Efficacy and Safety Evaluation of Mirodenafil Dihydrochloride in Early Alzheimer's Disease: A Phase 3 Double-Blind, Randomized, Placebo-Controlled Trial

Trial ID: 2023-508306-15-00
Protocol: AR1001-ADP3-US01
Sponsor: Aribio Co. Ltd.

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Diseases & Conditions

Dementia Alzheimer's type

Objectives

The primary objective of this Phase 3 double-blind, randomized, placebo-controlled trial is to evaluate the **efficacy** of AR1001 compared with placebo in participants with early **Alzheimer's disease**. This objective is clinically relevant as it aims to determine the potential therapeutic benefits of AR1001, which contains the active substance **mirodenafil dihydrochloride**, in slowing or altering the progression of Alzheimer's disease, a condition characterized by cognitive decline and memory loss.

Secondary objectives include further evaluation of the efficacy of AR1001 compared with placebo in participants with early Alzheimer's disease. This involves a more detailed assessment of the drug's impact on disease progression and symptom management, providing additional insights into its potential as a treatment option.

Participants

The clinical trial involves a total of **820 participants** diagnosed with **Alzheimer's Disease**. The study population comprises both male and female subjects, aged between 55 to 85 years. Participants are required to have mild cognitive impairment or mild dementia consistent with Alzheimer's Disease, as defined by stages 3 to 4 according to the National Institute on Aging and Alzheimer's Association (NIA-AA) at screening. The selection process ensures that participants have a history of subjective cognitive and memory decline with onset within five years before screening, confirmed by a study partner. Additionally, participants must have a Mini-Mental State Examination (MMSE) score of 20 or higher and a Clinical Dementia Rating (CDR) global rating of 0.5 or 1. The trial includes individuals with a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score based on the Delayed Memory Index (DMI) score of 85 or less. Participants are required to have a positive biomarker for brain amyloid pathology. The trial population is selected to include individuals who can provide informed consent and have a consistent study partner available for the duration of the study. The study does not specify any particular lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is a **Phase 3**, double-blind, randomized, placebo-controlled study designed to evaluate the efficacy and safety of AR1001 in participants with early **Alzheimer's Disease**. The trial will span 52 weeks, with the primary objective being to assess the change in the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) from baseline to week 52. Secondary endpoints include changes in the Alzheimer's Disease Assessment Scale - Cognitive Subscale 13 (ADAS-Cog 13), the Amsterdam-Instrumental Activities of Daily Living Questionnaire-Short Version (A-IADL-Q-SV), the Geriatric Depression Scale-15 (GDS-15), and the Mini-Mental Status Examination (MMSE) over the same period.

Participants will be randomly assigned to receive either AR1001, administered as a film-coated tablet, or a placebo. The maximum daily dose of AR1001 is 30 mg, with a total treatment period of 107 days. The trial will commence with a screening visit to confirm eligibility based on criteria such as age, cognitive impairment level, and biomarker status. Following randomization, participants will attend regular follow-up visits to monitor safety, efficacy, and compliance. These visits will include assessments of cognitive function, daily living activities, and mood. The end-of-study visit will occur at week 52, where final evaluations will be conducted to assess the primary and secondary endpoints.

Participant involvement is expected to last approximately 52 weeks, with conditions for early termination including significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial aims to provide robust data on the potential benefits of AR1001 in slowing the progression of early Alzheimer's Disease, contributing to the understanding of its therapeutic profile.

Treatment

The clinical trial involves the administration of **AR1001**, an experimental medication formulated as a **film-coated tablet**. The active substance in AR1001 is **mirodenafil dihydrochloride**, a chemical compound. The medication is administered orally, with a maximum daily dose of 30 mg. The total maximum dose over the treatment period is 22,530 mg, with the treatment period extending up to 107 days. The pharmaceutical form of AR1001 is consistent throughout the trial, ensuring uniformity in administration. Participant compliance with the dosing schedule is monitored to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, a **placebo tablet** is used as a comparator in this double-blind, randomized, placebo-controlled trial. The placebo is designed to mimic the appearance of the AR1001 film-coated tablet but contains no active pharmaceutical ingredients. The use of a placebo allows for the assessment of the efficacy and safety of AR1001 by providing a control group for comparison. The placebo is administered orally, following the same dosing schedule as the experimental medication, to maintain the integrity of the study design.

