The NADAPT Study (NCT06162013) is an active Phase 2/3 clinical trial investigating NAD replenishment therapy for patients with atypical parkinsonian syndromes, including Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), and Corticobasal Syndrome (CBS). This trial represents a novel approach to neurodegenerative disease treatment by targeting fundamental cellular metabolism rather than directly targeting pathological proteins.
Atypical parkinsonian syndromes are severe neurodegenerative diseases with rapid progression and limited treatment options. Patients typically survive only 3-10 years following diagnosis, with no disease-modifying therapies currently approved. The NADAPT study explores whether replenishing cellular NAD+ levels may provide neuroprotective benefits in these conditions.
| Field |
Value |
| NCT ID |
NCT06162013 |
| Status |
Recruiting |
| Start Date |
March 5, 2024 |
| Phase |
Phase 2/3 |
| Sponsor |
To be determined |
| Clinicaltrials.gov |
NCT06162013 |
| Enrollment |
Approximately 200 participants (estimated) |
| Study Duration |
Approximately 78 weeks (18 months) |
| Study Design |
Randomized, double-blind, placebo-controlled |
NAD+ (nicotinamide adenine dinucleotide) is a critical coenzyme involved in multiple cellular processes that become impaired in neurodegenerative diseases:
- Mitochondrial function: NAD+ is essential for oxidative phosphorylation and ATP production
- Sirtuin activity: NAD+-dependent deacetylases regulate mitochondrial biogenesis, stress response, and aging
- DNA repair: PARP enzymes require NAD+ for DNA damage repair
- Cellular signaling: NAD+ serves as a substrate for various signaling pathways
In neurodegenerative conditions, NAD+ levels decline in the brain, contributing to:
- Mitochondrial dysfunction and energy deficiency
- Impaired cellular stress responses
- Increased neuroinflammation
- Accelerated neuronal death
NAD replenishment has shown promise in multiple preclinical models:
- Nicotinamide riboside (NR) protected dopaminergic neurons in MPTP models
- NMN administration improved mitochondrial function in PINK1 knockout models
- NAD+ precursors restored mitochondrial biogenesis
- NAD+ depletion accelerated tau pathology in mouse models
- Sirtuin activation reduced tau acetylation and aggregation
- NAD+ replenishment improved cognitive function in tau transgenic mice
¶ Aging and Neurodegeneration
- Age-related NAD+ decline correlates with mitochondrial dysfunction
- NAD+ precursors extend lifespan in animal models
- Improvement in multiple age-related biomarkers
The neuroprotective effects of NAD+ replenishment operate through multiple pathways:
- Mitochondrial Restoration: NAD+ supports oxidative phosphorylation and ATP production
- Sirtuin Activation: SIRT1 and SIRT3 promote mitochondrial biogenesis and antioxidant defenses
- DNA Repair Enhancement: PARP activation improves DNA repair capacity
- Anti-inflammatory Effects: NAD+ metabolism modulates inflammatory responses
- Autophagy Induction: Cellular cleanup mechanisms are enhanced
The NADAPT study employs a rigorous randomized, double-blind, placebo-controlled design:
- Randomization: 1:1 ratio of active treatment to placebo
- Blinding: Double-blind (participants and investigators blinded)
- Duration: 78 weeks of treatment plus follow-up
The study enrolls patients with three distinct diagnoses:
- PSP Cohort: Patients with Progressive Supranuclear Palsy
- MSA Cohort: Patients with Multiple System Atrophy
- CBS Cohort: Patients with Corticobasal Syndrome
- Active Treatment: NAD precursor (exact compound to be confirmed)
- Placebo: Matching inactive formulation
To evaluate the safety and efficacy of NAD replenishment therapy in patients with atypical parkinsonian syndromes.
