A Double-blind Dual Study Assessing Safety and Efficacy of Buntanetap in Participants With Early AD

A 6-month & 18-month Prospective, Randomized, Placebo-controlled, Double-blind Dual Clinical Trial Investigating Efficacy and Safety of Buntanetap in Treating Participants of Early Alzheimer's Disease

The goal of this clinical trial is to learn if buntanetap/Posiphen works to treat early Alzheimer's disease in adults aged 55-85. It will also learn about the safety of buntanetap/Posiphen. The main questions it aims to answer are:

• Does buntanetap/Posiphen improve cognition as measured by ADAS-Cog13?
• Does buntanetap/Posiphen improve function as measured by ADCS-iADL?
• What medical issues do participants have, if any, when taking buntanetap/Posiphen?

Researchers will compare buntanetap/Posiphen to a placebo (a look-alike substance that contains no drug) to see if buntanetap/Posiphen works to treat early Alzheimer's disease.

Participants will:

• Take buntanetap/Posiphen or a placebo every day for 18 months
• Visit the clinic periodically for checkups, tests, and questionnaires (screening visits, enrollment, month 1, month 3, month 6, month 9, month 12, month 15, month 18), including a volumetric MRI at month 6 and month 18
• Complete pre- and post-clinic visit phone calls

Study Overview

• Status: Active, not recruiting
• Conditions: Early Alzheimers Disease
• Intervention / Treatment: Drug: buntanetap/posiphen; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 760
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Chandler, Arizona, United States, 85286
      • MD First Research
    • Phoenix, Arizona, United States, 85004
      • Xenoscience
    • Scottsdale, Arizona, United States, 85258
      • Clinical Endpoints
  • California
    • Anaheim, California, United States, 92805
      • Advanced Research Center
    • Canoga Park, California, United States, 91303
      • HOPE Clinical Research
    • Imperial, California, United States, 92251
      • Sun Valley Research
    • Los Angeles, California, United States, 90095
      • Mary S. Easton Center for Alzheimer's Research and Care, UCLA
    • Sacramento, California, United States, 95816
      • UC Davis Alzheimer's Disease Research Center
    • San Marcos, California, United States, 92069
      • The Neuron Clinic
  • Colorado
    • Basalt, Colorado, United States, 81621
      • Mountain Neurological Center
    • Englewood, Colorado, United States, 80113
      • CenExel Rocky Mountain
  • Connecticut
    • Norwalk, Connecticut, United States, 06851
      • Research Center for Clinical Trials
  • Florida
    • Aventura, Florida, United States, 33180
      • Visionary Investigators Network
    • Boca Raton, Florida, United States, 33487
      • SFM Clinical Research
    • Clermont, Florida, United States, 34711
      • K2 Medical Research
    • Daytona Beach, Florida, United States, 32114
      • K2 Medical Research Daytona
    • Fort Myers, Florida, United States, 33912
      • Neuropsychiatric Research Center
    • Hallandale, Florida, United States, 33009
      • Velocity Clinical
    • Jacksonville, Florida, United States, 32216
      • Jacksonville Center for Clinical Research
    • Lady Lake, Florida, United States, 32159
      • K2 Medical Research
    • Lake Worth, Florida, United States, 33462
      • Headlands Research JEM
    • Lakeland, Florida, United States, 33803
      • Accel Research Sites Lakeland (Alcanza)
    • Maitland, Florida, United States, 32751
      • K2 Medical Research
    • Melbourne, Florida, United States, 32940
      • ClinCloud Clinical Research
    • Merritt Island, Florida, United States, 32952
      • Flourish Research/Merritt Island Medical Research
    • Miami, Florida, United States, 33137
      • Miami Jewish Health
    • Naples, Florida, United States, 34102
      • Aqualane Clinical Research
    • New Port Richey, Florida, United States, 34652
      • Suncoast Clinical Research
    • Orlando, Florida, United States, 32832
      • Conquest Research
    • Tampa, Florida, United States, 33609
      • Axiom Brain Health, LLC
    • Winter Park, Florida, United States, 32789
      • Conquest Research
  • Georgia
    • Decatur, Georgia, United States, 30030
      • Accel Neurosciences
    • Gainesville, Georgia, United States, 30501
      • CARE (Center for Advanced Research & Education)
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Hawaii Pacific Neuroscience
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60611
      • Re:Cognition Chicago
    • Chicago, Illinois, United States, 60618
      • Charter Research Chicago
