Dementia, Mild Cognitive Impairment
Conditions
Brief summary
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 participants with Mild Cognitive Impairment (MCI) or mild dementia.
Detailed description
Approximately 60 participants 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 at least 7 days and up to 21 days. All participants 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.
Interventions
DRUGCST-2032, matching placebo for CST-2032, CST-107, matching placebo for CST-107
CST-2032 and matching placebo white tablets, CST-107 and matching placebo yellow tablets
Sponsors
CuraSen Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Male or female participants ≥ 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 participants taking medications: stable dose and regimen for at least 30 days (90 days for anti-psychotic medications) prior to Day -1 and the dose must remain unchanged through the End of Study Visit unless required for management of adverse events (AEs). * Cognitive decline not primarily caused by vascular, traumatic, or medical problems (alternative causes of cognitive decline are ruled out). * Adequate visual and auditory abilities and motor skills 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). * Montreal Cognitive Assessment (MoCA) score ≥ 14 and ≤ 26. * Unless confirmed to be azoospermic (vasectomized or secondary to medical cause), males must agree to use a male condom from Day -1 until the End of Study 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 End of Study 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/m\^2, inclusive at Screening. * Stable medical conditions for 30 days 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. * Able to speak, understand and read English.
Exclusion criteria
* Participants with poorly controlled hypertension despite lifestyle modifications and/or pharmacotherapy. * Participants with pulmonary disease, including asthma, 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 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 (participants with psychotic disorders may be enrolled if their condition is effectively managed, i.e., must be receiving stable doses of anti-psychotic medications(s) 90 days prior to randomization and must remain on that dose throughout both treatment periods.) * Evidence of any significant clinical disorder or laboratory finding (e.g., potassium levels below normal range) that renders the participant unsuitable for receiving an investigational drug including clinically significant or unstable hematologic, moderate and severe impairment of hepatic function (as defined by the National Cancer Institute Organ Dysfunction Working Group), cardiovascular, pulmonary, gastrointestinal, endocrine (including thyrotoxicosis, excluding managed hypo and hyperthyroidism), immunologic, dermatologic, neurologic, musculoskeletal, metabolic, renal, or other systemic disease or laboratory abnormality. * Participants with a history of malignant disease within 5 years, including solid tumors and hematologic malignancies (exceptions: \[a\] basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured; \[b\] low-grade adenocarcinoma of the prostate, which are slow growing, and are unlikely to progress or metastasize during the clinical trial). * Any clinically significant medical condition or disease as determined by medical history, physical examination 12-lead electrocardiogram (ECG) and clinical laboratory assessments conducted that, in the view of the Principal Investigator, will interfere with participation in the study or interpretation of results. * Clinically significant abnormalities of 12-lead ECG (as determined by a central reader), including QTcF \> 440 ms, for males and females, and/or HR \< 50 beats per minute, or evidence of bundle branch blocks, as indicated on the Mean ECG Analysis Report 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 and/or concurrent 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. * Prior and/or concurrent treatment with any beta-AR agonists or beta-AR blockers (includes oral meds, IV or inhaled) or any meds that impact adrenergic signaling within the last month prior to Screening. Participants may be on stable doses of serotonin-noradrenaline reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs), or any treatment for ADHD including noradrenaline reuptake inhibitors (NRIs), or amphetamines within the last month prior to Screening. * A history of heart failure, sinus bradycardia, second- or third-degree heart block, hypokalemia, attack of unconsciousness possibly associated with torsades de points or family history of Long QT Syndrome. * 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 human immunodeficiency virus (HIV), 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. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent Adverse Events | Change from Baseline after 14 days of treatment | The number of participants experiencing treatment-emergent adverse events after receiving 3mg CST-2032 co-administered with 3mg CST-107 compared to placebo |
| Vital Signs | Change from Baseline after 14 days of treatment respectively (4 hours post dose) | Change from Baseline in supine blood pressure (diastolic blood pressure and systolic blood pressure) after CST-2032 co-administered with CST-107 compared to placebo |
| Electrocardiograms (ECGs) | Change from Baseline after 14 days of treatment respectively (4 hour post-dose) | Change from Baseline in QTc interval using the Fredericia (QTcF) corrections after treatment with CST-2032 co-administered with CST107 compared to placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline after 7 and 14 days of treatment respectively. | Measures changes in cognition by testing psychomotor speed (selecting a flashing circle on a touch tablet screen as quickly as possible). Lower response times indicate better performance. |
| Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline after 7 and 14 days of treatment respectively. | Measures changes in cognition by testing attention (remembering the location of an abstract pattern on a touch tablet screen). Lower error scores indicate better performance. |
| Change From Baseline in DSST Score | Change from Baseline after 7 and 14 days of treatment respectively. | Change from Baseline in Digit Symbol Substitution Test (DSST) after CST-2032 co-administered with CST-107 compared to placebo. Participants are asked to copy simple graphic symbols that are paired to the digits 1-9 within a specified time period. Using a key, the examinee is asked to draw each symbol under its corresponding number. The examinee's score is determined by the number of symbols correctly drawn within a 90-second time limit. Higher scores indicate better performance. |
| Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline after 7 and 14 days of treatment respectively. | 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. The outcome variable was the mean 'difficulty multiplier', which is a calculation adjustment of the participant's accuracy on target relative to current target speed, averaged over the entire testing session. The difficulty multiplier ranges from 0 to 10. Attainment of a higher difficulty multiplier indicates better performance. |
| Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Change from Baseline after 14 days of treatment. | 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. Lower response times indicate better performance; negative response times indicate improvement from baseline |
| Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline after 7 and 14 days of treatment respectively. | Measures changes in cognition by testing memory (recall of 18 words flashed onto a touch tablet screen). An increase in number of words recognized indicates better performance. |
| Change From Baseline in DSST Total Incorrect | Change from Baseline after 7 and 14 days of treatment respectively. | Change from Baseline in Digit Symbol Substitution Test (DSST) after CST-2032 co-administered with CST-107 compared to placebo. Participants are asked to copy simple graphic symbols that are paired to the digits 1-9 within a specified time period. Using a key, the examinee is asked to draw each symbol under its corresponding number. The incorrect score is the number of symbols incorrectly drawn within a 90-second time limit. Lower scores indicate better performance; negative scores indicate better performance relative to baseline. |
| Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline after 7 and 14 days of treatment respectively. | Measures response inhibition (impulse control). Participants 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). Lower response times indicate better performance. |
Countries
New Zealand, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall All participants enrolled in study | 64 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Overall |
|---|---|
| Age, Continuous | 68.0 years STANDARD_DEVIATION 7.96 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 59 Participants |
| Region of Enrollment New Zealand | 8 participants |
| Region of Enrollment United States | 56 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 59 |
