Parkinson's Disease With Mild Cognitive Impairment Treated With Nicotinic Agonist Drug

Parkinson Disease Clinical Trial

— PD-MIND  

Official title:

Parkinson's Disease With Mild Cognitive Impairment Treated With Nicotinic Agonist Drug

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT04810104
• Other study ID #: PD-MIND
• Secondary ID: 2019-002423-15
• Status: Withdrawn
• Phase: Phase 2
• Start date: October 2022
• Est. completion date: April 2024

Study information

• Verified date: June 2022
• Source: King's College London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To test for the first time the potential of a nicotinic agonist on cognitive symptoms in people with mild cognitive impairment (MCI) in Parkinson's disease (PD), referred to as PD-MCI.

Description:

There is an unmet clinical need to treat PD-MCI. As outlined previously, PD-MCI is common, has important clinical consequences, and there is currently no available treatment. Moreover, the underlying pathology of cognitive impairment in PD indicates that nicotinic agonists may be particularly relevant for this condition. This is a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study of AZD0328, a selective α7 nicotinic receptor agonist, in PD-MCI. The study is an international, multi-centre study, which will take place across sites in Europe. PD-MIND will for the first time test the potential of a nicotinic agonist on cognition in PD-MCI. The primary outcome is attention, as it is a key cognitive domain in the PD-MCI profile and most likely to be affected by a α7 nicotinic agonist. Exploratory outcome measures will guide decisions on the design and conduct of future larger Phase 3 trials. Qualifying participants will be randomly assigned at baseline to either receive 0.5mg twice a day (bis in die, BID) of AZD0328 or placebo for 12 weeks. A total of 160 participants with PD-MCI will be enrolled to the study: 80 in the active (AZD0328) group and 80 in the control (placebo) group. Participants will undertake face-to-face assessments at screening, baseline, and then 3- 6- and 12- weeks after beginning study treatment (see Figure 2 for trial design overview). A subset of 90 participants will also undergo an MRI biomarker component prior to study drug administration and at study end.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: April 2024
• Est. primary completion date: January 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 80 Years

Eligibility

Inclusion Criteria:

• Aged between 50 to 80 years (inclusive) at time of consent
• Duration of motor symptoms of at least 1 year
• Hoehn and Yahr stage between 1 and 3 (inclusive) in ON state
• Diagnosis of PD according to United Kingdom (UK) Brain Bank criteria
• Score on Clinical Dementia Rating (CDR) scale = 0.5
• Diagnosis of PD-MCI according to MDS PD-MCI, Level I criteria
• Duration of cognitive impairment of at least 3 months (to distinguish from mild delirium)

Exclusion Criteria:

• Insufficient fluency in English or local language to complete assessments
• Severe visual or auditory impairment that may interfere with participant's ability to complete assessments
• Unable to provide informed consent at screening visit
• Participation in a clinical study involving an investigational drug within 4 months prior to screening
• Smoking (cigarettes, pipes, cigars, e-cigarettes etc.) or use of smokeless tobacco products (chewing / dipping tobacco, snuff etc.) or anti-smoking nicotine containing products (patches/gum/sprays etc.), within the last 12 weeks
• HADS depression subscale score = 11
• History of deep brain stimulation or other neurosurgical procedure
• Diagnosis of dementia, including Parkinson's disease dementia (PDD) or Dementia with Lewy Bodies (DLB).
• Diagnosis of schizophrenia, bipolar disorder or other psychotic disorder
• Malignant neoplasms within 3 years of screening (except for basal or squamous cell carcinoma of the skin); or had curative surgery/treatment and has been free of malignancy for at least 12 months)
• Any medical condition that in the opinion of the investigator may be contributing to cognitive impairment, above and beyond that caused by the participant's PD,
• Current evidence of any other medical condition not stably or adequately controlled, and which in the opinion of the investigator may affect participant safety or study participation
• Using any prohibited medications or permitted medications that do not meet stable dosing regimen requirements, as specified in section 5.7
• Clinically significant vital sign or ECG measure at screening or baseline visit, that in the opinion of the investigator would prevent participant from safely participating in this study
• Clinically significant clinical laboratory result from screening visit, that in the opinion of the investigator would prevent participant from safely participating in this study
• Significant renal function impairment as indicated by estimated glomerular filtration rate (eGFR) < 45ml/min); Note: The eGFR is calculated using a formula derived from the Modification of Diet in Renal Disease Study (MDRD formula): eGFR= [186.3 x (Creatinine/88.4)-1.154 x (Age)-0.203] x [0.742 if female] x [1.210 if black]
• Unable to complete computerised cognitive test battery
• Marked cerebrovascular disease from MRI or CT scan within last 12 months (defined as Fazekas scale = grade 3)
• Females who are breast-feeding
• Female participants assessed as being of child-bearing potential that have a positive pregnancy test at screening or baseline
• The participant does not understand or agree to comply with the contraception or reproductive requirements of the study

