland University Hospital 

Participating countries: Norway 

 

Rational/hypothesis 

While the NADPARK study showed significant biological and clinical effects with 1000mg NR daily, higher doses have not been explored in PD. Therefore, it remains unknow whether improved biological and clinical responses can be achieved by escalating the dose. Moreover, it is not known whether similar dose-responses will be observed in other neurodegenerative disorders, like Alzheimer’s disease (AD). These questions are critical to address, so that NR-therapy can be correctly dosed and tailored to individual patients to achieve an optimal neurometabolic response.  

The overarching objective of N-DOSE is to determine the Optimal Biological Dose (OBD) of NR in AD. We define the OBD of NR 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.  

The outcomes of this project will take us closer to developing NR into an AD-drug, so that we may harness its full therapeutic potential and maximize its clinical benefit and impact.  

Inclusion criteria 

1. Diagnosis of probable mild to moderate AD according to the core clinical criteria updated in the NIA and Alzheimer’s Association guidelines 
2. Biomarker evidence consistent with AD neuropathologic change, defined by CSF markers 
3. Diagnosed with AD within three years from enrolment 
4. Mild to moderate dementia, i.e. CDR 0.5-2 (inclusive) at enrolment 
5. Age 50 to 85 years (inclusive) at the time of enrollment 
6. A study partner able to provide study data and assist the participant in the study drug administration.  
7. Capacity to provide written informed consent for study participation, defined as Montreal Cognitive Assessment (MOCA) score > 16 (corresponding to Mini Mental State Evaluation (MMSE) score > 21.  
8. Standard treatments for dementia, i.e. cholinesterase inhibitors and memantine can be used if stable for 12 weeks prior to screening and baseline visits. 

Exclusion criteria 

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

• Diagnosis of dementia other than probable AD 
• Comorbidity that precludes study participation or data interpretation 
• Any psychiatric disorder that would interfere with compliance in the study 
• Any severe somatic illness that would interfere with compliance and participation in the study 
• Use of high dose vitamin B3 supplementation within 30 days of enrolment 
• Metabolic, neoplastic, or other physically or mentally debilitating disorders at baseline visit 
• Inability to undergo neuroimaging with PET/MRI 

 Design 

A phase II, randomized, double-blind dose optimization trial of NR in AD will be conducted. A total of 80 patients with AD will be recruited and randomized to either placebo (n=20), 1000mg of NR daily for the entire duration of the study (n=20), or an escalating dose of NR from 1000, to 2000, to 3000mg daily with escalation happening every month (n=40). Patients will be followed for 3 months with the following measures taken at baseline and monthly: 

1. Clinical assessment with appropriate standardized scales (e.g., ADAS-COG, MoCA, MMSE, IQ-CODE, MADRS, etc.) 
2. Safety blood parameters 
3. Screening for adverse events 
4. Blood, serum, urine and CSF collection for metabolomics, proteomics, transcriptomics, epigenomics (as appropriate in each tissue). NADome will be analyzed using HPLC-MS in blood which has been snap-frozen in liquid nitrogen within 1min from collection, CSF, and potentially urine. 
5. Feces collection for metagenomics 
6. MRI and 31P-MRS for cerebral NAD measurements 
7. FDG-PET 

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:  

1. Determine the safety and tolerability of increasing NR doses in AD, measured by the frequency and severity of adverse events, and changes in vital signs and clinical laboratory values. 
2. Determine whether NR-therapy improves clinical dysfunction in AD, and whether this effect is dose-dependent.  
3. Determine the effect of NR therapy on the NAD metabolome and other metabolites in peripheral blood cells and CSF, and whether this effect is dose-dependent.  

Experimental objectives:  

1. Determine whether NR-therapy ameliorates proteostasis, via enhancing lysosomal and proteasomal function, and whether this effect is dose-dependent.  
2. Determine whether NR-therapy influences histone acetylation status in AD, and whether this effect is dose-dependent.  
3. Determine whether NR-therapy decreases neuroinflammation and whether this effect is dose-dependent.  
4. 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: 
5. Decreased availability of methyl-donors (e.g., SAM). 
6. Decreased DNA methylation (globally or at specific sites). 
7. Decreased synthesis of neurotransmitters like dopamine and serotonin. 
8. Aberrant folate and one-carbon metabolism 
9. Determine the effects of increasing NR-dose on gene and protein expression in AD.  
10. Determine whether NR-therapy influences the gut microbiome in AD, and whether this effect is dose-dependent.  

