Clinical trial NCT05686044: A Dose-ranging Study to Investigate Efficacy of Buntanetap in Mild to Moderate AD
Official title: A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, Multicenter Study of Buntanetap in Participants With Mild to Moderate Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Alzheimer Disease
Keywords: Alzheimer
Lead sponsor: Annovis Bio Inc.
Sponsor class: INDUSTRY
First posted: 2023-01-17
Enrollment: 351
Sex: ALL
Minimum age (years): 55
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to measure efficacy and safety of three different doses of buntanetap/Posiphen compared with placebo in participants with mild to moderate Alzheimer's disease.

Study details include:

The double-blind treatment duration will include a screening period of up to 42 days followed by 12 weeks of treatment at home.

The study duration will be 4-5 months. There will be 4 in-clinic visits and 1 phone call.

Detailed description: 320 mild to moderate AD participants will be randomized to 7.5 mg, 15 mg, 30mg of buntanetap/Posiphen once daily (QD) or placebo. If they provide informed consent, they will undergo a Screening Visit, and if they are considered eligible per the inclusion and exclusion criteria, they will proceed to participate in the treatment period. Randomized participants will visit the clinic for the first-time dosing in clinic, followed by an at home dosing period of 12 weeks, with daily administration of 7.5 mg, 15 mg or 30 mg of buntanetap/Posiphen or placebo. Participants will be required to visit clinics Day 0 (baseline), 6 weeks, and 12 weeks (end-of-trial), where they will undergo study procedures that include safety assessments (AE and concomitant medication monitoring, 12-lead ECGs, clinical laboratory testing, vital signs assessments, and physical examinations) and psychometric tests (Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog11), Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Scale (ADCS-ADL), Digital Symbol Substitution Test (DSST), Mini Mental State Examination (MMSE)). At the end of blood sampling, the participants will need to stay for a minimum of 1 hour of observation. After all end-of-study procedures are complete, the subject will be discharged to home. A 24-hour follow-up call will occur after all clinical visits to assess the participants current condition and if there are any additional adverse events or questions.

The study will be a 12-weeks, placebo-controlled and double-blind trial: participants, investigators and the sponsor will be blinded to the participants' treatment.

Qualified participants will be randomly assigned at a 1:1:1:1 ratio to one of the four treatment arms: buntanetap/Posiphen 7.5 mg, buntanetap/Posiphen 15 mg, buntanetap/Posiphen 30mg, and placebo, through an Interactive Randomization System, after a screening period of up to 42 days.

ADAS-Cog 11, ADCS-CGIC, ADCS-ADL, DSST, and MMSE will be assessed by clinicians who have successfully completed the requisite certifications/trainings for each assessment.

One interim analysis is planned. It will take place when 90 enrolled subjects (\~30%) have completed the Week 6 assessments to re-assess the sample size. No interim analyses are planned for the purpose of stopping the study early for futility.

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of Alzheimer's disease according to National Institute on Aging and National Institute on Aging and Alzheimer's Association criteria for probable AD
2. Male or female aged 55 - 85 years.
3. MMSE 14-24.
4. 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 to study visits at designated times.
5. 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 4 weeks 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, and the absence of sperm has been confirmed. 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 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.
6. 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 subject 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
   * Intrauterine device (IUD)
   * Intrauterine hormone-releasing system (IUS)
   * Bilateral tubal occlusion
7. Participants can provide written informed consent. If PI deems that participant cannot fully understand the consent form to give consent, their legally authorized representative (LARs) can provide written informed consent. Participants can comply with scheduled visits, and other study-related procedures to complete the study with the help of the study partner.
8. No evidence of current suicidal ideation or previous suicide attempt in the past 2 months as evaluated in the Columbia Suicide Severity Rating Scale nor suicidal behavior in the past 6 months as per investigator.
9. Stability of permitted medications for at least 4 weeks prior to screening.

   1. Cholinesterase inhibitors and/or memantine medication
   2. Anticonvulsant medications used for epilepsy or mood stabilization, neuropathic pain indications.
   3. Mood-stabilizing psychotropic agents, including, but not limited to, lithium.
10. Adequate visual and hearing ability (physical ability to perform all the study assessments) as per investigator.
11. Good general health with no disease expected to interfere with the study as per investigator.

Exclusion Criteria:

1. Has a history of a 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). Mild depression or history of depression that is stable on treatment with a selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI) medication at a stable dose is acceptable.
2. Has non-AD dementia, such as vascular dementia, Lewy body dementia, frontotemporal disease, Parkinson disease dementia, B12 and thyroid deficiency caused dementia.
3. History of a seizure disorder, if stable on medication is acceptable.
4. 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, or torsades de pointes.
5. Has bradycardia (\<50 bpm) or tachycardia (\>100 bpm) on the ECG at screening.
6. Has uncontrolled Type-1 or Type-2 diabetes. A subject with HbA1c levels up to 7.5% can be enrolled if the investigator believes the subject's diabetes is under control.
7. Has clinically significant renal (CKD-EPI with normal \<60 mL/min/BSA (body surface area) or hepatic impairment (ALP \> 2.0 ULN and/or total bilirubin \> 2.0 ULN) .
8. 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.
9. 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 Investigators. 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.
10. 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 prostate cancer or skin cancers are not excluded).
11. Alcohol / Substance use disorder, moderate to severe, in the last 5 years according to the most current version DSM.
12. 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.
13. Participants with learning disability or developmental delay.
14. Participants whom the site PI deems to be otherwise ineligible.
15. Participants with a known allergy to the investigational drug or any of its components. Here are all the inactive ingredients of the investigational medicinal product:

    * Silicified Microcrystalline Cellulose
    * Dibasic Calcium Phosphate Dihydrate
    * Mannitol
    * Magnesium Stearate
    * Hypromellose (capsule shells structure)
    * titanium dioxide (opacifier of the capsule shells)
16. Subject is currently pregnant, breast-feeding and/or lactating.
17. Subject is currently taking strong and moderate CYP3A4 inhibitors and/or inducers. (e.g., CYP3A4 inhibitors Itraconazole, Ketoconazole, Azamulin, Troleandomycin, Verapamil; CYP3A4 inducers Rifampicin)

Primary outcomes:
measure: Change From Baseline to Week 12 in ADAS-Cog11
timeFrame: Baseline to the end of treatment period (12 weeks)
measure: ADCS-CGIC at Week 12
timeFrame: Baseline to the end of treatment period (12 weeks)
Secondary outcomes:
measure: Change From Baseline to Week 12 in ADCS-ADL
timeFrame: Baseline to end of treatment period (12 weeks)
Other outcomes:
measure: Change From Baseline to Week 12 in Plasma Biomarkers
timeFrame: Baseline to the end of treatment period (12 weeks)
Locations:
city: Gilbert
country: United States
facility: CCT Research - Gilbert Neurology Partners
state: Arizona
city: Phoenix
country: United States
facility: CCT Research - Foothills Center
state: Arizona
city: Fort Smith
country: United States
facility: The Belinga Clinic
state: Arkansas
city: Imperial
country: United States
facility: Sun Valley Research Center
state: California
city: Los Alamitos
country: United States
facility: CenExel Clinical Clinical Research, Inc
state: California
city: Englewood
country: United States
facility: Cenexel Rocky Mountain Clinical Research
state: Colorado
city: Stamford
country: United States
facility: Ki Health Partners LLC D/B/A New England Institute for Clinical Research
state: Connecticut
city: Aventura
country: United States
facility: Visionary Investigators Network
state: Florida
city: Clermont
country: United States
facility: K2 Medical Research
state: Florida
city: Coral Springs
country: United States
facility: The Neurology Institute - Coral Springs
state: Florida
city: Cutler Bay
country: United States
facility: JY Research Inst.
state: Florida
city: Daytona Beach
country: United States
facility: Arrow Clinical trial
state: Florida
city: DeLand
country: United States
facility: Accel Research Sites - DeLand Clinical Research Unit
state: Florida
city: Hialeah
country: United States
facility: New Life Medical Research Center
state: Florida
city: Hollywood
country: United States
facility: CenExel RCA
state: Florida
city: Homestead
country: United States
facility: Coral Clinic Reserach LLC
state: Florida
city: Lady Lake
country: United States
facility: Charter Research
state: Florida
city: Maitland
country: United States
facility: ClinCloud, LLC
state: Florida
city: Maitland
country: United States
facility: K2 Medical Research
state: Florida
city: Merritt Island
country: United States
facility: Merritt Island Clinical Research LLC
state: Florida
city: Miami
country: United States
facility: Premier Clinical Research Institute, Inc
state: Florida
city: Miami
country: United States
facility: Gold Coast Health Research, LLC
state: Florida
city: Miami
country: United States
facility: Medical Professional Clinical Research Center, Inc
state: Florida
city: Miami
country: United States
facility: Reliant Medical Research
state: Florida
city: Miami
country: United States
facility: Ezy Medical Research Co.
state: Florida
city: Miami
country: United States
facility: Nuovida Research Center
state: Florida
city: Ocala
country: United States
facility: Renstar Medical Research
state: Florida
city: Pembroke Pines
country: United States
facility: Visionary Investigators Network
state: Florida
city: Pompano Beach
country: United States
facility: Napa Research
state: Florida
city: Tampa
country: United States
facility: K2 Medical Research
state: Florida
city: The Villages
country: United States
facility: K2 Summit Research
state: Florida
city: Viera
country: United States
facility: ClinCloud, LLC
state: Florida
city: Winter Park
country: United States
facility: Conquest Research, LLC
state: Florida
city: Winter Park
country: United States
facility: Charter Research
state: Florida
city: Decatur
country: United States
facility: CenExel iResearch, LLC
state: Georgia
city: Gainesville
country: United States
facility: Center for Advanced Research & Education
state: Georgia
city: Honolulu
country: United States
facility: Hawaii Pacific Neuroscience, LLC
state: Hawaii
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
city: Indianapolis
country: United States
facility: Josephson Wallack Munshower Neurology, P.C.
state: Indiana
city: Bangor
country: United States
facility: Northern Light Acadia Hospital
state: Maine
city: Waltham
country: United States
facility: MedVadis Research
state: Massachusetts
city: Farmington Hills
country: United States
facility: Quest Research Institue
state: Michigan
city: Flint
country: United States
facility: Insight Research Institute
state: Michigan
city: Berlin
country: United States
facility: Hassman Research Institute
state: New Jersey
city: Toms River
country: United States
facility: CenExel Clinical Research, Inc
state: New Jersey
city: Syracuse
country: United States
facility: Velocity Clinical Research
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Canton
country: United States
facility: Neuroscience Centre (CINAC)
state: Ohio
city: Centerville
country: United States
facility: Dayton Center for Neurological Disorders, Inc
state: Ohio
city: Houston
country: United States
facility: NeuroCare Plus
state: Texas
city: Round Rock
country: United States
facility: Be Well Clinical Studies, LLC
state: Texas
city: Round Rock
country: United States
facility: Central Texas Neurology Consultants
state: Texas
city: Spokane
country: United States
facility: Inland Northwest Research
state: Washington
Study officials:
References: