The NADAPT Study: a Randomized Double-blind Trial of NAD Replenishment Therapy for Atypical Parkinsonism

Multiple System Atrophy Clinical Trial

— NADAPT  

Official title:

The NADAPT Study: a Randomized Double-blind Trial of NAD Replenishment Therapy for Atypical Parkinsonism

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06162013
• Other study ID #: 2023/634814
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: January 2024
• Est. completion date: December 2028

Study information

• Verified date: November 2023
• Source: Haukeland University Hospital
• Contact: Charalampos Tzoulis, MD, PhD
• Phone: 55975061
• Email: charalampos.tzoulis[@]helse-bergen.no
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Progressive supranuclear palsy (PSP), Multiple system atrophy (MSA) and corticobasal syndrome (CBS) are severe neurodegenerative diseases with rapid progression and no effective treatment. Patients quickly succumb to increasing motor and non-motor symptoms and survival ranges from ~3 years to ~10 years.

Although PSP, MSA and CBS are rare diseases they constitute a major and mostly unaddressed challenge to health-care providers due to the severity of disease and lack of treatment.

The main hypothesis for the NADAPT trial is that oral administration of NR can boost cellular NAD levels in the central nervous system of patients with PSP, MSA and CBS, and rectify metabolism and inhibit neurodegeneration, resulting in delayed disease progression and amelioration of symptoms for these patients.

To test whether NR is a neuroprotective therapy for atypical parkinsonism, the investigators will perform the NADAPT clinical trial. The investigators will include 130 patients with Progressive supranuclear palsy (PSP), 165 patients with Multiple system atrophy (MSA) and an indeterminate number of patients with corticobasal syndrome (CBS). The participants will be stratified by disease into three cohorts and randomized to either 3000mg NR daily or placebo.

The trial will include patients from all of Norway. Patients will be followed for 78 weeks with both in-clinic visits and decentralized safety measurements and reporting of patient reported outcomes (PROMs). After completion of the 78 weeks follow-up, patients are offered to continue in an open-label NR-only extension study, this extension study will last until follow-up is completed for the last patients in NADAPT.

Description:

Background/Rationale: Atypical parkinsonian syndromes (APS) are rapidly progressive, debilitating, and incurable neurodegenerative diseases, including progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS). These are classified as rare and orphan disorders according to EU regulation, with a reported prevalence of 7/100,000 for PSP, 4.4/100,000 for MSA, and 0.6-1/100,000 for CBS, although accurate numbers for CBS are lacking. Currently, there are no neuroprotective therapies able to delay the progression of APS. Moreover, unlike Parkinson's disease (PD), symptomatic therapy is largely ineffective. Without options for disease modification or symptom relief, patients succumb to rapidly increasing motor and cognitive disability, and become quickly care-dependent, with an estimated overall survival from diagnosis between 3-8 years for PSP, 6-10 years for MSA and ~7 years for CBS. Despite being a source of morbidity and mortality comparable to amyotrophic lateral sclerosis (ALS), there are currently no clinical treatment studies on PSP, MSA, or CBS in Norway, and very few initiatives globally. Given the complete lack of therapy - neuroprotective, symptomatic or palliative - these disorders constitute an important and urgent challenge to health care and society.

Taken together, the findings of our NAD-replenishment trials, NADPARK (NCT03816020) and NR-SAFE (NCT05344404), provide robust experimental evidence that: 1) NR has a dose-dependent symptomatic antiparkinsonistic effect, which occurs on the top of optimal dopaminergic therapy; 2) Nominate NR as a potential neuroprotective therapy for parkinsonism, able to ameliorate cerebral metabolism and dampen neuroinflammation.

Encouraged by these findings, the investigators proposed that NAD-replenishment therapy via oral NR intake could show promise as both symptomatic and neuroprotective therapy for APS. Given the complete lack of treatment options for individuals with PSP, this trial is both timely and necessary.

