A Study of CST-2032 and CST-107 in Subjects With Mild Cognitive Impairment or Mild Dementia Due to Parkinson's or Alzheimer's Disease

Study Overview
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Brief Summary
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This is a Phase 2a, randomized, placebo-controlled, double-blind, crossover study to evaluate the effects CST-2032 administered with CST-107 on cognition in subjects with Mild Cognitive Impairment (MCI) or mild dementia.

Detailed Description
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Approximately 60 subjects will be enrolled in a 2 period, 2-way crossover design following study eligibility confirmation during the screening period. During each treatment period, subjects will receive daily doses of CST-2032 administered with CST-107 or matching placebo for 14 days. Each treatment period will be separated by a washout period of 7 days. All subjects will complete clinical, cognitive and pharmacodynamic assessments during each treatment period. PK blood samples will be collected prior to, during and after study medication administration.

Official Title
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A Phase 2a, Randomized, Placebo-Controlled, Double-Blind, Crossover Study to Evaluate the Effects of CST-2032 and CST-107 on Cognition in Subjects With Mild Cognitive Impairment or Mild Dementia Due to Parkinson's or Alzheimer's Disease

Conditions
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Mild Cognitive Impairment, Dementia

Intervention / Treatment
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* Drug: CST-2032, matching placebo for CST-2032, CST-107, matching placebo for CST-107


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects ≥ 50 and ≤ 85 years of age at time of informed consent. Diagnosis of mild cognitive impairment OR mild dementia due to either: Parkinson's disease associated with REM sleep behavior disorder (RBD+PD) and positive response to the RBD Single-Question Screen (RBD1Q) and without hallucinations; OR Alzheimer's Disease (AD). For subjects taking anti-Parkinsonian medication: stable daily dosing for at least 1 month prior to Screening and through the End of Study If the subject is taking a single drug for AD (e.g., donepezil or other cholinesterase inhibitors or memantine; dual therapy is excluded), they must have been on a stable dose for at least 2 months prior to Day 1, and the dose must remain unchanged during the study unless required for management of adverse events (AEs). Cognitive decline not primarily caused by traumatic, or medical problems (alternative causes of cognitive decline are ruled out). Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments. Has a spouse or caregiver who can accompany the subject at specified study visits (if required based on cognitive function). A score of greater than or equal to one standard deviation below age and educational norms in the Digit Symbol Substitution Test (DSST) during screening or within 6 months prior to Screening. Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 26. Adaptive criteria for enrollment based on the locus ceruleus (LC) neuromelanin sensitive magnetic resonance imaging (NM-MRI) contrast-to-noise ratio (CNR). Unless confirmed to be azoospermic (vasectomized or secondary to medical cause), males must agree to use a male condom from Day 1 until the follow-up visit when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a condom during each episode of penile-vaginal penetration until after the Follow-Up Visit. Females of childbearing potential (i.e., not postmenopausal or surgically sterile) who have a male partner must have a negative serum pregnancy test result and must agree to one of the following from start of Screening through 30 days after the last study medication administration: use a highly effective method of birth control; or monogamous relationship with a male partner of confirmed sterility; or practice complete abstinence. Females of non-childbearing potential may be enrolled if it is documented that they are postmenopausal. Body weight greater or equal to 50 kg and body mass index (BMI) between 18 and 35 kg/m2, inclusive at Screening. Stable medical conditions for 3 months prior to Screening visit (e.g., controlled hypertension, dyslipidemia). Willing to follow the protocol requirements and comply with protocol restrictions. Capable of providing informed consent and complying with study procedures. Exclusion Criteria: Subjects with poorly controlled hypertension despite lifestyle modifications and/or pharmacotherapy. Subjects with pulmonary disease, including asthma if requiring the use of a β2-adrenergic bronchodilator, or evidence of clinically significant moderate or severe pulmonary symptoms. Clinical signs indicating syndromes such as corticobasal degeneration, supranuclear gaze palsy, multiple system atrophy, chronic traumatic encephalopathy, signs of frontotemporal dementia, history of stroke, head injury or encephalitis, cerebellar signs, early severe autonomic involvement, or Babinski sign. Current evidence or history in the past two years of: epilepsy, focal brain lesion, head injury with loss of consciousness or meeting DSM-V diagnostic criteria for psychotic disorders, such as schizophrenia or bipolar disorder, or have unstable concomitant psychiatric symptomatology except for depressed mood. Evidence of any significant clinical disorder or laboratory finding that renders the participant unsuitable for receiving an investigational drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine (including thyrotoxicosis, excluding managed hypo and hyperthyroidism), metabolic, renal, or other systemic disease or laboratory abnormality. History of malignant disease within 5 years, including solid tumors and hematologic malignancies (except basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured). Any clinically significant illness or disease as determined by medical and surgical history, physical examination, 12-lead electrocardiogram (ECG) and clinical laboratory assessments conducted at Screening. Clinically significant abnormalities of ECG, including QTcF > 450 ms, for males and QTcF > 470 ms for females, and/or HR < 50 beats per minute, or evidence of clinically significant bundle branch blocks, as indicated by 12-lead ECG during the Screening Period. A calculated creatinine clearance of ≤60 mL/min according to the Cockcroft-Gault equation. Current use of any prohibited prescription medication, over-the-counter medication, or herbal supplements including green tea/products during Screening or throughout study, unless approved by both the Investigator and the Sponsor Medical Monitor. Prior treatment with any investigational drug ≤90 days prior to dosing (Day 1), or ≤5 half-lives of the drug (whichever is longer), or current enrollment in any other study treatment or disease study, except for observational studies. Known or suspected alcohol or substance abuse within the past 12 months and/or positive test for alcohol or drugs of abuse at Screening or Day 1. Suicidal ideation with actual intent or plan (Yes answer on the C-SSRS ideation items 4 or 5) within 3 months prior to study Screening. Positive screening test for hepatitis C antibody (HCV Ab) or current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] at Screening). Subjects with immunity to hepatitis B (defined as negative HbsAg and positive hepatitis B surface antibody [HbsAb]) are eligible to participate in the study. Positive screening test for human immunodeficiency virus (HIV). Current infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Females who are breastfeeding. Any other reason for which the PI considers it is not in the best interest of the participant to undertake the study.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CST-2032 (3mg)/CST-107 (3mg) to Placebo<br>Subjects will receive daily doses of CST-2032 (3mg) co-administered with CST-107 (3mg) for 14 days, followed by a washout period of no drug for 7 days, followed by matching placebo for CST-2032 and matching placebo for CST-107 for 14 days. | Drug: CST-2032, matching placebo for CST-2032, CST-107, matching placebo for CST-107<br>* CST-2032 and matching placebo white tablets, CST-107 and matching placebo yellow tablets<br>|
| Experimental: Placebo to CST-2032 (3mg)/CST-107 (3mg)<br>Subjects will receive matching placebo for CST-2032 and matching placebo for CST-107 for 14 days followed by a washout period of no drug for 7 days, followed by daily doses of CST-2032 (3mg) co-administered with CST-107 (3mg) for 14 days. | Drug: CST-2032, matching placebo for CST-2032, CST-107, matching placebo for CST-107<br>* CST-2032 and matching placebo white tablets, CST-107 and matching placebo yellow tablets<br>|
| Experimental: CST-2032 (6mg)/CST-107 (3mg) to Placebo<br>Subjects will receive daily doses of CST-2032 (6mg) co-administered with CST-107 (3mg) for 14 days, followed by a washout period of no drug for 7 days, followed by matching placebo for CST-2032 and matching placebo for CST-107 for 14 days. | Drug: CST-2032, matching placebo for CST-2032, CST-107, matching placebo for CST-107<br>* CST-2032 and matching placebo white tablets, CST-107 and matching placebo yellow tablets<br>|
| Experimental: Placebo to CST-2032 (6mg)/CST-107 (3mg)<br>Subjects will receive matching placebo for CST-2032 and matching placebo for CST-107 for 14 days followed by a washout period of no drug for 7 days, followed by daily doses of CST-2032 (6mg) co-administered with CST-107 (3mg) for 14 days. | Drug: CST-2032, matching placebo for CST-2032, CST-107, matching placebo for CST-107<br>* CST-2032 and matching placebo white tablets, CST-107 and matching placebo yellow tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-emergent adverse events | The number of subjects experiencing treatment-emergent adverse events after receiving CST-2032 doses of 3mg and 6mg co-administered with a CST-107 dose of 3mg compared to placebo | Change from Baseline after 14 days of treatment | 
| Vital Signs | Change from Baseline in supine blood pressure (diastolic blood pressure and systolic blood pressure) after CST-2032 doses of 1mg and 6mg co-administered with a CST-107 dose of 3mg compared to placebo | Change from Baseline after 14 days of treatment | 
| Electrocardiograms (ECGs) | Change from Baseline in QTc interval using the Fredericia (QTcF) and Bazett (QTcB) corrections after CST-2032 doses of 1mg and 6mg co-administered with a CST107 dose of 3mg compared to placebo | Change from Baseline after 14 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in CANTAB Reaction Time Task | Measures changes in cognition by testing psychomotor speed (selecting a flashing circle on a touch tablet screen as quickly as possible). | Change from Baseline after 14 days of treatment | 
| Change from Baseline in CANTAB Rapid Visual Information Processing | Measures changes in cognition by testing sustained attention, response accuracy, target sensitivity and reaction times. Single digits appear in random order in the center of a touch tablet screen and subjects must detect a series of 3-digit target sequences and respond by touching the button at the bottom of the screen when they see the final number of the sequence. | Change from Baseline after 14 days of treatment | 
| Change from Baseline in CANTAB Verbal Recognition Memory | Measures changes in cognition by testing memory (recall of 18 words flashed onto a touch tablet screen). | Change from Baseline after 14 days of treatment | 
| Change from Baseline in CANTAB Adaptive Tracking Task | Measures changes in visual and motor coordination and vigilance. In this task, a small circle (target) continuously moves across the screen in a semi-randomized fashion, so as to minimize the subject's ability to predict the trajectory of the target. The subject is instructed to use his/her finger on the touch screen to move a small dot so that it is consistently within the center of the moving target on the screen. During the test, the speed of the circle is adjusted in response to the subject's ability to keep the dot in the circle, ensuring that the test is adapted to the individual subject. | Change from Baseline after 14 days of treatment | 
| Change from Baseline in CANTAB Paired Associates Learning Test | Measures changes in cognition by testing attention (remembering the location of an abstract pattern on a touch tablet screen). | Change from Baseline after 14 days of treatment | 
| Change from Baseline in CANTAB Stop Signal Task | Measures response inhibition (impulse control). Subjects must respond to an arrow stimulus by selecting one of two options, depending on the direction in which the arrow points. If an audio tone is present, subjects must withhold making that response (inhibition). | Change from Baseline after 14 days of treatment | 
| Change from Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Faces with six different basic emotions (happiness, fear, anger, disgust, sadness, surprise) are briefly displayed on a screen and participants are required to indicate the expression of the face via a button-press. | Change from Baseline after 14 days of treatment |