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Mild Cognitive Impairment
• Parkinson Disease

Intervention

Drug:
• AZD0328
Active study drug
• Placebo
Non-active study drug

Locations

Country	Name	City	State
n/a

Sponsors (10)

Lead Sponsor	Collaborator
King's College London	AstraZeneca, Helse Stavanger HF, Innovative Medicines Initiative, Masaryk University, Michael J. Fox Foundation for Parkinson's Research, Norges Parkinsonforbund, Norway, Parkinsons Org UK, Stichting Lygature, University of Exeter

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Screening/Baseline whole-brain and regionally specific brain volumes as predictors of treatment response	MRI scans	At screening/baseline (pre-medication dosing)
Other	Screening/Baseline whole-brain perfusion as well as perfusion in ROIs as predictors of treatment response	MRI scans	At screening/baseline (pre-medication dosing)
Other	Screening/Baseline functional resting-state connectivity of the large-scale cognitive brain networks as predictors of treatment response	MRI scans	At screening/baseline (pre-medication dosing)
Other	Placebo-controlled change in levels of exploratory blood-based biomarkers for neuroprotection and/or disease modification changes	Blood-based biomarkers (e.g. cytokines, amyloid species, tau and alpha-synuclein)	At baseline and week 12
Other	Change in levels of study medication in blood from baseline to week 12	Levels of study medication in blood	From baseline to week 12 (end of treatment period)
Primary	Change in Attentional Intensity Index composite factor score from baseline to week 12	The Attentional Intensity Index composite factor score combines the speed scores from the three attention tasks (simple reaction time, choice reaction time and digit vigilance), and has been validated using factor analysis. The measure reflects the ability to focus attention and process information.	From baseline to week 12 (end of treatment period).
Secondary	Change in Attentional Intensity Index composite factor score from baseline to week 6	The Attentional Intensity Index composite factor score combines the speed scores from the three attention tasks (simple reaction time, choice reaction time and digit vigilance), and has been validated using factor analysis. The measure reflects the ability to focus attention and process information.	From baseline to week 6 (mid-point of treatment period)
Secondary	Change in Sustained Attention Index composite factor score from baseline to week 6 and week 12	The Sustained Attention Index composite factor score combines the accuracy scores from choice reaction time and digit vigilance tasks, and reflects the ability to sustain attention and ignore distraction.	From baseline to week 6 (mid-point of treatment period) and week 12 (end of treatment period)
Secondary	Change in Working Memory Index composite factor score from baseline to week 6 and week 12	The Working Memory Index composite factor score combines the accuracy scores from the two working memory tasks to form this measure, which reflects the capability of holding information in working memory.	From baseline to week 6 (mid-point of treatment period) and week 12 (end of treatment period)
Secondary	Change in Episodic Memory Index composite factor score from baseline to week 6 and week 12	The Episodic Memory Index composite factor score combines the verbal recall and recognition tasks with visual recognition. It reflects the longer term memory capability, like how well someone can remember a short story or what they had for dinner last night, or what they did on their last birthday.	From baseline to week 6 (mid-point of treatment period) and week 12 (end of treatment period)
Secondary	Change in Memory Speed Retrieval Index composite factor score from baseline to week 6 and week 12	The Memory Speed Retrieval Index composite factor score combines the speed scores from the two working memory tasks and the picture recognition task. Factor analysis has established that the speed of retrieval from working memory and episodic memory load on a common factor, and the score reflects the time taken to successfully retrieve information held in memory.	Fom baseline to week 6 (mid-point of treatment period) and week 12 (end of treatment period)
Secondary	Change in MoCA score from screening to week 12	The Montreal Cognitive Assessment (MoCA) assesses 8 cognitive areas: visuospatial/executive, naming, memory, attention, language, abstraction, delayed recall, and orientation. Scores range from 0 to 30, with lower scores indicative of greater cognitive impairment.	From screening to week 12 (end of treatment period)
Secondary	Change in Sustained Attention Index composite factor score from week 12 to week 16	The Sustained Attention Index composite factor score combines the accuracy scores from choice reaction time and digit vigilance tasks, and reflects the ability to sustain attention and ignore distraction.	From week 12 (end of treatment period) to week 16 (4 weeks after end of study medication dosing)