| other Total, other adverse events | 19 / 59 | 20 / 59 |
| serious Total, serious adverse events | 0 / 59 | 1 / 59 |
Outcome results
Primary
Electrocardiograms (ECGs)
Change from Baseline in QTc interval using the Fredericia (QTcF) corrections after treatment with CST-2032 co-administered with CST107 compared to placebo
Time frame: Change from Baseline after 14 days of treatment respectively (4 hour post-dose)
Population: Safety set - all participants who received at least 1 dose of study drug (CST-2032, CST-107 or placebo). Participants were reported based on the treatment received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Electrocardiograms (ECGs) | 4.402 msec | Standard Deviation 8.5028 |
| CST-2032 and CST-107 | Electrocardiograms (ECGs) | 4.532 msec | Standard Deviation 11.3533 |
| AD Participants - Placebo | Electrocardiograms (ECGs) | 2.771 msec | Standard Deviation 12.5605 |
| AD Participants - CST-2032/CST-107 | Electrocardiograms (ECGs) | 3.411 msec | Standard Deviation 14.4734 |
| Overall - Placebo | Electrocardiograms (ECGs) | 3.515 msec | Standard Deviation 10.8381 |
| Overall - CST-2032/CST-107 | Electrocardiograms (ECGs) | 3.909 msec | Standard Deviation 13.0718 |
Primary
Treatment-emergent Adverse Events
The number of participants experiencing treatment-emergent adverse events after receiving 3mg CST-2032 co-administered with 3mg CST-107 compared to placebo
Time frame: Change from Baseline after 14 days of treatment
Population: Safety Set - All participants who received at least 1 dose of blinded study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Treatment-emergent Adverse Events | 19 Participants |
| CST-2032 and CST-107 | Treatment-emergent Adverse Events | 20 Participants |
Primary
Vital Signs
Change from Baseline in supine blood pressure (diastolic blood pressure and systolic blood pressure) after CST-2032 co-administered with CST-107 compared to placebo
Time frame: Change from Baseline after 14 days of treatment respectively (4 hours post dose)
Population: Safety set - all participants who received at least 1 dose of study drug (CSR-2032, CST-107 or placebo). Participants were reported based on the treatment received. It is noted that whilst all the above participants were included in the overall analysis, there were some participants for whom data was not available at individual timepoints and the resulting corrected number of participants analyzed is presented per parameter below.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Vital Signs | Systolic blood pressure - Supine Change from Baseline at Day 14 | -1.1 mmHg | Standard Deviation 22.17 |
| Placebo | Vital Signs | Diastolic blood pressure - Supine Change from Baseline at Day 14 | -0.6 mmHg | Standard Deviation 14.77 |
| CST-2032 and CST-107 | Vital Signs | Systolic blood pressure - Supine Change from Baseline at Day 14 | -5.2 mmHg | Standard Deviation 19.24 |
| CST-2032 and CST-107 | Vital Signs | Diastolic blood pressure - Supine Change from Baseline at Day 14 | -1.6 mmHg | Standard Deviation 12.4 |
| AD Participants - Placebo | Vital Signs | Systolic blood pressure - Supine Change from Baseline at Day 14 | 1.3 mmHg | Standard Deviation 11.18 |
| AD Participants - Placebo | Vital Signs | Diastolic blood pressure - Supine Change from Baseline at Day 14 | 1.5 mmHg | Standard Deviation 8.21 |
| AD Participants - CST-2032/CST-107 | Vital Signs | Systolic blood pressure - Supine Change from Baseline at Day 14 | 0.6 mmHg | Standard Deviation 9.53 |
| AD Participants - CST-2032/CST-107 | Vital Signs | Diastolic blood pressure - Supine Change from Baseline at Day 14 | 2.4 mmHg | Standard Deviation 7.25 |
| Overall - Placebo | Vital Signs | Systolic blood pressure - Supine Change from Baseline at Day 14 | 0.2 mmHg | Standard Deviation 16.88 |
| Overall - Placebo | Vital Signs | Diastolic blood pressure - Supine Change from Baseline at Day 14 | 0.6 mmHg | Standard Deviation 11.55 |
| Overall - CST-2032/CST-107 | Vital Signs | Systolic blood pressure - Supine Change from Baseline at Day 14 | -2.0 mmHg | Standard Deviation 14.79 |
| Overall - CST-2032/CST-107 | Vital Signs | Diastolic blood pressure - Supine Change from Baseline at Day 14 | 0.6 mmHg | Standard Deviation 9.98 |
Secondary
Change From Baseline in CANTAB 5-Choice Reaction Time
Measures changes in cognition by testing psychomotor speed (selecting a flashing circle on a touch tablet screen as quickly as possible). Lower response times indicate better performance.
Time frame: Change from Baseline after 7 and 14 days of treatment respectively.
