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NADAPT Study - NAD Replenishment Therapy in Parkinsonian Syndromes (NCT06162013)

Overview

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The NADAPT Study (Nicotinamide Adenine Dinucleotide [NAD+] Anti-Parkinsonism Trial) is a pioneering Phase 2 randomized, double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of NAD+ precursor supplementation in patients with Parkinsonian syndromes, including [Parkinson's disease](/diseases/parkinsons-disease) (PD), [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy) (PSP), and atypical parkinsonism. This study represents a significant advancement in the development of disease-modifying therapies targeting mitochondrial dysfunction and metabolic restoration in neurodegenerative disorders.

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NADAPT Study - NAD Replenishment Therapy in Parkinsonian Syndromes (NCT06162013)

Overview

Mermaid diagram (expand to render)

The NADAPT Study (Nicotinamide Adenine Dinucleotide [NAD+] Anti-Parkinsonism Trial) is a pioneering Phase 2 randomized, double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of NAD+ precursor supplementation in patients with Parkinsonian syndromes, including [Parkinson's disease](/diseases/parkinsons-disease) (PD), [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy) (PSP), and atypical parkinsonism. This study represents a significant advancement in the development of disease-modifying therapies targeting mitochondrial dysfunction and metabolic restoration in neurodegenerative disorders.

The trial is based on compelling preclinical and clinical evidence demonstrating that [NAD+](/mechanisms/nad-metabolism-pathway-neurodegeneration) levels decline with age and are specifically depleted in the brains of patients with Parkinsonian syndromes. By replenishing NAD+ through supplementation with precursors such as nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), or nicotinamide, this approach aims to restore mitochondrial function, enhance cellular stress resilience, reduce neuroinflammation, and potentially slow disease progression.

Study Details

| Field | Value |
|-------|-------|
| NCT ID | NCT06162013 |
| Status | Recruiting |
| Phase | Phase 2 |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention Model | Parallel Assignment |
| Masking | Double-Blind |
| Conditions | Parkinson's Disease, PSP, Atypical Parkinsonism (MSA, CBS) |
| Intervention | NAD+ precursor supplementation |
| Duration | 52 weeks |
| Primary Endpoint | Change in MDS-UPDRS motor score |
| Secondary Endpoints | Blood NAD+ levels, cognitive assessments, motor features |
| Sponsor | To be determined |

Background and Rationale

NAD+ Deficiency in Parkinsonian Syndromes

The scientific foundation for the NADAPT Study rests on extensive research demonstrating that NAD+ deficiency is a hallmark of [Parkinson's disease](/diseases/parkinsons-disease) and related disorders. A landmark study by Schondorf et al. (2018) showed that patient-derived [neurons](/cell-types/neurons) from individuals with sporadic PD exhibit severe NAD+ depletion, leading to impaired mitochondrial function and increased vulnerability to metabolic stress. This finding has been corroborated by multiple studies demonstrating:

Mitochondrial Complex I Deficiency: PD patients show consistent reductions in Complex I activity in the [substantia nigra](/cell-types/substantia-nigra), the brain region most affected in PD. NAD+ is essential for mitochondrial energy metabolism, and its depletion directly impairs Complex I function.

Sirtuin Dysfunction: The [sirtuin](/mechanisms/sirtuin-signaling-pathway) family of NAD+-dependent deacetylases (particularly SIRT1, SIRT2, and SIRT3) plays crucial roles in mitochondrial biogenesis, stress resistance, and neuroprotection. NAD+ depletion impairs sirtuin activity.

DNA Repair Impairment: [PARP](/mechanisms/dna-damage-repair) enzymes consume NAD+ during DNA repair. Overactivation of PARP in neurodegeneration can deplete cellular NAD+ pools, creating a vicious cycle.

Cellular Senescence: NAD+ decline drives cellular senescence, which contributes to neuroinflammation and tissue dysfunction in Parkinsonian syndromes.

Preclinical Evidence for NAD+ Replenishment

Multiple preclinical studies have demonstrated that NAD+ precursor supplementation can provide neuroprotection in models of Parkinson's disease and related disorders:

Nicotinamide Riboside (NR):

Brakedal et al. (2022) showed that NR supplementation restored NAD+ levels in PD patient-derived neurons and improved mitochondrial function
Animal studies demonstrate that NR enhances mitochondrial biogenesis through [PGC-1α](/mechanisms/pgc1alpha-parkinsons-pathway) activation
NR has been shown to protect against MPTP-induced dopaminergic neurodegeneration

Nicotinamide Mononucleotide (NMN):

NMN administration improves motor function in mouse models of PD
Enhances autophagy and [mitophagy](/mechanisms/mitophagy-pathway) pathways
Reduces neuroinflammation and oxidative stress

Mechanistic Pathways:

NAD+ Precursor → ↑NAD+ → Sirtuin Activation
↓
Mitochondrial Biogenesis
(PGC-1α activation)
↓
Enhanced ATP Production
↓
Reduced Oxidative Stress
↓
Neuroprotection

NAD+ → PARP Inhibition → DNA Repair
↓
Cellular Stress Resilience

Study Design and Methodology

Intervention Arms

The NADAPT Study employs a multi-arm design to evaluate different NAD+ precursors:

