Phase 3, Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Efficacy and Safety of AR1001 in Participants With Early Alzheimer's Disease (Polaris-AD)

• ClinicalTrials.gov Identifier: NCT05531526
• Recruitment Status: Recruiting
• First Posted: September 8, 2022
• Last Update Posted: March 22, 2024
• Sponsor: AriBio Co., Ltd.
• Information provided by (Responsible Party): AriBio Co., Ltd.

Tracking Information

• First Submitted Date: August 31, 2022
• First Posted Date: September 8, 2022
• Last Update Posted Date: March 22, 2024
• Actual Study Start Date: December 23, 2022
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 19, 2022)

Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) [ Time Frame: 52 weeks ]

Change in the CDR-SB from Baseline to Week 52

Original Primary Outcome Measures (submitted: September 2, 2022)

To evaluate the efficacy of AR1001 compared to Placebo in participants with Early Alzheimer's disease [ Time Frame: 52 weeks ]

• Change in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) from Baseline to Week 52

Current Secondary Outcome Measures (submitted: November 27, 2023)

• Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-Cog 13) [ Time Frame: 52 weeks ]
  Change in ADAS-Cog 13 from Baseline to Week 52
• Amsterdam-Instrumental Activities of Daily Living Questionnaire-Short Version (A-IADL-Q-SV) [ Time Frame: 52 weeks ]
  Change in the A-IADL-Q-SV from Baseline to Week 52
• Geriatric Depression Scale (GDS) [ Time Frame: 52 weeks ]
  Change in the GDS from Baseline to Week 52
• Mini-Mental Status Examination (MMSE) [ Time Frame: 52 weeks ]
  Change in the MMSE from Baseline to Week 52

Original Secondary Outcome Measures (submitted: September 2, 2022)

• ADAS-Cog 13 [ Time Frame: 52 weeks ]
  Change of ADAS-Cog 13 (Alzheimer's Disease Assessment Scale-cognitive subscale) from Baseline to Week 52
• Change in cerebral spinal fluid (CSF) and/or plasma p-tau181 [ Time Frame: 52 weeks ]
  Change in cerebral spinal fluid (CSF) and/or plasma p-tau181 from Baseline to Week 52
• ADL Scale (ADCS-ADL) [ Time Frame: 52 weeks ]
  Change of Alzheimer's Disease Cooperative Study ADL Scale (ADCS-ADL) from Baseline to Week 52
• Integrated Alzheimer's Disease Rate Scale [ Time Frame: 52 weeks ]
  Change of Integrated Alzheimer's Disease Rate Scale (iADRS) from Baseline to Week 52
• Amsterdam-IADL short version (A-IADL) [ Time Frame: 52 weeks ]
  Change of Amsterdam-IADL short version (A-IADL) from Baseline to Week 52
• Geriatric Depression Scale (GDS) [ Time Frame: 52 weeks ]
  Change of Geriatric Depression Scale (GDS) from Baseline to Week 52
• Mini-Mental Status Examination (MMSE) [ Time Frame: 52 weeks ]
  Change of Mini-Mental Status Examination (MMSE) from Baseline to Week 52
• The Rey-Osterrieth Complex Figure Test (RCFT) [ Time Frame: 52 weeks ]
  Change of The Rey-Osterrieth Complex Figure Test (RCFT) from Baseline to Week 52
• Quality of Life in Alzheimer's Disease (QOL-AD) [ Time Frame: 52 weeks ]
  Change of Quality of Life in Alzheimer's Disease (QOL-AD) from Baseline to Week 52

Current Other Pre-specified Outcome Measures (submitted: December 19, 2022)

• Safety Analysis [ Time Frame: 156 weeks ]
  • Frequency of treatment emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)
  • Changes in C-SSRS (Columbia Suicide Severity Rating Scale)
• Biomarker Analysis [ Time Frame: 156 weeks ]
  Change in plasma/CSF biomarker levels from Baseline to Week 52 and the end of the Extension Phase.
• Exploratory Analysis [ Time Frame: 156 weeks ]
  Change in both primary and secondary endpoints from Baseline and Week 52 to the end of the extension study.