Population: Full Analysis Set - All randomized participants who took at least 1 dose of blinded study drug (CST-2032 + CST-107 or placebo). Participants were analyzed according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline at Day 7 | 1.56 milliseconds | Standard Error 16.12 |
| Placebo | Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline at Day 14 | 0.38 milliseconds | Standard Error 16.12 |
| CST-2032 and CST-107 | Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline at Day 7 | -5.86 milliseconds | Standard Error 16.37 |
| CST-2032 and CST-107 | Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline at Day 14 | 15.74 milliseconds | Standard Error 16.37 |
| AD Participants - Placebo | Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline at Day 7 | -29.53 milliseconds | Standard Error 9.762 |
| AD Participants - Placebo | Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline at Day 14 | -31.09 milliseconds | Standard Error 9.77 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline at Day 7 | -18.59 milliseconds | Standard Error 9.899 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline at Day 14 | -40.83 milliseconds | Standard Error 10.024 |
| Overall - Placebo | Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline at Day 7 | -14.21 milliseconds | Standard Error 9.529 |
| Overall - Placebo | Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline at Day 14 | -15.37 milliseconds | Standard Error 9.533 |
| Overall - CST-2032/CST-107 | Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline at Day 7 | -11.06 milliseconds | Standard Error 9.657 |
| Overall - CST-2032/CST-107 | Change From Baseline in CANTAB 5-Choice Reaction Time | Change from Baseline at Day 14 | -13.21 milliseconds | Standard Error 9.719 |
Secondary
Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved
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. The outcome variable was the mean 'difficulty multiplier', which is a calculation adjustment of the participant's accuracy on target relative to current target speed, averaged over the entire testing session. The difficulty multiplier ranges from 0 to 10. Attainment of a higher difficulty multiplier indicates better performance.
Time frame: Change from Baseline after 7 and 14 days of treatment respectively.
Population: Full Analysis Set - All randomized participants who took at least 1 dose of blinded study treatment (CST-2032 + CST-107 or placebo). Participants were analyzed according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline at Day 7 | 0.07 score on a scale | Standard Error 0.091 |
| Placebo | Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline at day 14 | 0.06 score on a scale | Standard Error 0.091 |
| CST-2032 and CST-107 | Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline at Day 7 | 0.11 score on a scale | Standard Error 0.093 |
| CST-2032 and CST-107 | Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline at day 14 | -0.06 score on a scale | Standard Error 0.093 |
| AD Participants - Placebo | Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline at Day 7 | 0.37 score on a scale | Standard Error 0.106 |
| AD Participants - Placebo | Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline at day 14 | 0.36 score on a scale | Standard Error 0.106 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline at Day 7 | 0.42 score on a scale | Standard Error 0.106 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline at day 14 | 0.34 score on a scale | Standard Error 0.107 |
| Overall - Placebo | Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline at Day 7 | 0.22 score on a scale | Standard Error 0.073 |
| Overall - Placebo | Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline at day 14 | 0.21 score on a scale | Standard Error 0.073 |
| Overall - CST-2032/CST-107 | Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline at Day 7 | 0.27 score on a scale | Standard Error 0.074 |
| Overall - CST-2032/CST-107 | Change From Baseline in CANTAB Adaptive Tracking Mean Level of Difficulty Achieved | Change from Baseline at day 14 | 0.15 score on a scale | Standard Error 0.074 |
Secondary
Change From Baseline in CANTAB Delayed Verbal Recognition
Measures changes in cognition by testing memory (recall of 18 words flashed onto a touch tablet screen). An increase in number of words recognized indicates better performance.
Time frame: Change from Baseline after 7 and 14 days of treatment respectively.
Population: Full Analysis Set - All randomized participants who took at least 1 dose of blinded study drug (CST-2032 + CST-107 or placebo). Subjects were analyzed according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline at Day 14 | -1.08 words | Standard Error 0.637 |
| Placebo | Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline at Day 7 | 0.15 words | Standard Error 0.628 |
| CST-2032 and CST-107 | Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline at Day 14 | 0.47 words | Standard Error 0.637 |
| CST-2032 and CST-107 | Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline at Day 7 | 0.11 words | Standard Error 0.637 |
| AD Participants - Placebo | Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline at Day 14 | 0.30 words | Standard Error 0.745 |
| AD Participants - Placebo | Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline at Day 7 | 1.64 words | Standard Error 0.744 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline at Day 7 | 0.14 words | Standard Error 0.754 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline at Day 14 | -0.07 words | Standard Error 0.762 |
| Overall - Placebo | Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline at Day 7 | 1.02 words | Standard Error 0.502 |
| Overall - Placebo | Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline at Day 14 | -0.25 words | Standard Error 0.506 |
| Overall - CST-2032/CST-107 | Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline at Day 7 | 0.17 words | Standard Error 0.509 |
| Overall - CST-2032/CST-107 | Change From Baseline in CANTAB Delayed Verbal Recognition | Change from Baseline at Day 14 | 0.21 words | Standard Error 0.512 |
Secondary
Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors
Measures changes in cognition by testing attention (remembering the location of an abstract pattern on a touch tablet screen). Lower error scores indicate better performance.