Primary Outcome 

The between-visit difference in the dose-escalation group (i.e., baseline vs NR 1000mg, NR 1000mg vs NR 1500mg, NR 2000mg vs NR 3000mg) in:  

1. Cerebral NAD levels (measured by 31P-MRS) 
2. CSF NAD and related metabolite levels (measured by HPLC-MS metabolomics) 
3. NRRP expression (measured by FDG-PET) 

The between-visit difference in the placebo group (i.e., V1 vs V2, V2 vs V3, V3 vs V4) will be assessed to determine the specificity of the findings to the NR-therapy. The between visit difference in the 1000mg NR group will be assessed to identify any time effects and differentiate those from dose-effects.  

Secondary outcomes:  

The between-visit difference in the dose-escalation group (baseline vs NR 1000mg, NR 1000mg vs NR 2000mg, NR 200mg vs NR 3000mg) in:  

1. Frequency and severity of adverse events, and changes in vital signs and clinical laboratory values. 
2. Disease severity, measured by ADAS-COG score, CDR sum of boxes and individual psychometric scores 
3. Levels of metabolites in PBMC and CSF, measured by HPLC-MS and the NADmed method. 

Experimental outcomes:  

The pairwise between-dose difference in the dose-escalation group (baseline vs NR 1000mg, NR 1000mg vs NR 2000mg, NR 2000mg vs NR 3000mg) in:  

1. Gene and protein expression levels of factors involved in lysosomal and proteasomal function.  
2. Levels of histone panacetylation, and levels and genomic distribution of H3K27 and H4K16 acetylation in PBMC, measured by immunoblotting and chromatin immunoprecipitation sequencing (ChIPseq). 
3. Levels of inflammatory cytokines in serum and CSF, measured using ELISA 
4. Levels of one carbon metabolism metabolites, measured by HPLC-MS metabolomics in PBMC and CSF; levels of monoamine neurotransmitters in CSF; levels and genomic distribution of DNA methylation, measured by Illumina Infinium MethylationEPIC Kit.   
5. Gene and protein expression levels in PBMC, measured by RNA sequencing (RNAseq) and proteomics (LC-MS), respectively.  
6. Gut microbiome, assessed by metagenomics in faecal samples.  

Start date for enrolment: 01 September 2022 

Expected end date: 31 May 2022 

The STRAT-PARK study: a clinical cohort initiative to stratify PD 

Recruiting: YES 

ClinicalTrials.gov ID: not registered 

Ethics approval body/ID: REK / 74985 

Type of study: longitudinal cohort, observational study 

Single/multi-center: multi-center 

Participating countries: Norway, Canada 

Rational/hypothesis 

The heterogeneity of Parkinson ́s disease (PD) is a major obstacle preventing the development of patient-tailored therapies. Here, we aim to stratify PD by identifying and characterizing subgroups of patients with distinct clinical and/or molecular characteristics. Moreover, we aim to develop biomarkers enabling patient stratification in clinical practice. 

We will establish a population-based cohort from three centres across Norway and Canada. We will follow the cohort yearly and map the longitudinal change of the molecular landscape in clinically accessible tissues of patients and controls. This will elucidate molecular processes implicated in disease initiation and progression and provide an early, crude clustering of patients according to molecular background. Subsequently, we will apply state-of-the-art computational analyses to perform multidimensional integration of our database and identify biomarkers for molecular stratification of PD. Biomarkers will be validated in other appropriate cohorts and assessed for innovation and commercialization potential. Successful biomarkers will enable patient selection for participation in tailored trials. 

Inclusion criteria 

The following inclusion criteria apply:  

1. Have a clinical diagnosis of idiopathic PD according to the MDS clinical diagnostic criteria for Parkinson’s disease 
2.  FP-CIT single-photon emission CT (DaTscan) confirming nigrostriatal degeneration  
3. Hoehn and Yahr score ≤ 4 at enrolment  
4. Capacity to provide written informed consent for study participation. 
5. Age 30-100 years 

Exclusion criteria 

• Comorbidity that precludes study participation. 

Design 

The STRAT-PARK study represents a vast clinical endeavour, co-led by Neuro-SysMed PIs Charalampos Tzoulis in Norway and Mandar Jog in Canada. A total of 1,500-2,000 patients and controls will be recruited from three clinical centres: Haukeland University Hospital (HUS) in Bergen, St. Olavs University Hospital in Trondheim and The London Movement Disorders Centre (LMDC), Ontario, Canada. Subjects will be followed at yearly visits with repeated clinical investigations, neuroimaging, blood and cerebrospinal fluid sampling and muscle biopsy. We are particularly interested in the muscle specimens as this is a post-mitotic tissue that may express epigenetic, mitochondrial and other molecular markers of disease that are undetectable in blood. As part of our clinical characterization, we will implement novel methods of objective motor assessment using body suits with integrated movement sensors, implemented in collaboration with co-PI Prof. Mandar Jog, who is a leading world expert in motion biomechanics for PD and related movement disorders. 

Start date for enrolment: 01 January 2021 

Expected end date: 31 December 2050