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.

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.

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. 123I-Ioflupane dopamine transporter imaging (DaTSCAN) or FDOPA- PET has been performed. A negative DaTSCAN cannot be more than two years old at baseline.
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 baseline PSPRS score of <40 for PSP, or baseline UMSARS score < 3 on items: 1, 2, 7-9.
8. Score ≥ 20 on the Mini-Mental State Examination (MMSE) at screening.
9. 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/use of NR or any investigational drugs or device, within 90 days of screening.
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 active neoplastic malignancy (other than non-metastatic dermatological conditions) within two years of the screening visit (Visit 0) or current clinically significant hematological, endocrine, cardiovascular, renal, hepatic, gastrointestinal, or neurological disease. Active neoplastic malignancy is defined as having a known malignant focus and/or receiving anti-cancer treatment. For the non-cancer conditions, if the condition has been stable for at least the one year before the screening visit (Visit 0) and/or 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.
10. Severe dysphagia with inability to swallow study-drug safely at baseline.

Double-blinded trial.