Time frame: Change from Baseline after 7 and 14 days of treatment respectively.
Population: Full Analysis Set - All randomized participants who took at least 1 dose of blinded study drug (CST-2032 + CST-107 or placebo). Participants were analyzed according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline at Day 7 | -4.46 incorrect patterns | Standard Error 2.517 |
| Placebo | Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline at Day 14 | -0.11 incorrect patterns | Standard Error 2.517 |
| CST-2032 and CST-107 | Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline at Day 7 | -4.21 incorrect patterns | Standard Error 2.546 |
| CST-2032 and CST-107 | Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline at Day 14 | -4.85 incorrect patterns | Standard Error 2.546 |
| AD Participants - Placebo | Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline at Day 7 | 2.05 incorrect patterns | Standard Error 2.495 |
| AD Participants - Placebo | Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline at Day 14 | 2.69 incorrect patterns | Standard Error 2.498 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline at Day 7 | 0.81 incorrect patterns | Standard Error 2.522 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline at Day 14 | 0.65 incorrect patterns | Standard Error 2.545 |
| Overall - Placebo | Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline at Day 7 | -1.28 incorrect patterns | Standard Error 1.785 |
| Overall - Placebo | Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline at Day 14 | 1.03 incorrect patterns | Standard Error 1.785 |
| Overall - CST-2032/CST-107 | Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline at Day 7 | -1.87 incorrect patterns | Standard Error 1.804 |
| Overall - CST-2032/CST-107 | Change From Baseline in CANTAB Paired Associates Learning Tool - Total Adjusted Errors | Change from Baseline at Day 14 | -2.22 incorrect patterns | Standard Error 1.813 |
Secondary
Change From Baseline in CANTAB Stop Signal Reaction Time
Measures response inhibition (impulse control). Participants 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). Lower response times indicate better performance.
Time frame: Change from Baseline after 7 and 14 days of treatment respectively.
Population: Full Analysis Set - All randomized participants who took at least 1 dose of blinded study drug (CST-2032 + CST-107 or placebo). Participants were analyzed according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline at Day 7 | 30.81 milliseconds | Standard Error 14.45 |
| Placebo | Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline at Day 14 | 31.65 milliseconds | Standard Error 14.45 |
| CST-2032 and CST-107 | Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline at Day 7 | 0.33 milliseconds | Standard Error 14.975 |
| CST-2032 and CST-107 | Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline at Day 14 | 2.25 milliseconds | Standard Error 14.697 |
| AD Participants - Placebo | Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline at Day 7 | -22.27 milliseconds | Standard Error 14.824 |
| AD Participants - Placebo | Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline at Day 14 | -34.68 milliseconds | Standard Error 14.838 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline at Day 7 | -12.02 milliseconds | Standard Error 15.038 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline at Day 14 | -8.61 milliseconds | Standard Error 15.238 |
| Overall - Placebo | Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline at Day 7 | 1.89 milliseconds | Standard Error 10.521 |
| Overall - Placebo | Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline at Day 14 | -4.70 milliseconds | Standard Error 10.524 |
| Overall - CST-2032/CST-107 | Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline at Day 7 | -6.39 milliseconds | Standard Error 10.756 |
| Overall - CST-2032/CST-107 | Change From Baseline in CANTAB Stop Signal Reaction Time | Change from Baseline at Day 14 | -4.07 milliseconds | Standard Error 10.756 |
Secondary
Change From Baseline in DSST Score
Change from Baseline in Digit Symbol Substitution Test (DSST) after CST-2032 co-administered with CST-107 compared to placebo. Participants are asked to copy simple graphic symbols that are paired to the digits 1-9 within a specified time period. Using a key, the examinee is asked to draw each symbol under its corresponding number. The examinee's score is determined by the number of symbols correctly drawn within a 90-second time limit. Higher scores indicate better performance.
