A Phase 2 Clinical Study of Simenafil Hydrochloride Tablets in the Treatment of Alzheimer's Disease

Prior treatment

• Significant focal lesions shown on MRI within 3 months prior to screening or at screening, meeting any of the following: 1) more than 2 infarcts with a diameter greater than 2 cm; 2) infarcts in key regions such as the thalamus, hippocampus, entorhinal cortex, perirhinal cortex, angular gyrus, and other cortical and subcortical gray matter nuclei; 3) white matter damage with a Fazekas Scale grade ≥ 3. Focal lesions judged by the investigator not to affect cognition or function are excepted.
• Based on the investigator's assessment and the Columbia-Suicide Severity Rating Scale (C-SSRS), participants who had suicidal intent within 6 months prior to screening or are at risk of impulsive behavior or suicide during the study, i.e., those who answer "yes" to item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) of the C-SSRS "suicidal ideation" items, or who have had an actual suicide attempt within the past 1 year. Non-suicidal self-injurious behavior within the past 1 year does not constitute an exclusion criterion; however, if the investigator clinically assesses that the participant currently has a significant risk of self-injury, the participant should still be excluded.
• Participants with a history of drug abuse or illicit drug use within 1 year prior to screening.
• Participants with a history of myocardial infarction, unstable angina, coronary artery disease and/or New York Heart Association (NYHA) class III or IV heart failure within 1 year prior to screening.
• Participants who are using a cholinesterase inhibitor and/or memantine at Screening but have been receiving stable-dose treatment for less than 3 months.
• Participants who have a history of, or are receiving at Screening, anti-amyloid therapy, anti-tau therapy, or any investigational treatment for Alzheimer's disease.
• Participants who have used the following prohibited medications prior to randomization without meeting the corresponding washout period requirements (if the same drug falls under multiple prohibited categories, the longer prohibition period shall apply), or who are expected to require concomitant use of the following prohibited medications during the study:
  • Other PDE5 inhibitors, with a washout period of at least 5 half-lives (of the prohibited drug) prior to randomization;
  • Nitrates, nitric oxide (NO) donors, soluble guanylate cyclase stimulators, or alpha-blockers, with a washout period of at least 5 half-lives (of the prohibited drug) prior to randomization;
  • Strong CYP3A4 inhibitors, moderate CYP3A4 inhibitors, strong CYP3A4 inducers, or moderate CYP3A4 inducers, with a washout period of at least 30 days prior to randomization, except for topical use.
• Participants who have participated in any drug or device clinical trial and received investigational drug or device within 3 months prior to Screening, or who are currently participating in another clinical trial.

Other illness

• Dementia due to other causes, including but not limited to vascular dementia, central nervous system infection, Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, post-traumatic dementia, other physical or chemical factors (e.g., drug intoxication, alcohol intoxication, carbon monoxide poisoning), major somatic diseases (e.g., hepatic encephalopathy, pulmonary encephalopathy, etc.), intracranial space-occupying lesions (e.g., subdural hematoma, brain tumors), endocrine disorders (e.g., thyroid disease), or vitamin B12 or folate deficiency, or dementia due to any other known cause.
• Participants with a psychiatric disorder diagnosed by a psychiatrist that, in the investigator's judgment, may confound the interpretation of the drug effect, affect cognitive assessments, or affect the participant's ability to complete the study, including but not limited to schizophrenia, bipolar I disorder, bipolar II disorder, major depressive disorder, delirium, etc.
• Participants with central nervous system diseases, including but not limited to stroke, neuromyelitis optica, Parkinson's disease, epilepsy, etc.
• Participants with hereditary degenerative retinal diseases such as retinitis pigmentosa, or a history of non-arteritic anterior ischemic optic neuropathy (NAION), or other serious ocular diseases that, in the investigator's judgment, may affect the participant's safety assessment, completion of scales, or study compliance.
• Participants with known allergy to any component of simenafil hydrochloride tablets or the placebo, or a history of allergy to phosphodiesterase type 5 (PDE5) inhibitors.
• Participants with a history of cancer or malignancy within 5 years prior to screening, except for the following:
  • Basal or squamous cell carcinoma of the skin or cervical cell dysplasia that has been adequately treated.
  • Stage 1 cervical carcinoma in situ that has been completely treated for at least 2 years prior to screening, with no recurrence.
  • Prostate cancer confined to the prostate that has been adequately treated (e.g., surgery and/or radiotherapy, or watchful waiting), with normal or low prostate-specific antigen (PSA) levels that have remained stable for at least 2 years prior to screening; where necessary, relevant examinations will be performed at the investigator's discretion.
  • Non-metastatic breast cancer that has been adequately treated.
• Participants with uncontrolled hypertension (systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 95 mmHg) or hypotension (systolic blood pressure \< 90 mmHg or diastolic blood pressure \< 60 mmHg).

Lab values

• Participants meet any of the following:
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin \> 2.5 × the upper limit of normal (any one).
  • Vitamin B12 \< the lower limit of normal.
  • Known history of human immunodeficiency virus (HIV) positivity, or positive HIV 1/2 test at screening.
  • Positive hepatitis B virus surface antigen (HBsAg) test.
  • Known history of hepatitis C virus (HCV), or positive HCV antibody (HCVAb) test at screening (unless confirmatory PCR is negative).
  • Known history of neurosyphilis, or positive Treponema pallidum specific antibody (TP Ab) at screening.

Other

• Participants with a Geriatric Depression Scale 15-item (GDS-15) score ≥ 8 at Screening.
• Participants who have a contraindication to PET or MRI in the Investigator's judgment. Note: MRI contraindication applies only to participants who are required to undergo the corresponding examination.
• Female participants who are lactating, or female participants of childbearing potential with a positive pregnancy test.
• Participants with any other factors that make them unsuitable for participation in the study, in the investigator's judgment.

• Male or female participants aged 55 to 90 years of age inclusive at the time of signing the informed consent form.
• Mild cognitive impairment due to AD or mild AD dementia defined by stages 3 to 4 according to the National Institute on Aging and Alzheimer's Association (NIA-AA) 2024 diagnostic and staging criteria at Screening.
• At screening, participants show positive cerebral amyloid pathology on amyloid beta (Aβ) positron emission tomography (PET) imaging.
• Participants with a history of subjective cognitive and memory decline with onset within 5 years before Screening, confirmed by a relative, caregiver, or other informant familiar with their medical history.
• Participants who have a Mini-Mental State Examination (MMSE) score ≥ 20 at Screening.
• Participants who have a Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 or 1, and a CDR memory box score ≥ 0.5 at Screening.
• Participants must have a stable and reliable adult study partner. The study partner should have known the participant for at least 1 year, maintain frequent and adequate contact with the participant during the study (at least 4 days per week and at least 2 hours per day), be familiar with the participant's daily cognitive, functional, and living status, be able to understand the requirements of study participation, accompany the participant to all study visits, and provide reliable information for relevant scale assessments. The study partner should not be changed during the study whenever possible. The study partner voluntarily signs the informed consent form to participate as a study partner.
• From signing the informed consent form until 3 months after the last dose, women of childbearing potential (WOCBP) and male participants with female partners of childbearing potential agree to use effective contraception.
• Participants fully understand the purpose, content, and possible adverse reactions of this study, voluntarily participate in the clinical trial and sign the written informed consent form, and are able to complete the entire study process in accordance with study requirements and comply with study regulations.