The investigators will conduct the NADAPT trial, a randomized, double blinded, phase II trial testing the efficacy of NAD replenishment therapy with nicotinamide riboside (NR) as a disease modifying therapy for APS. 130 patients with PSP, 165 patients with MSA, and an undetermined number of patients with CBS will be stratified by disease and randomized 1:1 per disease to receive either 3000mg NR a day or placebo (Fig 1). Follow up will be 18 months and consist of both in-clinic visits and decentralized patient-reported outcomes. NADAPT follows a basket trial design, essentially encompassing three trials in one, and drawing added value from the parallel enrolment and follow up.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 330
• Est. completion date: December 2028
• Est. primary completion date: December 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 85 Years

Eligibility

Inclusion Criteria:

1. Participant must understand the nature of the study and be able to provide written, informed consent.

2. Male or female aged 30-85 years at baseline.

3. DaTSCAN confirming nigrostriatal degeneration (in PSP and MSA, but not necessarily in CBS).

4. Meet the MDS criteria for possible or probable PSP; or

5. Meet the MDS criteria for clinically possible or probable MSA; or

6. Meet the consensus criteria for probable or possible CBS.

7. A time since diagnosis for PSP, MSA, or CBS of = 3 years at baseline.

8. A baseline PSPRS score of <40 for PSP, or baseline UMSARS score < 3 on items: 1, 2, 7-9.

9. Score = 20 on the Mini-Mental State Examination (MMSE) at screening.

10. Able to ambulate independently or with assistance defined as the ability to take at least 5 steps with a walker (guarding is allowed provided there is no contact) or the ability to take at least 5 steps with the assistance of another person who can only have contact with one upper extremity.

Exclusion Criteria:

1. Insufficient fluency in local language to complete neuropsychological and functional assessments.

2. Evidence of differential diagnoses to PSP, MSA or CBS including: PD; dementia with Lewy bodies; Alzheimer's disease; motor neuron disease; history of repeated and/or major stroke; history of repeated and/or severe brain or spinal cord; history of neuroleptic use (except quetiapine) for prolonged period within the last 6 months; history of severe encephalitis; street drug-related parkinsonism; vascular parkinsonism; familial PSP, FTD, or known pathogenic MAPT mutation; prion disease; other neurological disease or MRI findings that could explain the PSP, MSA or CBS symptoms.

3. Presence of other significant neurological or psychiatric disorders including (but not limited to) psychotic disorders; severe bipolar or unipolar depression; seizure disorder; tumor or other space-occupying lesion.

4. Treatment with any putative disease-modifying agent within 90 days of baseline.

5. A history of alcohol or substance abuse within 1 year prior to baseline (Visit 1) and deemed to be clinically significant by the site investigator

6. Any malignancy (other than non-metastatic dermatological conditions) within 5 years of the screening visit (Visit 1) or current clinically significant hematological, endocrine, cardiovascular, renal, hepatic, gastrointestinal, or neurological disease. For the non-cancer conditions, if the condition has been stable for at least the one year before the screening visit (Visit 1) and is judged by the site investigator not to interfere with the subject's participation in the study, the subject may be included.

7. Clinically significant laboratory abnormalities at screening that cannot be corrected to baseline and that is deemed incompatible with study participation by investigator.

8. History of deep brain stimulator surgery other than sham surgery for deep brain stimulation (DBS) clinical trial.

9. History of a clinically significant medical condition that would interfere with the subject's ability to comply with study instructions, would place the subject at increased risk, or might confound the interpretation of the study results.

Related Conditions & MeSH terms

• Corticobasal Degeneration
• Corticobasal Syndrome
• Multiple System Atrophy
• Parkinsonian Disorders
• Progressive Supranuclear Palsy
• Shy-Drager Syndrome
• Supranuclear Palsy, Progressive

Intervention

Dietary Supplement:
• Nicotinamide Riboside
Nicotinamide Riboside 3000mg/day

Other:
• Placebo
Placebo. Identical in taste and appearance as the intervention.

Locations

Country	Name	City	State
Norway	Haukeland University Hospital	Bergen	Vestland
Norway	Oslo University Hospital	Oslo

Sponsors (11)

Lead Sponsor	Collaborator
Haukeland University Hospital	Akershus Universitetssykehus HF, Helse Fonna HF, Helse Førde HF, Helse Møre og Romsdal HF, Nevro Arendal AS, Nordlandssykehuset HF, Oslo universitetssykehus HF, Sykehuset Østfold HF, Universitetssykehuset Nord Norge HF, Vestre Viken HF