Time frame: Change from Baseline after 7 and 14 days of treatment respectively.
Population: Full Analysis Set - All randomized participants who took at least 1 dose of blinded study drug (CST-2032 + CST-107 or placebo). Participants were analyzed according to the treatment assigned at randomization. It is noted that whilst all the above participants were included in the overall analysis, there were some participants for whom data was not available at individual timepoints and the resulting corrected number of participants analyzed is presented per parameter below.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in DSST Score | Change from Baseline at Day 14 | 2.79 correct symbols | Standard Error 0.938 |
| Placebo | Change From Baseline in DSST Score | Change from Baseline at Day 7 | 2.09 correct symbols | Standard Error 0.938 |
| CST-2032 and CST-107 | Change From Baseline in DSST Score | Change from Baseline at Day 7 | 3.21 correct symbols | Standard Error 0.949 |
| CST-2032 and CST-107 | Change From Baseline in DSST Score | Change from Baseline at Day 14 | 2.57 correct symbols | Standard Error 0.949 |
| AD Participants - Placebo | Change From Baseline in DSST Score | Change from Baseline at Day 7 | 3.07 correct symbols | Standard Error 0.905 |
| AD Participants - Placebo | Change From Baseline in DSST Score | Change from Baseline at Day 14 | 2.95 correct symbols | Standard Error 0.906 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in DSST Score | Change from Baseline at Day 7 | 3.71 correct symbols | Standard Error 0.915 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in DSST Score | Change from Baseline at Day 14 | 4.71 correct symbols | Standard Error 0.915 |
| Overall - Placebo | Change From Baseline in DSST Score | Change from Baseline at Day 7 | 2.64 correct symbols | Standard Error 0.669 |
| Overall - Placebo | Change From Baseline in DSST Score | Change from Baseline at Day 14 | 2.88 correct symbols | Standard Error 0.669 |
| Overall - CST-2032/CST-107 | Change From Baseline in DSST Score | Change from Baseline at Day 7 | 3.45 correct symbols | Standard Error 0.676 |
| Overall - CST-2032/CST-107 | Change From Baseline in DSST Score | Change from Baseline at Day 14 | 3.71 correct symbols | Standard Error 0.676 |
Secondary
Change From Baseline in DSST Total Incorrect
Change from Baseline in Digit Symbol Substitution Test (DSST) after CST-2032 co-administered with CST-107 compared to placebo. Participants are asked to copy simple graphic symbols that are paired to the digits 1-9 within a specified time period. Using a key, the examinee is asked to draw each symbol under its corresponding number. The incorrect score is the number of symbols incorrectly drawn within a 90-second time limit. Lower scores indicate better performance; negative scores indicate better performance relative to baseline.
Time frame: Change from Baseline after 7 and 14 days of treatment respectively.