Efficacy

The efficacy of AR1001 in participants with early Alzheimer's disease will be assessed through a series of primary and secondary endpoints over a 52-week period. The primary endpoint is the change in the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) from baseline to week 52. This scale is a widely used tool for evaluating the severity of dementia symptoms and will provide a quantitative measure of the treatment's impact on disease progression.

Secondary endpoints include changes from baseline to week 52 in several other validated scales: the Alzheimer's Disease Assessment Scale - Cognitive Subscale 13 (ADAS-Cog 13), the Amsterdam-Instrumental Activities of Daily Living Questionnaire-Short Version (A-IADL-Q-SV), the Geriatric Depression Scale-15 (GDS-15), and the Mini-Mental Status Examination (MMSE). These scales will assess various aspects of cognitive function, daily living activities, mood, and overall mental status, providing a comprehensive evaluation of the treatment's efficacy.

Data collection will occur at specified intervals throughout the trial, with assessments conducted at baseline and at the conclusion of the 52-week treatment period. The use of these standardized and validated instruments ensures the reliability and validity of the efficacy assessments, allowing for a robust analysis of the treatment's effects on early Alzheimer's disease.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female participants aged 55 to 85 years of age inclusive at the time of signing the informed consent form (ICF)
Mild cognitive impairment or mild dementia consistent with AD defined by stages 3 to 4 according to the National Institute on Aging and Alzheimer’s Association (NIA-AA) at Screening
Participants with a history of subjective cognitive and memory decline with onset within 5 years before Screening, confirmed by study partner.
Participants who have a MMSE score ≥ 20
Participants with a CDR global rating of 0.5 or 1
Participants with a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score based on the Delayed Memory Index (DMI) score ≤ 85
If an historic magnetic resonance imaging (MRI) is available, findings must exclude other causes of dementia
Positive biomarker for brain amyloid pathology as indicated by assessment of at least one of the following: a. Current or historical CSF assessment with FDA-cleared and/or CE-marked assays (e.g., Lumipulse® Aβ ratio [1-42/1-40] ≤ 0.072, Elecsys® pTau 181/Aβ[1-42] > 0.023, Elecsys® total Tau/Aβ[1-42] > 0.28. b. Historical amyloid positron emission tomography (PET) assessment with FDA-cleared and/or CE-marked tracer for AD diagnosis, confirmed by the Sponsor or central read.
Participants and caregiver(s) who can sign an informed consent to participate in the study. Participants are expected to have the capacity to consent to study participation. Investigators will assess and confirm participants’ capacity to consent/assent.
Participants who have 1 (or more) identified adult study partner(s) who, in the opinion of the Investigator, has a personal contact of a minimum of 5 days a week with the participant and are able to report knowledgably about the participant’s cognition, function, behavior, safety and compliance with the protocol. The informant/care partner must be available by phone to provide information to the Investigator and study staff about the participant as well as agree to attend in-person clinic visits that require partner input for scale completion. The informant/care partner must be able to understand the requirements of participation and provide informed consent and should be available for the duration of the study. The same informant/care partner is required to be consistent across all study visits except under rare, unavoidable circumstances (e.g., unexpected informant health crisis) that are approved by the Investigator and Sponsor.

