Alzheimer's Disease With Vascular Pathology
Conditions
Keywords
Alzheimer's disease, AD, ADv, CY6463, Subcortical small-vessel disease, Elderly, 60 and older, Probable AD dementia, Vascular dementia, Mixed dementia
Brief summary
This study is being conducted to test the safety, tolerability, and pharmacokinetics of the investigational drug CY6463 compared with placebo in individuals who are aged 60 years or older and have Alzheimer's disease (AD) along with common cardiovascular risk factors.
Detailed description
CY6463 is an investigational drug being developed as a symptomatic and potentially disease-modifying therapy for Alzheimer's disease (AD) and other serious central nervous system disorders. As a soluble guanylate cyclase (sGC) stimulator, CY6463 can cross the blood-brain barrier and boosts the activity of the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) pathway. This signaling pathway is important in many aspects of brain health, including in the control of blood flow in the brain, how brain cells use energy, and how those cells communicate with one another. Impairment of this pathway is a critical part of the origin of many neurodegenerative diseases that can cause a loss of brain function including memory and decision-making abilities. There are clear links between disrupted NO signaling and impaired brain function in patients with AD and vascular pathology (ADv). (Vascular pathology refers to abnormalities of the blood vessels that are more likely to occur when a person has cardiovascular risk factors like high blood pressure, diabetes, and/or obesity.) It is hypothesized that CY6463 may help patients with ADv maintain or recover some of their original cognitive function. In this study, participants will be randomized to receive approximately 87 sequential days (\ 3 months) of study drug (CY6463 or placebo) once daily (QD) and will complete 7 scheduled site visits over the course of the study, from Screening through Follow up.
Interventions
DRUGCY6463
CY6463 Oral Tablet
DRUGPlacebo
Placebo Oral Tablet
Sponsors
Tisento Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provide written informed consent prior to the performance of any protocol-specified procedure or, if unable to provide informed consent due to cognitive status, provides assent to participate, with a legally authorized representative (LAR) providing written informed consent on behalf of the participant. 2. 60 years of age or older 3. Meets core clinical criteria for probable AD dementia according to the 2011 National Institute on Aging-Alzheimer's Associated guidelines. Can be based on medical history. 4. Mini-Mental State Examination (MMSE) score of 20 to 26 (inclusive) 5. Confirmation of AD pathophysiology 6. At least 2 cardiovascular risk factors per protocol criteria 7. Magnetic resonance imaging (MRI) scan (existing MRI obtained ≤6 months before Screening is acceptable) findings of mild-to-moderate subcortical small-vessel disease 8. If receiving concomitant or chronic medication(s), has had no change for ≥4 weeks before study drug initiation and has no plans to alter the regimen(s) during the study 9. If male, agrees to refrain from donating sperm from the Screening visit through 90 days after taking the final study drug dose 10. If male, agrees to use protocol-specified, effective contraception methods from the signing of the informed consent form (ICF) until ≥90 days after taking the final study drug dose. 11. If female, is postmenopausal/not of reproductive potential defined per protocol 12. Agrees to the study procedures, including undergoing lumbar puncture for cerebrospinal fluid (CSF) samples
Exclusion criteria
1. Severe visual, auditory, social, or cognitive impairment 2. Dementia-related disorder other than AD or vascular dementia (eg, Parkinson's disease, Huntington's disease, frontotemporal dementia, schizophrenia, Lewy body dementia) 3. Symptomatic large-vessel disease, symptomatic carotid artery disease, large vessel infarcts, or strategic lacunar infarcts or infarcts\>15 mm 4. History of significant central nervous system (CNS) trauma that has affected brain function 5. Low blood pressure (BP), defined as systolic BP ≤90 mmHg or diastolic BP ≤60 mmHg. 6. Orthostatic hypotension. 7. Unable to undergo MRI 8. Unable to undergo lumbar puncture procedure 9. Unable to participate in electroencephalography (EEG) protocol due to hearing impairment or inability to tolerate EEG cap or headphones 10. Uncontrolled or unstable chronic disease 11. Kidney impairment requiring dialysis; history of renal transplant 12. Needs continuous direct medical care and nursing supervision. 13. Family history of short QT syndrome or long QT syndrome 14. Clinically significant cardiac involvement 15. History of cancer. Exceptions: localized cutaneous basal or squamous cell carcinoma in the last 5 years, low-grade localized prostate/cervical cancers, or previous localized prostate/cervical cancers that have a low likelihood of recurrence 16. Is not suited for study participation in the clinical judgment of the investigator Additional inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-emergent Adverse Events (TEAEs) From Study Drug Initiation Through Follow-up | From first dose of study treatment through ~14 (±4) days after the final dose | TEAE is defined as an adverse event with an onset that occurs after receiving the study drug, until the end of the Follow-up period |
Countries
United States
Participant flow
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive either CY6463 or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo QD for approximately 87 sequential days. | 6 |
| CY6463 CY6463 QD for approximately 87 sequential days. | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Placebo | CY6463 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 6 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 0 / 6 | 2 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 |
Outcome results
Primary
Incidence of Treatment-emergent Adverse Events (TEAEs) From Study Drug Initiation Through Follow-up
TEAE is defined as an adverse event with an onset that occurs after receiving the study drug, until the end of the Follow-up period
Time frame: From first dose of study treatment through ~14 (±4) days after the final dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Incidence of Treatment-emergent Adverse Events (TEAEs) From Study Drug Initiation Through Follow-up | 0 Participants |
| CY6463 | Incidence of Treatment-emergent Adverse Events (TEAEs) From Study Drug Initiation Through Follow-up | 2 Participants |