Population: Full Analysis Set - All randomized participants who took at least 1 dose of blinded study drug (CST-2032 + CST-107 or placebo). Partcipants were analyzed according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in DSST Total Incorrect | Change from Baseline at Day 7 | 1.41 incorrect symbols | Standard Error 0.534 |
| Placebo | Change From Baseline in DSST Total Incorrect | Change from Baseline at Day 14 | 0.37 incorrect symbols | Standard Error 0.534 |
| CST-2032 and CST-107 | Change From Baseline in DSST Total Incorrect | Change from Baseline at Day 7 | -0.03 incorrect symbols | Standard Error 0.543 |
| CST-2032 and CST-107 | Change From Baseline in DSST Total Incorrect | Change from Baseline at Day 14 | 0.29 incorrect symbols | Standard Error 0.543 |
| AD Participants - Placebo | Change From Baseline in DSST Total Incorrect | Change from Baseline at Day 7 | -0.69 incorrect symbols | Standard Error 0.475 |
| AD Participants - Placebo | Change From Baseline in DSST Total Incorrect | Change from Baseline at Day 14 | -0.89 incorrect symbols | Standard Error 0.476 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in DSST Total Incorrect | Change from Baseline at Day 14 | -1.65 incorrect symbols | Standard Error 0.482 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in DSST Total Incorrect | Change from Baseline at Day 7 | -1.55 incorrect symbols | Standard Error 0.482 |
| Overall - Placebo | Change From Baseline in DSST Total Incorrect | Change from Baseline at Day 7 | 0.28 incorrect symbols | Standard Error 0.359 |
| Overall - Placebo | Change From Baseline in DSST Total Incorrect | Change from Baseline at Day 14 | -0.30 incorrect symbols | Standard Error 0.359 |
| Overall - CST-2032/CST-107 | Change From Baseline in DSST Total Incorrect | Change from Baseline at Day 14 | -0.72 incorrect symbols | Standard Error 0.364 |
| Overall - CST-2032/CST-107 | Change From Baseline in DSST Total Incorrect | Change from Baseline at Day 7 | -0.81 incorrect symbols | Standard Error 0.364 |
Secondary
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. Lower response times indicate better performance; negative response times indicate improvement from baseline
Time frame: Change from Baseline after 14 days of treatment.
Population: Full Analysis Set - All randomized participants who took at least 1 dose of blinded study drug (CST-2032 + CST-107 or placebo). Participants were analyzed according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Surprise Expressions - Change from Baseline at Day 14 | -235.05 milliseconds | Standard Error 85.92 |
| Placebo | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Negative Expressions - Change from Baseline at Day 14 | -251.85 milliseconds | Standard Error 66.35 |
| Placebo | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Happy Expressions - Change from Baseline at Day 14 | -178.52 milliseconds | Standard Error 69.13 |
| CST-2032 and CST-107 | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Surprise Expressions - Change from Baseline at Day 14 | -186.53 milliseconds | Standard Error 85.89 |
| CST-2032 and CST-107 | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Negative Expressions - Change from Baseline at Day 14 | -222.02 milliseconds | Standard Error 66.35 |
| CST-2032 and CST-107 | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Happy Expressions - Change from Baseline at Day 14 | -209.77 milliseconds | Standard Error 68.8 |
| AD Participants - Placebo | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Negative Expressions - Change from Baseline at Day 14 | -51.17 milliseconds | Standard Error 43.41 |
| AD Participants - Placebo | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Happy Expressions - Change from Baseline at Day 14 | 23.34 milliseconds | Standard Error 68.28 |
| AD Participants - Placebo | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Surprise Expressions - Change from Baseline at Day 14 | 16.26 milliseconds | Standard Error 64.96 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Happy Expressions - Change from Baseline at Day 14 | -89.75 milliseconds | Standard Error 68.97 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Surprise Expressions - Change from Baseline at Day 14 | -153.09 milliseconds | Standard Error 65.64 |
| AD Participants - CST-2032/CST-107 | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Negative Expressions - Change from Baseline at Day 14 | -76.53 milliseconds | Standard Error 43.86 |
| Overall - Placebo | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Negative Expressions - Change from Baseline at Day 14 | -135.72 milliseconds | Standard Error 37.38 |
| Overall - Placebo | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Happy Expressions - Change from Baseline at Day 14 | -74.41 milliseconds | Standard Error 44.21 |
| Overall - Placebo | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Surprise Expressions - Change from Baseline at Day 14 | -96.45 milliseconds | Standard Error 50.7 |
| Overall - CST-2032/CST-107 | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Surprise Expressions - Change from Baseline at Day 14 | -169.06 milliseconds | Standard Error 50.99 |
| Overall - CST-2032/CST-107 | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Happy Expressions - Change from Baseline at Day 14 | -145.62 milliseconds | Standard Error 44.4 |
| Overall - CST-2032/CST-107 | Change From Baseline in Negative Emotional Bias in the Facial Expression Recognition Task (FERT) | Reaction Time for Negative Expressions - Change from Baseline at Day 14 | -149.30 milliseconds | Standard Error 37.42 |