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Exclusion Criteria

Participants who are female and are either pregnant, nursing, or of childbearing potential and not practicing acceptable effective contraception
Participants who have signs of significant ongoing delirium which may raise doubts about participant’s competence that would potentially interfere with study assessments
Participants who have any diagnosis of dementia or cognitive decline other than that related to AD, including, but not limited to concomitant history of significant head trauma, alcohol abuse, frontotemporal dementia, Huntington Disease, Parkinsonism (e.g., Parkinson’s disease, Dementia with Lewy Bodies, etc.), significant cerebrovascular disease and/or significant seizure disorder.
Participants with any current psychiatric diagnosis if, in the judgment of the Investigator, the psychiatric disorder (e.g., schizophrenia) or symptom is likely to confound interpretation of drug effect, affect cognitive assessments, or affect the participant’s ability to complete the study.
Participants with a history of vascular dementia
Participants with evidence of other neurological conditions thought to interfere with the evaluations in this study
Participants with a history of myocardial infarction, unstable angina, significant coronary artery disease, and/or New York Heart Association (NYHA) class III or IV heart failure within the last 12 months
Participants with uncontrolled hypertension (e.g., systolic blood pressure (BP) >160 mmHg or diastolic BP > 95 mmHg) or hypotension (e.g., systolic BP <90 mmHg or diastolic BP <50 mmHg). Participants may undergo repeated testing to ensure that accurate BP readings are obtained.
Participants with a body mass index (BMI) ≥ 35 kg/m2
Participants with any of the following: a. Elevation (>2.5× upper limit of normal [ULN]) of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin (unless known prior history of Gilbert’s syndrome). b. Deficiency (< lower limit of normal [LLN]) of vitamin B12 c. Known history of human immunodeficiency virus (HIV) positivity or positive test for HIV 1/2 at screening unless negative on confirmatory polymerase chain reaction (PCR) d. Known history of hepatitis C virus (HCV) or positive test for HCV antibody (HCV Ab) at screening unless negative on confirmatory PCR test e. Positive test for Hepatitis B surface antigen (HBsAg) f. Known history of neurosyphilis or positive test for syphilis immunoglobulin G (IgG) at screening
Participants who have history of cancer or malignant tumor within 5 years prior to screening with the exception of: a. Basal or squamous cell carcinoma of the skin or cervical dysplasia, which has been adequately treated. b. In situ Grade 1 cervical cancer, fully treated at least 2 years prior to screening, and without recurrence. c. Prostate cancer, confined to the prostate gland, which has been adequately treated (e.g., surgery and/or radiation, or watchful waiting) with normal or low and stable prostate-specific antigen (PSA) levels for 2 years prior to Screening. d. Adequately treated non-metastatic breast cancer.
Participants who, in the opinion of the Investigator have an inadequately treated thyroid disorder.
Participants with inherited degenerative retinal disease
Participants who have an undiagnosed or uncontrolled seizure disorder (and/or an epileptic syndrome), which has or could lead to cognitive impairment either from repeated seizures or the medications used to control the seizure disorder.
Participants who are being treated, or likely to require treatment during the study, with any medications prohibited by the study protocol
Participants who have participated in any investigational drug or device trial within the previous 30 days or 5 half-lives of an investigational drug at Screening, whichever is longer.
Participants taking a cholinesterase inhibitor and/or memantine not on a stable dose for at least 3 months prior to screening. Treatment and dosing should remain stable, with no changes throughout the trial.
Participants who have been and/or are currently being treated with anti-amyloid, anti-tau, or any investigational therapy for AD
Participants who currently take any other PDE-5 inhibitors (e.g., sildenafil)
Participants who are currently receiving (or unable to stop use for at least 14 days [2 weeks] prior to receiving the first dose of the AR1001 and throughout the study) prescription or nonprescription medications or other products known to be potent inhibitors or inducers of cytochrome P450 isozyme 3A4 (CYP3A4).
Alcohol or substance use disorder within the past 5 years according to Diagnostic and Statistical Manual of Mental Disorders (DSM-5)
Participants who have previously participated in a clinical trial with AR1001
Participants who, in the opinion of the Investigator, who are unsuitable to participate in the trial
Participants who, in the opinion of the Investigator, are at significant risk of suicide
GDS-15 score ≥8 at Screening
Participants requiring a lumbar puncture (LP) to verify amyloid pathology who have a contraindication to undergoing LP in the opinion of the Investigator. Participants requiring LP who are receiving ongoing anticoagulant therapy or antiplatelet therapy (other than aspirin and non-steroidal anti-inflammatory drugs [NSAIDs]) should also be excluded if it is considered unsafe or contraindicated to temporarily discontinue the therapy

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Czechia	Not Recruiting	26 Apr 2024	76
Denmark	Not Recruiting	26 Apr 2024	28
France	Not Recruiting	26 Apr 2024	82
Germany	Not Recruiting	26 Apr 2024	35
Italy	Not Recruiting	26 Apr 2024	68
The Netherlands	Not Recruiting	26 Apr 2024	—
Poland	Not Recruiting	26 Apr 2024	50
Spain	Not Recruiting	26 Apr 2024	102
Netherlands	—	—	38