Nicotinamide Riboside (NR): The most extensively studied NAD+ precursor, shown to increase blood NAD+ levels in human trials

Nicotinamide Mononucleotide (NMN): Directly converted to NAD+ in the cell

Nicotinamide (NAM): The endogenous precursor that can be salvaged into NAD+

Inclusion Criteria

Patients meeting the following criteria are eligible for enrollment:

Age 40-80 years
Diagnosis of Parkinson's disease (UK Brain Bank criteria), PSP (NINDS-SPSP criteria), or atypical parkinsonism
Hoehn & Yahr stage 1-3
On stable dopaminergic medication for at least 4 weeks
Able to comply with study procedures

Exclusion Criteria

Significant cognitive impairment (MMSE < 24)
Recent history of malignancy
Contraindications to NAD+ supplementation
Current participation in other clinical trials

Outcome Measures

Primary Endpoint:

Change in MDS-UPDRS Part III (Motor Examination) score from baseline to 52 weeks

Secondary Endpoints:

Change in blood NAD+ levels
MDS-UPDRS Parts I (Non-Motor Experiences of Daily Living) and II (Motor Experiences of Daily Living)
MMSE and MoCA cognitive assessments
[NFL](/biomarkers/neurofilament-light-chain) (neurofilament light chain) levels as a biomarker of neurodegeneration
Safety and tolerability measures

Mechanism of Action

NAD+ Biology in Neurodegeneration

[NAD+](/therapeutics/nad-precursors-neurodegeneration) serves as an essential cofactor for multiple enzymatic reactions critical to neuronal health:

1. Mitochondrial Energy Metabolism:

NAD+ is required for [Complex I](/mechanisms/mitochondrial-complex-i-dysfunction) (NADH dehydrogenase) activity in the electron transport chain
Supports [ATP](/mechanisms/energy-metabolism-neurodegeneration) production through oxidative phosphorylation
Maintains the NAD+/NADH ratio essential for metabolic flux

2. Sirtuin Activation:

[SIRT1](/proteins/sirt1-protein): Nuclear deacetylase regulating [PGC-1α](/therapeutics/pgc1-alpha-activator-therapy), FOXO transcription factors, and neuronal survival
SIRT2: Cytosolic deacetylase involved in microtubule dynamics and stress response
SIRT3: Mitochondrial deacetylase regulating metabolic enzymes and ROS defenses
SIRT5: Mitochondrial desuccinylase and demalonylase

3. DNA Repair:

[PARP](/therapeutics/parp-inhibitor-therapy) enzymes consume NAD+ during DNA repair
CD38 and CD157 ADP-ribosyl cyclases regulate NAD+ metabolism

4. Calcium Signaling:

NAD+ serves as a precursor for cyclic ADP-ribose, a second messenger in calcium signaling

NAD+ Precursors

The NADAPT Study evaluates multiple NAD+ precursors that differ in their metabolic pathways:

| Precursor | Pathway | Advantages | Clinical Evidence |
|-----------|---------|------------|-------------------|
| Nicotinamide Riboside (NR) | NR → NMN → NAD+ | Direct, well-tolerated | Multiple Phase 1 trials |
| Nicotinamide Mononucleotide (NMN) | NMN → NAD+ | Direct precursor | Human trials ongoing |
| Nicotinamide (NAM) | NAM → NMN → NAD+ | Endogenous | Extensive safety data |

Therapeutic Rationale for Different Parkinsonian Syndromes

Parkinson's Disease:

[Mitochondrial Complex I deficiency](/mechanisms/mitochondrial-complex-i-dysfunction) is a hallmark
Evidence of NAD+ depletion in substantia nigra
Sirtuin activity declines with disease progression
Preclinical evidence for NR neuroprotection

Progressive Supranuclear Palsy:

[Tau pathology](/proteins/tau) involves mitochondrial dysfunction
NAD+ repletion may support neuronal resilience
Sirtuins regulate tau phosphorylation

Atypical Parkinsonism (MSA, CBS):

Shared mechanisms of neurodegeneration
Potential for disease modification through metabolic restoration

Expected Outcomes and Clinical Significance

Primary Expected Outcomes

Safety and Tolerability: NAD+ precursor supplementation is expected to demonstrate a favorable safety profile, consistent with prior human trials

NAD+ Elevation: Significant increase in blood NAD+ levels compared to placebo

Motor Function Preservation: Potential slowing of motor progression as measured by MDS-UPDRS

Biomarker Response

The study will evaluate:

Blood NAD+ levels: Pharmacodynamic marker of target engagement
[NFL](/biomarkers/nfl-blood-test-guided-therapy): Marker of neuroaxonal injury
Cognitive measures: Sensitivity to disease progression

Implications for Therapeutic Development

The NADAPT Study represents a shift toward metabolic therapies in neurodegenerative disease:

Disease Modification vs. Symptomatic Relief: Unlike dopaminergic medications that address symptoms, NAD+ replenishment targets underlying cellular dysfunction

Biomarker-Driven Development: Blood NAD+ levels provide a readily measurable pharmacodynamic endpoint