Original Other Pre-specified Outcome Measures (submitted: September 2, 2022)

• Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [ Time Frame: 160 weeks ]
  Safety Analysis to assess frequency of treatment emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)
• Changes of C-SSRS (Columbia Suicide Severity Rating Scale). [ Time Frame: 160 weeks ]
  To evaluate the safety of AR1001 compared to Placebo in participants with Early Alzheimer's disease in assessing changes of C-SSRS (Columbia Suicide Severity Rating Scale).
• Exploratory - To evaluate the efficacy of AR1001 in the extension study [ Time Frame: 160 weeks ]
  Change of both primary and secondary endpoints from Baseline and Week 52 to the end of the extension study. Additional exploratory objectives may be defined as new relevant information is obtained. • Change of both primary and secondary endpoints from Baseline and Week 52 to the end of the extension study. Additional exploratory objectives may be defined as new relevant information is obtained.• Change of both primary and secondary endpoints from Baseline and Week 52 to the end of the extension study. Additional exploratory objectives may be defined as new relevant information is obtained. Change of both primary and secondary endpoints from Baseline and Week 52 to the end of the extension study. Additional exploratory objectives may be defined as new relevant information is obtained.
• Exploratory - To evaluate AD related biomarkers [ Time Frame: 160 weeks ]
  Change in plasma biomarker levels from Baseline to Week 52 and the end of the Extension Phase.
• Exploratory - To evaluate AD related biomarkers [ Time Frame: 52 weeks ]
  Change in CSF biomarker levels of amyloid from Baseline to Week 52.
• Estimands [ Time Frame: 52 weeks ]
  The primary estimand is as follows: Treatment regimen: AR1001 30 mg QD or Placebo Population: Early Alzheimer's disease as define by nclusion and exclusion criteria Endpoint: Clinical Dementia Rating - Sum of Boxes Summary measure: difference between treatments i mean change from baseline to Week 52 How to account for inter-current events: A hypothetica trategy will be used to account for the ICE of earl tudy discontinuation of study drug in order to estimat what would have occurred in the absence of this ICE.The primary estimand is as follows: Treatment regimen: AR1001 30 mg QD or Placebo Population: Early Alzheimer's disease as define by nclusion and exclusion criteria Endpoint: Clinical Dementia Rating - Sum of Boxes Summary measure: difference between treatments i mean change from baseline to Week 52

Descriptive Information

• Brief Title: Phase 3, Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Efficacy and Safety of AR1001 in Participants With Early Alzheimer's Disease (Polaris-AD)
• Official Title: A Phase 3 Double-blind, Randomized, Placebo-controlled, Multi-center Trial to Evaluate the Efficacy and Safety of AR1001 Over 52 Weeks in Participants With Early Alzheimer's Disease (Polaris-AD)
• Brief Summary: This AR1001-ADP3-US01 protocol is a double-blind, randomized, placebo-controlled, multi- center, parallel-group comparison pivotal Phase 3 study to evaluate the efficacy and safety of AR1001 for the treatment of participants with early AD.

Detailed Description

The purpose of this Study is to evaluate the efficacy and safety of AR1001 in participants with Early Alzheimer's Disease (AD).

AR1001 is a small molecule that has demonstrated its potential as a therapeutic agent for AD via its polypharmacological characteristics with multiple mechanisms to ameliorate AD pathology.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

A Phase 3 Double-blind, Randomized, Placebo-controlled, Multi-center Trial to Evaluate the Efficacy and Safety of AR1001 over 52 Weeks in Participants with Early Alzheimer's Disease

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

double-blind, randomized, placebo-controlled

Primary Purpose: Treatment

• Condition: Alzheimer Disease

Intervention

• Drug: AR1001
  AR1001 Active Oral Tablet
• Drug: Placebo
  Placebo Oral Tablet

Study Arms

• Active Comparator: Group A - Active Comparator
  Active, AR1001 30 mg QD will be administered daily for 52 weeks during the Treatment Phase of the study. In the Extension Phase, all eligible participants who choose to participate will receive AR1001 30 mg QD for 104 weeks.
  Intervention: Drug: AR1001
• Placebo Comparator: Group B - Placebo Comparator
  Placebo QD will be administered daily for 52 weeks during the Treatment Phase of the study. In the Extension Phase, all eligible participants who choose to participate will receive AR1001 30 mg QD for 104 weeks.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 19, 2023): 1150
• Original Estimated Enrollment (submitted: September 2, 2022): 770
• Estimated Study Completion Date: December 2027
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Male or female participants aged 55 to 90 years of age inclusive at the time of signing the informed consent form
2. 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
3. Participants with a history of subjective cognitive and memory decline with onset within 5 years before Screening, confirmed by study partner.
4. Participants who have a MMSE score greater than or equal to 20
5. Participants with a CDR global rating of 0.5 or 1
6. Participants with a RBANS score based on the Delayed Memory Index (DMI) score less than or equal to 85
7. If an historic magnetic resonance imaging (MRI) is available, findings must exclude other causes of dementia.