- PSP Cohort: Between-group difference in PSP Rating Scale (PSPRS) total score from baseline to week 78
The PSPRS is a validated tool measuring:
- Motor symptoms (gait, balance, facial expression)
- Oculomotor function
- Bulbar function
- Cognitive/behavioral features
- Disability
- MSA Cohort: Change in Unified Multiple System Atrophy Rating Scale (UMSARS)
- CBS Cohort: Change in Corticobasal Syndrome Rating Scale (CBS-RS)
- Motor assessments: MDS-UPDRS parts I-III
- Cognitive assessments: MMSE, MoCA
- Quality of life: PDQ-39, EQ-5D
- Biomarkers: NAD+ levels, mitochondrial function markers, neuroinflammation markers
- Safety: Adverse events, laboratory values, vital signs
- Participant must understand the nature of the study and provide written informed consent
- Male or female aged 30-85 years at baseline
- 123I-Ioflupane dopamine transporter imaging (DaTSCAN) or FDOPA-PET performed
- Clinical diagnosis consistent with PSP, MSA, or CBS per established criteria
- Significant medical conditions that may interfere with study participation
- Current treatment with NAD+ precursors or supplements
- Contraindications to the study drug
- Pregnant or breastfeeding
- Participation in other clinical trials within 30 days
Atypical parkinsonian syndromes represent a significant unmet medical need:
- No approved disease-modifying therapies: All treatments are symptomatic
- Rapid progression: Median survival 6-9 years
- Severe disability: Patients require extensive care
- Limited response to dopaminergic therapy: Unlike PD
The NADAPT trial represents an important shift in neurodegenerative disease treatment:
- Targeting cellular metabolism: Rather than specific pathological proteins
- Disease-modifying potential: Aiming to slow or halt progression
- Broad applicability: May benefit multiple neurodegenerative conditions
- Repurposing potential: NAD precursors are already available as supplements
| Approach |
Target |
Current Status |
| NADAPT |
Cellular metabolism |
Phase 2/3 |
| Anti-tau immunotherapies |
Tau protein |
Phase 2/3 |
| Anti-α-syn immunotherapies |
α-synuclein |
Phase 2/3 |
| Gene therapy |
Specific genes |
Phase 1/2 |
- Form: Vitamin B3 derivative
- Mechanism: Converted to NAD+ via the NR kinase pathway
- Clinical trials: Ongoing in PD, AD, and aging
- Safety: Well-tolerated in human trials
- Form: Nucleotide precursor
- Mechanism: Directly converted to NAD+
- Clinical trials: Multiple trials in aging and metabolic disease
- Safety: Generally well-tolerated
- Form: Vitamin B3
- Mechanism: Preceding step in NAD+ biosynthesis
- Considerations: May inhibit sirtuins at high doses
| Precursor |
Bioavailability |
Conversion |
Clinical Evidence |
| NR |
Good |
Multi-step |
Moderate |
| NMN |
Good |
Single step |
Growing |
| NAM |
Variable |
Feedback inhibition |
Extensive |
| NRPT |
Good |
Optimized |
Early |
- Blood NAD+ levels: Can be measured to confirm target engagement
- Response variability: Individual differences in NAD+ metabolism
- Dose optimization: May guide individual dosing
- Neurofilament light chain (NfL): Marker of neuronal injury
- Tau and α-synuclein: Disease-specific pathology markers
- Mitochondrial biomarkers: Markers of energy metabolism
Potential biomarkers to predict treatment response:
- Baseline NAD+ levels
- Mitochondrial function assessments
- Genetic variants in NAD+ metabolism genes
NAD+ precursors have generally favorable safety profiles:
- NR: Well-tolerated up to 1000mg/day in clinical trials
- NMN: Safe in human studies up to 500mg/day
- Common adverse events: Generally mild GI symptoms
- Flushing: Common with niacin, less so with NR/NMN
- Liver enzymes: Monitor for elevated transaminases
- Drug interactions: Potential interactions with certain medications
The trial includes comprehensive safety monitoring:
- Regular vital sign measurements
- Laboratory assessments (hematology, chemistry)
- Adverse event monitoring
- Physical examinations
NAD+ replenishment is part of a broader approach to mitochondrial support:
Related approaches include:
Patients interested in participating should:
- Visit ClinicalTrials.gov
- Contact the trial sites directly
- Discuss with their movement disorder specialist
Key factors for consideration:
- Confirmed diagnosis of PSP, MSA, or CBS
- Age 30-85 years
- Ability to attend regular study visits
- Willingness to undergo randomization
- Access to potential active treatment
- Comprehensive medical evaluation
- Contribution to advancing science
- Close monitoring by clinical team
¶ Current Status and Timeline
- Recruitment status: Actively recruiting
- Primary completion: Expected 2026
- Results publication: Expected 2027-2028
If successful, NAD+ replenishment could:
- Become first disease-modifying therapy for atypical parkinsonism
- Be combined with other approaches (immunotherapy, gene therapy)
- Be applied to other neurodegenerative conditions
- Lead to biomarker-driven personalized treatment