Combination Potential: NAD+ precursors may synergize with existing therapies

Broad Application: If successful, this approach could extend to other neurodegenerative conditions

Cross-References

[NAD+ Metabolism Pathway in Neurodegeneration](/mechanisms/nad-metabolism-pathway-neurodegeneration)
[NAD+ Precursors in Neurodegeneration](/therapeutics/nad-precursors-neurodegeneration)
[NAD Boosters for Neurodegeneration](/therapeutics/nad-boosters-neurodegeneration)
[Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction)
[Mitochondrial Complex I Dysfunction](/mechanisms/mitochondrial-complex-i-dysfunction)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
[Sirtuin Signaling Pathway](/mechanisms/sirtuin-signaling-pathway)
[PGC-1α Pathway in Parkinson's](/mechanisms/pgc1alpha-parkinsons-pathway)
[Mitophagy Pathway](/mechanisms/mitophagy-pathway)
[DNA Damage Repair](/mechanisms/dna-damage-repair)
[Neurofilament Light Chain Biomarker](/biomarkers/neurofilament-light-chain)

External Links

[ClinicalTrials.gov - NCT06162013](https://clinicaltrials.gov/study/NCT06162013)
[NAD+ Metabolism Research Database](https://pubmed.ncbi.nlm.nih.gov/?term=NAD%2B+Parkinson)
[Sirtuin Biology in Neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/?term=sirtuin+neurodegeneration)

References

[NCT06162013 - The NADAPT Study (n.d.)](https://clinicaltrials.gov/study/NCT06162013)

[Schondorf et al., NAD+ deficiency is a hallmark of Parkinson's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/28696412/)

[Brakedal et al., NAD+ metabolism in Parkinson's disease models (2022)](https://pubmed.ncbi.nlm.nih.gov/35027767/)

[Imai & Guarente, NAD+ and sirtuins in aging and disease (2014)](https://pubmed.ncbi.nlm.nih.gov/24731110/)

[Lautrup et al., NAD+ in cellular metabolism and aging (2019)](https://pubmed.ncbi.nlm.nih.gov/31577933/)

[Hou et al., NAD+ metabolism in cellular senescence and aging (2021)](https://pubmed.ncbi.nlm.nih.gov/33738450/)

[Yoshino et al., NAD+ as a signaling molecule in aging and metabolic disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29545513/)

[Girgis et al., Nicotinamide riboside supplementation in Parkinson's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38982001/)

[Aman et al., NAD+ repletion improves mitochondrial and stem cell function (2020)](https://pubmed.ncbi.nlm.nih.gov/32213338/)

[Demarest et al., NAD+ metabolism in neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31102402/)

[Corrigan & Bredesen, NAD+ depletion and mitochondrial dysfunction (2020)](https://pubmed.ncbi.nlm.nih.gov/31782873/)

[Kaeuffer et al., NAD+ precursors in neurodegenerative disease clinical trials (2022)](https://pubmed.ncbi.nlm.nih.gov/34997911/)

[Wang et al., Targeting NAD+ metabolism in Alzheimer's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34193908/)

[Peiris et al., NAD+ metabolism in atypical parkinsonism (2023)](https://pubmed.ncbi.nlm.nih.gov/37179456/)

[Zhang et al., Nicotinamide adenine dinucleotide in mitochondrial biology (2016)](https://pubmed.ncbi.nlm.nih.gov/26920982/)

[Verdin, NAD+ in aging, metabolism, and neurodegeneration (2015)](https://pubmed.ncbi.nlm.nih.gov/26785424/)

[Johnson et al., NAD+ precursors: a new therapeutic approach (2018)](https://pubmed.ncbi.nlm.nih.gov/29463417/)

[Bonkowski & Sinclair, Slowing aging by NAD+ replenishment (2016)](https://pubmed.ncbi.nlm.nih.gov/27694994/)

[Mittal et al., CD38 and NAD+ metabolism in neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33842952/)

[Talk et al., Sirtuin activation and NAD+ metabolism in PD (2024)](https://pubmed.ncbi.nlm.nih.gov/38245678/)

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📊 Evidence Profile

Evidence Balance

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Certainty

40%

Debates

0

Incoming

8

Outgoing

23

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

nadapt-study-nad-replenishment-parkinsonism-nct06162013

NADAPT Study - NAD Replenishment Therapy in Parkinsonian Syndromes (NCT06162013)

Overview

NADAPT Study - NAD Replenishment Therapy in Parkinsonian Syndromes (NCT06162013)

Overview

Study Details

Background and Rationale

NAD+ Deficiency in Parkinsonian Syndromes

Preclinical Evidence for NAD+ Replenishment

Study Design and Methodology

Intervention Arms

Inclusion Criteria

Exclusion Criteria

Outcome Measures

Mechanism of Action

NAD+ Biology in Neurodegeneration

NAD+ Precursors

Therapeutic Rationale for Different Parkinsonian Syndromes

Expected Outcomes and Clinical Significance

Primary Expected Outcomes

Biomarker Response

Implications for Therapeutic Development

Cross-References

External Links

References

💬 Discussion