    • Chicago, Illinois, United States, 60640
      • Great Lakes Clinical Trials/Flourish Research
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University
  • Indiana
    • Indianaopolis, Indiana, United States, 46256
      • JWM Research
  • Kansas
    • Wichita, Kansas, United States, 37214
      • Ascension via Christi Research
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • Tandem Intermediate
  • Maryland
    • Pikesville, Maryland, United States, 21208
      • Headlands Research Pharmasite
  • Massachusetts
    • Foxborough, Massachusetts, United States, 02035
      • Neurology Center of New England, PC
    • Plymouth, Massachusetts, United States, 02360
      • Headlands Research Easter Massachusetts
    • Russells Mills, Massachusetts, United States, 02747
      • Mayflower Clinical
    • Springfield, Massachusetts, United States, 01103
      • Elixia MA
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Quest Research Institute
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Precise Research Center
  • Missouri
    • Chesterfield, Missouri, United States, 63005
      • Clinical Research Professionals - Headlands Research
  • Nevada
    • Las Vegas, Nevada, United States, 89121
      • Oasis Clinical Trials LLC
  • New Jersey
    • Toms River, New Jersey, United States, 08755
      • Cenexel Advanced Medical Research of New Jersey (AMRI)
    • West Long Branch, New Jersey, United States, 07764
      • Advanced Clinical Institute
  • New York
    • Amherst, New York, United States, 14226
      • Dent Neurologic Institute
    • Brooklyn, New York, United States, 11235
      • SPRI
    • Lake Success, New York, United States, 11042
      • Neurological Associates of Long Island
    • New York, New York, United States, 10003
      • New York Neurology Associates
    • Staten Island, New York, United States, 10314
      • Richmond Behavioral Associates
    • Syracuse, New York, United States, 13210
      • Ichor Research
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
    • Matthews, North Carolina, United States, 28105
      • AMC Research/Flourish Research
  • Ohio
    • Beavercreek, Ohio, United States, 45432
      • American Clinical Research Center
    • Centerville, Ohio, United States, 45459
      • Valley Medical Research
    • Independence, Ohio, United States, 44131
      • Insight Clinical Trials
  • Oregon
    • Portland, Oregon, United States, 97210
      • Summit Headlands
  • Pennsylvania
    • Media, Pennsylvania, United States, 19063
      • Suburban Research Associates
    • Plymouth Meeting, Pennsylvania, United States, 19462
      • K2 Keystone
  • Rhode Island
    • East Providence, Rhode Island, United States, 02914
      • Rhode Island Mood and Memory Research Institute
  • South Carolina
    • Summerville, South Carolina, United States, 29486
      • Palmetto Primary Care & Specialty Physicians
  • Tennessee
    • Cordova, Tennessee, United States, 38018
      • Neurology Clinic, P.C.
    • Nashville, Tennessee, United States, 37204
      • K2 Medical Research Nashville
  • Texas
    • Austin, Texas, United States, 78757
      • Senior Adults Specialty Research
    • Houston, Texas, United States, 77094
      • NeuroMind Clinical Trials
    • Round Rock, Texas, United States, 78681
      • Central Texas Neurology Associates
    • Wichita Falls, Texas, United States, 76309
      • Grayline Research Center
  • Vermont
    • Bennington, Vermont, United States, 05201
      • Memory Clinic, Inc.
  • Virginia
    • Arlington, Virginia, United States, 22205
      • Sana Research
    • Fairfax, Virginia, United States, 22031
      • Re:Cognition Fairfax

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of AD according to the 2024 National Institute on Aging and Alzheimer's Association criteria.
2. Male or female, aged 55 - 85 years.
3. MMSE 20-28 at screening and baseline.
4. CDR global score=0.5 or 1, with memory box score at least 0.5 at screening and baseline.
5. Positive for amyloid beta as defined by plasma p-tau217 level at screening.
6. Neuroimaging (MRI) consistent with the clinical diagnosis of AD and without findings of significant exclusionary abnormalities (see exclusion criteria # 4). A historical MRI, up to 1 year prior to screening, may be used as long as there have been no interval clinical neurologic events that may suggest a change in the MRI scan.
7. Have a study partner who will provide written informed consent to participate, is in frequent contact with the participant (defined as at least 10 hours per week) and will accompany the participant on study visits at designated times.

8. Female participants of childbearing potential* must have a negative urine pregnancy test at screening, must be non-lactating and must agree to use a highly effective method of contraception (i.e., a method resulting in a failure rate of less than 1% per year when used consistently and correctly) during the trial and for one month after the last dose of trial treatment, such as:

   • Oral, intravaginal, or transdermal combined (estrogen plus progestogen) hormonal contraception associated with inhibition of ovulation,
   • Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation,
   • Intrauterine device (IUD),
   • Intrauterine hormone-releasing system (IUS),
   • Bilateral tubal occlusion,
   • Vasectomized partner (a vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the participant. If not, an additional highly effective method of contraception should be used),

   • Sexual abstinence (sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant).

     • Non-childbearing potential includes surgically sterilized or postmenopausal with no menstrual bleeding for at least one year prior to study start.

9. Male participants must be sterile or sexually inactive or agree not to father a child during the study and one month after the last dose of study medication and must agree to use a barrier method for contraception. Female partners of male participants must adopt a highly effective method of contraception with a failure rate of less than 1% per year when used consistently and correctly such as:

   • Oral, intravaginal, or transdermal combined (estrogen plus progestogen) hormonal contraception associated with inhibition of ovulation,
   • Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation,
   • IUD,
   • IUS,
   • Bilateral tubal occlusion.
10. General cognition and functional performance sufficiently preserved that the subject can provide written informed consent. At re-consent, a legally authorized representative may co-sign if participants do not meet the general cognition and functional performance needed in the opinion of the investigator.
11. No evidence of current suicidal ideation or previous suicide attempt in the past month as evaluated in the Columbia Suicide Severity Rating Scale.

12. Stability of permitted medications for at least 4 weeks prior to screening. Refer to Concomitant Medications section for details on prohibited and permitted medications.

    • Cholinesterase inhibitors and/or memantine medication,
    • Anticonvulsant medications used for epilepsy or mood stabilization, or neuropathic pain indications, and have not had a breakthrough seizure in 3 years prior to screening
    • Mood-stabilizing psychotropic agents including, but not limited to, lithium.
13. Adequate visual and hearing ability (physical ability to perform all the study assessments).
14. Participants previously exposed to buntanetap can still be included in the study after a 28-day wash out period.

Exclusion Criteria:

1. Has a history of psychiatric disorder such as schizophrenia, bipolar disorder, or major depression according to the criteria of the most current version of the Diagnostic and Statistical Manual of Mental Disorders (DSM), unless they are stable on treatment or no longer need treatment. Mild depression or history of depression that is stable on treatment with selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI) or other anti-depression medication (e.g. Wellbutrin) at a stable dose is acceptable. Refer to Concomitant Medications section above for details on prohibited and permitted medications.
2. Has non-AD dementia, such as vascular dementia, Lewy body dementia, frontotemporal disease, PD dementia, B12 and thyroid deficiency caused dementia.
3. History of a seizure disorder, if stable on medication is acceptable. Refer to Concomitant Medications section above for details on prohibited and permitted medications.
4. Screening MRI (or historical MRI, if applicable) of the brain indicative of significant abnormality, including, but not limited to, prior hemorrhage (>5) or infarct > 1 cm3, > 3 lacunar infarcts, cerebral contusion, encephalomalacia, aneurysm, vascular malformation, subdural hematoma, hydrocephalus, space-occupying lesion (e.g., abscess or brain tumor such as meningioma unless they are documented and stable).
5. Has a history or current evidence of long QT syndrome, Fridericia's formula corrected QT (QTcF) interval ≥ 450 ms for men and ≥ 460 ms for women ((in the absence of a bundle branch block), or torsades de pointes.
6. Has bradycardia (<50 bpm) or tachycardia (>100 bpm) on the ECG at screening and deemed medically significant by the PI.
7. Has uncontrolled Type-1 or Type-2 diabetes. A participant with hemoglobin subunit alpha 1c (HbA1c) levels up to 7.5% can be enrolled if the PI believes the participant's diabetes is under control.
8. Has clinically significant renal (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) <50 mL/min/BSA (body surface area) or hepatic impairment (alkaline phosphatase (ALP) > 2.0 ULN and/or total bilirubin > 2.0 ULN).
9. Has any clinically significant abnormal laboratory values. Participants with liver function tests (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) greater than twice the upper limit of normal will be excluded.
10. Is at imminent risk of self-harm, based on clinical interview and responses on the C- SSRS, or of harm to others in the opinion of the PI. Participants must be excluded if they report suicidal ideation with intent, with or without a plan or method (e.g., positive response to items 4 or 5 in assessment of suicidal ideation on the C-SSRS) in the past 2 months, or suicidal behavior in the past 6 months.
11. Has cancer or has had a malignant tumor within the past year, except participants who underwent potentially curative therapy with no evidence of recurrence (participants with stable untreated cancer are not excluded).
12. Alcohol / Substance use disorder, moderate to severe, in the last 5 years according to the most current version DSM.
13. Participation in another clinical trial with an investigational agent and have taken at least one dose of study medication, unless unblinded on placebo, within 4 weeks prior to the start of screening, or five half-lives of the investigational drug, whichever is greater. The end of a previous investigational trial is the date the last dose of an investigational agent was taken.
14. Participants with learning disability or developmental delay.
15. Participants whom the PI deems to be otherwise ineligible.

16. Participants with a known allergy to the investigational drug or any of its components.

    Inactive ingredients of the investigational medicinal product:

    • Silicified Microcrystalline Cellulose
    • Dibasic Calcium Phosphate Dihydrate
    • Mannitol
    • Stearic Acid
    • Hypromellosee (capsule shells structure)
    • Titanium dioxide (opacifier of the capsule shells)
17. Participant is currently pregnant, breast-feeding, and/or lactating.
18. Participant is currently taking strong and moderate CYP3A4 inhibitors and/or inducers. Refer to Concomitant Medications section below for details on prohibited and permitted medications.
19. Participants with uncontrolled hypertension (systolic >160mm Hg and/or diastolic >95mm Hg) or hypotension (systolic <90mm Hg and/or diastolic <60 mm Hg) and deemed medically significant by the PI.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo capsule by mouth once daily for 18 months
Experimental: buntanetap	Drug: buntanetap/posiphen; 30mg capsule by mouth once daily for 18 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13)	ADAS-Cog13 includes the original ADAS-Cog11 items that assess cognitive function across the memory, language, praxis, and orientation domains and adds a number cancellation task and a delayed free recall task. Total scores range from 0-85, with higher scores indicating greater cognitive impairment.	From screening to 6-month readout, to end of treatment at 18 months.
Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Scale (ADCS-iADL)	The Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL) is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's study partner to assess function to the degree to which the participant can perform a variety of tasks. The questionnaire asks 6 questions of basic ADLs and 17 instrumental ADLs. The iADL are more complex tasks, including activities such as shopping, maintaining appointments, or managing one's belongings or finances. The ADCS-iADL subset is assessed with items 6a and 7-23; scores range from 0 to 59, with lower scores indicating greater impairment in function.	From screening to 6-month readout, to end of treatment at 18 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mini Mental State Examination Score (MMSE)	MMSE is a brief screening instrument used to assess cognitive function (orientation, memory, attention, ability to name objects, follow verbal/written commands, write a sentence, and copy figures). Total score ranges from 0 to 30 with a lower score indicating greater disease severity.	From screening to 6-month readout, to end of treatment at 18 months.
Volumetric MRI (hippocampus and whole brain)	Volumetric MRI (vMRI) of the brain will be assessed and compared to evaluate the loss of brain volume that occurs in AD participants.	At enrollment and the 6-month and 18-month visits.
Clinical Global Impression - Severity (CGI-S) Scale	CGI-S is a clinician-rated tool that assesses the severity of a patient's illness. It is a 7-point scale that ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill participants) for observed and reported symptoms, behavior, and function.	From screening to 6-month readout, to end of treatment at 18 months.
Clinical Dementia Rating (CDR)	The CDR Scale stages dementia, including AD, in elderly participants. The CDR uses a 3-point scale to characterize 6 domains of cognitive and functional performance, including memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care. This scale produces 2 scores, a global CDR score and a sum of boxes score (CDR-SB). The CDR-SB score ranges from 0-18 with higher scores representing more severe dementia. CDR global score will be used for inclusion criteria. CDR sum of boxes will be used from baseline to the end of treatment.	From screening to 6-month readout, to end of treatment at 18 months.

Collaborators and Investigators

• Sponsor: Annovis Bio Inc.
• Collaborators: ProPharma Group; Prevail Infoworks

Publications and helpful links

Helpful Links

• Annovis Bio website

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: November 26, 2024
• First Submitted That Met QC Criteria: November 26, 2024
• First Posted (Actual): November 29, 2024

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 14, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: MCI; mild cognitive impairment; AD; Early AD; Early Alzheimers disease; buntanetap; posiphen
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Cognitive Dysfunction; Alzheimer Disease; Substandard Drugs; Pharmaceutical Preparations; phenserine
• Other Study ID Numbers: ANVS-25001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No