Country where clinical trial is conducted

Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Daily function	Real-time wearable sensor-based data to evaluate symptoms of disease/disease burden in the home.	78 weeks
Other	Brain atrophy	MRI-volumetric measurements in the frontal lobe, third ventricle, superior cerebellar peduncle, midbrain, brainstem, and whole brain.	78 weeks
Other	Brain NAD metabolism	NAD levels in the brain parenchyma measured by 31P-MRS, and NAD metabolome in CSF.	78 weeks
Other	Markers of neuroinflammation	Levels of selected inflammatory cytokines in serum and CSF.	78 weeks
Other	CSF and serum biomarkers	Levels of amyloid beta peptide (Aß 1-42)	78 weeks
Other	CSF and serum biomarkers	Levels of tau and phosphorylated tau (PH-tau)	78 weeks
Other	CSF and serum biomarkers	Levels of Neurogranin (NGRN)	78 weeks
Other	CSF and serum biomarkers	Levels of neurofilament light (NfL)	78 weeks
Other	CSF and serum biomarkers	Levels of neurofilament phosphorylated heavy subunit (pNfH)	78 weeks
Other	Blood transcriptome.	Gene expression analyses in blood using RNA-sequencing	78 weeks
Other	Blood proteome.	Proteomics in blood and/or cerebrospinal fluid using mass spectrometry	78 weeks
Other	Blood metabolome.	Metabolomics in blood and/or cerebrospinal fluid using Liquid chromatography-mass spectrometry	78 weeks
Other	Affects brain metabolic patterns	Measured by FDG-PET in a subset of patients (30 per cohort).	78 weeks
Primary	PSP Cohort: Between group difference in PSP Rating Scale (PSPRS) total score from baseline to week 78	Our primary outcome measure for the PSP Cohort is the between group (placebo or NR) difference in Progressive Supranuclear Palsy Rating Scale (PSPRS) total score from baseline to week 78.	78 weeks
Primary	MSA Cohort: Between group difference in Unified MSA Rating Scale (UMSARS) total score from baseline to week 78	Our primary outcome measure for the MSA Cohort is the between group (placebo or NR) difference in the Unified Multiple System Atrophy Rating Scale (UMSARS) total score from baseline to week 78.	78 weeks
Primary	CBS Cohort: Between group difference in PSP Rating Scale (PSPRS) total score from baseline to week 78	Our primary outcome measure for the CBS Cohort is the between group (placebo or NR) difference in Progressive Supranuclear Palsy Rating Scale (PSPRS) total score from baseline to week 78.	78 weeks
Secondary	Safety and tolerability	Monitor frequency and severity of adverse events (AE)	79 weeks (Trial duration of 78 weeks plus 7 days after last dose of intervention or placebo)
Secondary	Specific motor/non-motor symptoms, activities of daily function, and quality of life as measured by the PSPRS	Measured by individual items of the PSPRS	78 weeks
Secondary	Specific motor/non-motor symptoms, activities of daily function, and quality of life as measured by the UMSARS	Measured by individual items of the UMSARS	78 weeks
Secondary	Specific motor/non-motor symptoms, activities of daily function, and quality of life as measured by the UPDRS	Measured by individual items of the Movement disorders society unified parkinson's disease rating scale (UPDRS)	78 weeks
Secondary	Specific motor/non-motor symptoms, activities of daily function, and quality of life as measured by the MoCA	Measured by individual items of the Montreal Cognitive Assesment (MoCA)	78 weeks
Secondary	Specific motor/non-motor symptoms, activities of daily function, and quality of life as measured by the SEADL	Measured by individual items of the Schwab and England Activities of Daily Living (SEADL)	78 weeks
Secondary	Specific motor/non-motor symptoms, activities of daily function, and quality of life as measured by the PSP-QoL	Measured by individual items of the PSP Quality of Life (PSP-QoL)	78 weeks
Secondary	Specific motor/non-motor symptoms, activities of daily function, and quality of life as measured by the MSA-QoL	Measured by individual items of the MSA Quality of Life (MSA-QoL)	78 weeks
Secondary	Specific motor/non-motor symptoms, activities of daily function, and quality of life as measured by the CGI-C	Measured by individual items of the Clinical Global Impression of Change (CGI-C)	78 weeks
Secondary	Specific motor/non-motor symptoms, activities of daily function, and quality of life as measured by the CGI-S	Measured by individual items of the Clinical Global Impressions Scale (CGI-S).	78 weeks
Secondary	Nigrostriatal degeneration	DaTSCAN tracer uptake in the striatum (total and anatomical parts).	78 weeks