Secondary	Change in Working Memory Index composite factor score from week 12 to week 16	The Working Memory Index composite factor score combines the accuracy scores from the two working memory tasks to form this measure, which reflects the capability of holding information in working memory.	From week 12 (end of treatment period) to week 16 (4 weeks after end of study medication dosing)
Secondary	Change in Episodic Memory Index composite factor score from week 12 to week 16	The Episodic Memory Index composite factor score combines the verbal recall and recognition tasks with visual recognition. It reflects the longer term memory capability, like how well someone can remember a short story or what they had for dinner last night, or what they did on their last birthday.	From week 12 (end of treatment period) to week 16 (4 weeks after end of study medication dosing)
Secondary	Change in Memory Speed Retrieval Index composite factor score from week 12 to week 16	The Memory Speed Retrieval Index composite factor score combines the speed scores from the two working memory tasks and the picture recognition task. Factor analysis has established that the speed of retrieval from working memory and episodic memory load on a common factor, and the score reflects the time taken to successfully retrieve information held in memory.	From week 12 (end of treatment period) to week 16 (4 weeks after end of study medication dosing)
Secondary	Change in MDS-UPDRS Part III motor examination subscale score from baseline to week 12	Part III of the Movement Disorder Society's (MDS) Unified Parkinson's Disease Rating Scale (UPDRS), is a motor examination and objective assessment of parkinsonism. This is based on 18 items assessed by the investigator, resulting in 33 scores by location and lateralization. These 33 scores are ratings on severity: from 0 (normal) to 4 (severe).The MDS-UPDRS-III total score ranges from 0 to 132, with higher scores indicative of more severe motor and functional impairment.	From baseline to week 12 (end of treatment period)
Secondary	Change in total score from the Non-Motor Symptom Scale from baseline to week 12	The Non-Motor Symptoms Scale (NMSS) is a 30-item rater-based scale to assess a wide array of non-motor symptoms in patients with Parkinson's disease. The NMSS measures severity (scored 0 - 3) and frequency (scored 1 - 4) of non-motor symptoms across nine dimensions. The NMSS total score ranges from 0 to 360, with higher score indicative of worse non-motor symptoms.	From baseline to week 12 (end of treatment period)
Secondary	Change in total score from the 39-item Parkinson's Disease Questionnaire from baseline to week 12	The 39-item Parkinson's Disease Questionnaire (PDQ-39) is a health-related quality-of-life questionnaire. The questionnaire contains 39 self-reported items on eight domains: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and body discomfort. Each item is scored on 5-point Likert-type scale from 0 (never) - 4 (always), over the past month. The PDQ-39 total score is 156: the lower the score reflects a better health-related quality-of-life.	From baseline to week 12 (end of treatment period)
Secondary	Change in MCI-CGIC from baseline to week 12	The MCI-adjusted Clinical Global Impression of Change (CGIC) score is generated in the context of a semi-structured interview and is an indication of the change in the participant's global status, cognition, behaviour, and functional abilities on a 7-point scale, with the best score being 'marked improvement' and the worst being 'marked worsening.'	From baseline to week 12 (end of treatment period)
Secondary	Change in depression and anxiety subscale scores from the HADS from baseline to week 12	The Hospital Anxiety and Depression Scale (HADS), has an anxiety (score 0 - 21) and a depression subscale (0 - 21), with higher subscales scores indicative of greater levels of depression / anxiety	From baseline to week 12 (end of treatment period)
Secondary	Incidence, nature and severity of AEs and SAEs during treatment period	Adverse Events (AEs) and Serious Adverse Events (SAEs)	From baseline to week 12 (end of study treatment)
Secondary	Incidence of dosage reduction or treatment discontinuation during treatment period	Dosage reduction or treatment discontinuation	From baseline to week 12 (end of study treatment)
Secondary	Incidence of clinically significant changes or abnormal electrocardiogram (ECG) assessments, vital sign measurements and clinical laboratory values during treatment period	Clinically significant laboratory values or vital sign measurements	From baseline to week 12 (end of study treatment)
Secondary	Changes in whole-brain and regionally specific brain volumes from baseline/screening to week 12	MRI scans	From screening/baseline (pre-medication dosing) to week 12 (end of study treatment)
Secondary	Changes in whole-brain perfusion as well as perfusion in regions of interests (ROIs) from baseline/screening to week 12	MRI scans	From screening/baseline (pre-medication dosing) to week 12 (end of study treatment)
Secondary	Changes in functional resting-state connectivity of the large-scale cognitive brain networks from baseline/screening to week 12	MRI scans	From screening/baseline (pre-medication dosing) to week 12 (end of study treatment)