Multidisciplinary Study of Novel NMDA Modulation for Neurodegenerative Disorder

Phase 2

Recruiting

• Conditions: Parkinson's Disease With Dementia
• Interventions: Drug: DAAOI-P; Drug: Placebo

• Registration Number: NCT04470037
• Lead Sponsor: China Medical University Hospital

Brief Summary

Alzheimer's disease (AD) and Parkinson's disease (PD) are currently the leading neurodegenerative disorders. Considering the fact that aged population is rapidly growing, it has become a critical issue to find more effective medications for these two disorders. The aim of this project is to examine the effectiveness and safety of DAAOI-P treatment for PD with dementia.

Detailed Description

Alzheimer's disease (AD) and Parkinson's disease (PD) are currently the leading neurodegenerative disorders. Despite some therapeutic benefits from the medications targeting at cholinergic and dopaminergic pathways in AD and PD respectively, it remains far away from a satisfied treatment goal. DAAOI-P is a D-amino acid oxidase (DAAO) inhibitor and an agent specific to facilitate NMDA receptor subunit 1 (NR1). The investigators have demonstrated that NMDA-enhancement can help PD-D patients. The aim of this project is to examine the effectiveness and safety of DAAOI-P treatment for PD with dementia. In addition to evaluating clinical treatment response, multidisciplinary examinations, including electroencephalography, transcranial magnetic stimulation, magnetic resonance imaging (MRI), and psychophysical methods to analyze the changes in perceptual sensitivity to faces, emotion expressions, and biological motion recognition will be arranged to elucidate the underlying mechanism of NMDA modulation in neurodegenerative disorder.

Study Timeline

• Study Start: 2016-04
• Study First Submitted: 2020-05-26
• Study First Submitted QC: 2020-07-09
• Study First Posted: 2020-07-14
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-20
• Last Update Posted: 2024-08-21
• Primary Completion: 2024-12
• Study Completion: 2025-03

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• PD-D will be diagnosed according to the criteria proposed by Movement Disorder Society task force statement. (Emre et al. 2007) . The following wordings are modified from the task force statement. I. Core features

  1. Diagnosis of PD according to Queen Square Brain Bank criteria

  2. A dementia syndrome with insidious onset and slow progression, developing within the context of established PD and diagnosed by history, clinical, and mental examination, defined as:

     • Impairment in more than one cognitive domain
     • Representing a decline from premorbid level
     • Deficits severe enough to impair daily life, independent of the impairment ascribable to motor or autonomic symptoms
     • MMSE score between 10-26.

II. Associated clinical features

1. Cognitive features: Impaired attention, executive functions, visuo-spatial functions or memory. Core functions of language are largely preserved.

2. Behavioral features:

   • Apathy
   • Changes in personality and mood
   • Hallucination• Delusions
   • Excessive daytime sleepiness

III. Features which do not exclude PD-D, but make the diagnosis uncertain

• Co-existence of any other abnormality which may by itself cause cognitive impairment, but judged not to be the cause of dementia.
• Time interval between the development of motor and cognitive symptoms is uncertain

IV. Features suggesting other conditions or diseases as cause of mental impairment, which, when present make it impossible to reliably diagnose PD-D

• Cognitive and behavioral symptoms appearing solely in the context of other conditions such as:

  1. Acute confusion due to systemic illnesses or drug intoxication.
  2. Major depression

• Features compatible with "Probable Vascular dementia" criteria according to NINDS-AIREN Criteria for the diagnosis of probable and possible PD-D [Probable PD-D] Both core features must be present. In associated clinical features, typical profile of cognitive deficits should be present in at least 2 of the 4 core cognitive domains. The presence of at least one behavioral symptom supports the diagnosis of probable PD-D. None of group III and IV features is present. [Possible PD-D] Both core features must be present. In associated clinical features, the cognitive impairment is atypical in one or more domains. The behavioral symptoms are not necessary to be present. One or more of the group III features may be present. No group IV feature is allowed to be present.

Exclusion Criteria

1. Patients with uncontrollable malignancy, severe heart failure, uremia under hemodialysis, or decompensated liver cirrhosis.
2. Patients taking anticholinergics within 30 days of recruitment.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
DAAOI-P	DAAOI-P	DAAOI-P 250-1500mg
Starch pill	Placebo	-

Primary Outcome Measures

Name	Time	Method
The improvement of gait and neuropsychiatric symptoms	week 0, 8, 16, 24	Change in Unified Parkinson's Disease Rating Scale (UPDRS); UPDRS: Unified Parkinson's Disease Rating Scale Minimum value: 0 Maximum value: 199 The higher score means a worse outcome.

Secondary Outcome Measures

Name	Time	Method
The improvement of Parkinson's disease	week 0, 8, 16, 24	Change in The 39-item Parkinson's Disease Questionnaire (PDQ-39); PDQ-39: The 39-item Parkinson's Disease Questionnaire Minimum value: 0 Maximum value: 156 The higher score means a worse outcome.
Behavioral Pathology of dementia	week 0, 8, 16, 24	Change in Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD); Behave-AD: Behavioral Pathology in Alzheimer's Disease Rating Scale Minimum value: 0 Maximum value: 75 The higher score means a worse outcome.
Face perception	week 0, 8, 16, 24	Changes in perceptual discriminability (d-prime index); Minimum value: 0 (chance level); Maximum value: 3.0 (nearly perfect)
Gait function	week 0, 8, 16, 24	The Cyclogram of Gait; Minimum value: 0 Maximum value: 100 The higher score means a better outcome.
Cognitive function	week 0, 8, 16, 24	Change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog); ADAS-Cog: Alzheimer's Disease Assessment Scale-Cognitive Subscale Minimum value: 0 Maximum value: 70 The higher score means a worse outcome.
Severity of dementia	week 0, 8, 16, 24	Change in Clinical Dementia Rating (CDR); CDR: Clinical Dementia Rating Minimum value: 0 Maximum value: 5 The higher score means a worse outcome.
Neuroimaging examinations	week 0, 24	Neuroimaging examinations contains: (1) Structural MRI, (2) Resting-state fMRI, and (3) Working memory fMRI.
Emotion recognition and imitation	week 0, 8, 16, 24	Changes in emotion recognition accuracy and imitation probability; Minimum value: 0%; Maximum value: 100% (Higher score indicate a better outcome)
Fall assessment	week 0, 8, 16, 24	The fall assessment test of China Medical University Hospital; Minimum value: 0 Maximum value: 10 The higher score means a worse outcome.
Neuropsychiatric symptoms	week 0, 8, 16, 24	Change in Neuropsychiatry Inventory (NPI); NPI: Neuropsychiatry Inventory Minimum value: 0 Maximum value: 144 The higher score means a worse outcome
Transcranial magnetic stimulation	week 0, 8, 16, 24	Change in Transcranial Magnetic Stimulation (TMS) assessments
Electroencephalography	week 0, 8, 16, 24	Changes in Mismatch negativity (MMN)

Trial Locations

Locations (1)

Department of Psychiatry, China Medical University Hospital; 🇨🇳 Taichung, Taiwan