8. Positive biomarker for brain amyloid pathology as indicated by assessment of at least one of the following:

   1. Current or historical CSF assessment with FDA-cleared assays, including Lumipulse® beta-amyloid ratio [1-42/1-40] ≤ 0.072, Elecsys® pTau 181/Aβ[1-42] greater than 0.023, Elecsys® tTau /Aβ[1-42] greater than 0.28, or other assays or cut-offs as they become FDA-cleared.
   2. Historical amyloid positron emission tomography (PET) assessment confirmed by the Sponsor or Designee.
9. Participants (or participant's legally authorized representative) and caregiver (s) who can sign an informed consent to participate in the study.
10. Participants who have one (or more) identified adult study partners (s) who, in the opinion of the Investigator, has sufficient contact with and knowledge about the participant as to be able to report knowledgably about the participant's cognition, function, behavior, and 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 literate 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.

Exclusion Criteria:

1. Participants who are female and are either pregnant, nursing, or of childbearing potential and not practicing effective contraception
2. Participants who have signs of significant delirium which, in the opinion of the Investigator, would interfere with this study
3. 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
4. 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
5. Participants with a history of vascular dementia
6. Participants with evidence of other neurological conditions thought to interfere with the evaluations in this study
7. 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 the last 12 months
8. Participants with uncontrolled hypertension (systolic blood pressure (BP) >160 mmHg or diastolic BP > 95 mmHg) or hypotension (systolic BP <90 mmHg or diastolic BP <50 mmHg). Participants may undergo repeated testing to ensure that accurate BP readings are obtained
9. Participants with a body mass index (BMI) > 35 kg/m2

10. Participants with any of the following:

    1. elevation (>2.5x upper limit of normal [ULN]) of AST (aspartate aminotransferase, ALT (alanine transaminase, or total bilirubin (unless known prior history of Gilbert's syndrome)
    2. deficiency (< lower limit of normal [LLN]) of Vitamin B12
    3. known history of HIV (human immunodeficiency virus) positivity or positive test for HIV 1/2 at screening
    4. known history of Hepatitis C virus (HCV) or positive test for HCV antibody (HCVAb) at screening (unless negative on confirmatory PCR test)'
    5. positive test for Hepatitis B surface antigen (HBsAg)
    6. known history of neurosyphilis or positive test for RPR at screening

11. Participants who have history of cancer or malignant tumor within 5 years prior to screening with the exception of:

    1. Basal or squamous cell carcinoma of the skin or cervical dysplasia, which has been adequately treated
    2. In situ Grade 1 cervical cancer, fully treated at least 2 years prior to screening, and without recurrence.
    3. 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
    4. Adequately treated non-metastatic breast cancer
12. Participants who in the opinion of the Investigator have an inadequately treated thyroid disorder
13. Participants with inherited degenerative retinal disease
14. 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
15. Participants who are being treated, or likely to require treatment during the study, with any medications prohibited by the study protocol
16. Participants who have participated in any investigational drug or device trial within the previous 30 days or five half-lives of an investigational drug at Screening, whichever is longer
17. Participants taking an oral 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.
18. Participants who have been and/or are currently being treated with anti-amyloid, anti-tau, or any other investigational therapies for AD
19. Participants who currently take any other PDE-5 Inhibitors (e.g., sildenafil)
20. 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 of cytochrome P450 isozyme 3A4 (CYP3A4)
21. Alcohol or substance use disorder within the past 5 years according to Diagnostic and Statistical Manual of Mental Disorders (DSM-5)
22. Participants who have previously participated in a clinical trial with AR1001
23. Participants, in the opinion of the Investigator, who are unsuitable to participate in the trial
24. Participants who in the opinion of the Investigator are at significant risk of suicide.
25. GDS-15 score greater than equal to 8 at Screening
26. Participants, in the opinion of the Investigator, who have any who have any contraindications to undergoing LP. Participants 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 to temporarily discontinue the therapy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 55 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: John Kim; 858-412-5467; Polaris-ad@aribiousa.com

• Listed Location Countries: Korea, Republic of, United States

Administrative Information

• NCT Number: NCT05531526
• Other Study ID Numbers: AR1001-ADP3-US01
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: AriBio Co., Ltd.
• Original Responsible Party: Same as current
• Current Study Sponsor: AriBio Co., Ltd.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Fred Kim; AriBio Co., Ltd.

• PRS Account: AriBio Co., Ltd.
• Verification Date: February 2024