Clinical trial NCT04810104: Parkinson's Disease With Mild Cognitive Impairment Treated With Nicotinic Agonist Drug
Official title: Parkinson's Disease With Mild Cognitive Impairment Treated With Nicotinic Agonist Drug
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Parkinson Disease
Mild Cognitive Impairment
Keywords: Parkinson's Disease
Mild Cognitive Impairment
Cognition
Lead sponsor: King's College London
Sponsor class: OTHER
Collaborators: name: Helse Stavanger HF
name: Michael J. Fox Foundation for Parkinson's Research
name: Parkinson's UK
name: AstraZeneca
name: Masaryk University
name: Norges Parkinsonforbund, Norway
name: University of Exeter
name: Stichting Lygature
name: Innovative Medicines Initiative
First posted: 2021-03-22
Enrollment: 0
Sex: ALL
Minimum age (years): 50
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study of AZD0328, a selective α7 nicotinic receptor agonist, in PD-MCI.
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Attentional Intensity Index composite factor score from baseline to week 12
timeFrame: From baseline to week 12 (end of treatment period).
Secondary outcomes:
measure: Change in Attentional Intensity Index composite factor score from baseline to week 6
timeFrame: From baseline to week 6 (mid-point of treatment period)
measure: Change in Sustained Attention Index composite factor score from baseline to week 6 and week 12
timeFrame: From baseline to week 6 (mid-point of treatment period) and week 12 (end of treatment period)
measure: Change in Working Memory Index composite factor score from baseline to week 6 and week 12
timeFrame: From baseline to week 6 (mid-point of treatment period) and week 12 (end of treatment period)
measure: Change in Episodic Memory Index composite factor score from baseline to week 6 and week 12
timeFrame: From baseline to week 6 (mid-point of treatment period) and week 12 (end of treatment period)
measure: Change in Memory Speed Retrieval Index composite factor score from baseline to week 6 and week 12
timeFrame: Fom baseline to week 6 (mid-point of treatment period) and week 12 (end of treatment period)
measure: Change in MoCA score from screening to week 12
timeFrame: From screening to week 12 (end of treatment period)
measure: Change in Sustained Attention Index composite factor score from week 12 to week 16
timeFrame: From week 12 (end of treatment period) to week 16 (4 weeks after end of study medication dosing)
measure: Change in Working Memory Index composite factor score from week 12 to week 16
timeFrame: From week 12 (end of treatment period) to week 16 (4 weeks after end of study medication dosing)
measure: Change in Episodic Memory Index composite factor score from week 12 to week 16
timeFrame: From week 12 (end of treatment period) to week 16 (4 weeks after end of study medication dosing)
measure: Change in Memory Speed Retrieval Index composite factor score from week 12 to week 16
timeFrame: From week 12 (end of treatment period) to week 16 (4 weeks after end of study medication dosing)
measure: Change in MDS-UPDRS Part III motor examination subscale score from baseline to week 12
timeFrame: From baseline to week 12 (end of treatment period)
measure: Change in total score from the Non-Motor Symptom Scale from baseline to week 12
timeFrame: From baseline to week 12 (end of treatment period)
measure: Change in total score from the 39-item Parkinson's Disease Questionnaire from baseline to week 12
timeFrame: From baseline to week 12 (end of treatment period)
measure: Change in MCI-CGIC from baseline to week 12
timeFrame: From baseline to week 12 (end of treatment period)
measure: Change in depression and anxiety subscale scores from the HADS from baseline to week 12
timeFrame: From baseline to week 12 (end of treatment period)
measure: Incidence, nature and severity of AEs and SAEs during treatment period
timeFrame: From baseline to week 12 (end of study treatment)
measure: Incidence of dosage reduction or treatment discontinuation during treatment period
timeFrame: From baseline to week 12 (end of study treatment)
measure: Incidence of clinically significant changes or abnormal electrocardiogram (ECG) assessments, vital sign measurements and clinical laboratory values during treatment period
timeFrame: From baseline to week 12 (end of study treatment)
measure: Changes in whole-brain and regionally specific brain volumes from baseline/screening to week 12
timeFrame: From screening/baseline (pre-medication dosing) to week 12 (end of study treatment)
measure: Changes in whole-brain perfusion as well as perfusion in regions of interests (ROIs) from baseline/screening to week 12
timeFrame: From screening/baseline (pre-medication dosing) to week 12 (end of study treatment)
measure: Changes in functional resting-state connectivity of the large-scale cognitive brain networks from baseline/screening to week 12
timeFrame: From screening/baseline (pre-medication dosing) to week 12 (end of study treatment)
Other outcomes:
measure: Screening/Baseline whole-brain and regionally specific brain volumes as predictors of treatment response
timeFrame: At screening/baseline (pre-medication dosing)
measure: Screening/Baseline whole-brain perfusion as well as perfusion in ROIs as predictors of treatment response
timeFrame: At screening/baseline (pre-medication dosing)
measure: Screening/Baseline functional resting-state connectivity of the large-scale cognitive brain networks as predictors of treatment response
timeFrame: At screening/baseline (pre-medication dosing)
measure: Placebo-controlled change in levels of exploratory blood-based biomarkers for neuroprotection and/or disease modification changes
timeFrame: At baseline and week 12
measure: Change in levels of study medication in blood from baseline to week 12
timeFrame: From baseline to week 12 (end of treatment period)
Locations:
Study officials:
affiliation: King's College London; Stavager Univeristy Hospital
name: Dag Aarsland, PhD
role: STUDY_DIRECTOR
References: