| Field |
Value |
| Trial ID |
NCT07316296 |
| Phase |
Phase 3 |
| Status |
Recruiting |
| Condition |
Parkinson's Disease |
| Intervention |
Noradrenergic arousal system modulator |
| Sponsor |
To be confirmed |
| Start Date |
2025 |
| Completion Date |
2027 |
¶ Background and Rationale
The noradrenergic system, centered in the locus coeruleus, plays a critical role in arousal, attention, and cognitive function. In Parkinson's disease, the locus coeruleus undergoes significant degeneration, contributing to:
- Non-motor symptoms: Attention deficits, executive dysfunction, and arousal disturbances
- Cognitive impairment: Noradrenergic dysfunction correlates with MCI and dementia in PD
- Sleep disorders: Dysregulation of sleep-wake cycles
- Autonomic dysfunction: Norepinephrine deficiency affects autonomic regulation
The loss of noradrenergic neurons in Parkinson's disease creates a hypodopaminergic state that exacerbates motor symptoms and contributes to non-motor manifestations. Restoring noradrenergic signaling may:
- Improve arousal and attention
- Enhance dopaminergic therapy responsiveness
- Address non-motor symptoms
- Potentially provide neuroprotective effects
- Design: Randomized, double-blind, placebo-controlled
- Duration: 52 weeks (plus optional extension)
- Population: Patients with Parkinson's disease (Hoehn & Yahr 2-3)
- Primary Endpoint: Change in arousal/attention measures
- Active treatment: Noradrenergic modulator at optimized dose
- Placebo: Matching placebo
- Diagnosed Parkinson's disease (UK Brain Bank criteria)
- Hoehn & Yahr stage 2-3
- Stable dopaminergic therapy for ≥4 weeks
- Evidence of noradrenergic dysfunction (clinical assessment)
- MMSE score ≥24
- Atypical Parkinsonism
- Significant psychiatric comorbidity
- Contraindications to noradrenergic agents
- Recent change in PD medications
| Measure |
Description |
Scale |
| Attention/Arousal |
Composite cognitive measure |
Cambridge Neuropsychological Test Automated Battery (CANTAB) |
| Arousal Score |
Clinical arousal assessment |
Noradrenergic Arousal Scale |
- Motor function: UPDRS Parts II/III
- Cognitive function: MoCA, attentional tasks
- Non-motor symptoms: NMSS (Non-Motor Symptom Scale)
- Quality of life: PDQ-39
- Sleep quality: PDSS-2
- Biomarkers: CSF catecholamine levels (exploratory)
- Adverse event monitoring
- Vital signs (including orthostatic BP)
- ECG monitoring
- Laboratory values
The intervention targets alpha-adrenergic receptors in the brain:
flowchart TD
A"Noradrenergic modulator" --> B"Alpha-2 adrenergic receptors"
B --> C"Enhanced norepinephrine signaling"
C --> D"Improved arousal and attention"
C --> E"Modulated prefrontal cortex activity"
E --> F"Better executive function"
D --> G"Reduced non-motor symptoms"
- Alpha-2A adrenergic receptors: Prefrontal cortex, locus coeruleus autoreceptors
- Alpha-2C adrenergic receptors: Striatum, limbic system
The noradrenergic and dopaminergic systems interact closely in Parkinson's disease:
- Locus coeruleus projections modulate dopaminergic neuron activity
- Norepinephrine enhances dopaminergic neurotransmission
- Combined dopaminergic-noradrenergic therapy may provide synergistic benefits
See Locus Coeruleus Degeneration for detailed pathway information.
- Improved arousal: Enhanced wakefulness and attention
- Better cognitive function: Improved executive function and processing speed
- Reduced non-motor symptoms: Addressing sleep and autonomic issues
- Potential disease modification: Neuroprotective effects through enhanced neurotrophic support
- Increased CSF norepinephrine levels
- Improved functional connectivity on fMRI
- Reduced locus coeruleus degeneration markers
¶ Current Status and Timeline
| Milestone |
Expected Date |
| Trial start |
Q1 2025 |
| Enrollment completion |
Q4 2026 |
| Primary analysis |
Q2 2027 |
| Results publication |
Q4 2027 |
¶ Research Gaps and Future Directions
- Biomarker development: Validating noradrenergic biomarkers for patient selection
- Combination therapy: Noradrenergic + dopaminergic approaches
- Disease staging: Timing of intervention in PD progression
- Personalized medicine: Genetic predictors of response
- Aston-Jones & Cohen, Locus coeruleus-norepinephrine function (2005)
- Braak et al., Staging of brain pathology in PD (2003)
- Zarow et al., Neuronal loss in locus coeruleus (2003)
- Berridge & Waterhouse, LC-noradrenergic system modulation (2003)
- Rommelfanger & Weinshenker, Norepinephrine and PD (2007)
- Georgiou-Karistianis et al., Noradrenergic dysfunction in PD (2019)
- Poewe et al., Non-motor symptoms in PD (2017)
- Kalia & Lang, Parkinson's disease (2015)