A Double-blind Study to Investigate Efficacy and Safety of Buntanetap Compared With Placebo in Participants With Early PD

A 6-month Prospective, Randomized, Double-blind, Placebo-controlled Clinical Trial Investigating the Efficacy, Safety, and Tolerability of Two Different Doses of Buntanetap or Placebo in Patients With Early Parkinson's Disease

The purpose of this study is to measure safety and efficacy of buntanetap/posiphen capsules compared with placebo capsules in participants with early PD.

Study details include:

• The study duration will be up to 7-8 months.
• The double-blind treatment duration will be up to 6 months.
• There will be 5 in-clinic visits and 7 phone calls

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease, Idiopathic
• Intervention / Treatment: Drug: Placebo; Drug: buntanetap/posiphen

Detailed Description

450 early Parkinson's Disease (PD) patients will be randomized to 10mg, 20 mg of buntanetap/posiphen or placebo. They will undergo a Screening Visit, and if they provide informed consent and are considered eligible per the inclusion and exclusion criteria, will proceed to participate in the treatment period. Randomized participants will visit the clinic for the first-time dosing in clinic with administration of 10 mg or 20mg of buntanetap/posiphen or placebo, followed by an at home dosing period of 6 months, with daily administration of 10 mg or 20mg of buntanetap/posiphen or Placebo. Participants will be required to visit clinics 1 month, 2 months, 3 months, and 6 months (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 (MDS-United Parkinson's Disease Rating Scale (MDS-UPDRS), Clinical Global Impression of Severity (CGIS), Wechsler Adult Intelligence Scales (WAIS), Mini-Mental State Examination (MMSE)) and Participant Global Impression of Change (PGIC). At the end of blood sampling, the subjects 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 to report.

Buntanetap/posiphen has shown to improve PD subjects' mobility. MDS-UPDRS sum of score of Part II + Part III and Total score of all four parts will be measured to assess its improvement on PD subjects daily living, mobility and complications. PGIC will also be measured to assess its effect.

Buntanetap/posiphen has shown to reduce inflammation and preserve axonal integrity and synaptic functions as well as neurotoxic proteins in previous Phase 2a studies. In this study we plan to measure plasma GFAP, NFL and potentially TDP43.

Reports of adverse events (AEs) and serious adverse events (SAEs) during exposure to buntanetap/posiphen will be collected to evaluate if there are any significant clinical safety issues for the study population. Extensive clinical and laboratory safety data already exist for buntanetap/posiphen; therefore, these safety measures will be sufficient in the proposed study.

For clinical, functional, and cognitive assessment measures, The subjects will be administered the Hoehn & Yahr and the MMSE for determination of inclusion into the study. The MDS-UPDRS and PGIC will be administered for subjects' movement and daily function. The Coding subtest from the WAIS 4th edition will serve as a sensitive measure of Central Nervous System (CNS) dysfunction. MMSE will also be measured to assess subjects' cognitive change.

• Study Type: Interventional
• Enrollment (Actual): 523
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 12163
    • Neurologie Berlin - Gemeinschaftspraxis Dr. Ehret / Dr. von Pannwitz
  • Berlin, Germany, 13088
    • Alexianer St. Joseph-Krankenhaus Berlin-Weissensee
  • Bavaria
    • Haag, Bavaria, Germany, 83527
      • Curiositas-ad-sanum GmbH
  • Brandenburg
    • Beelitz, Brandenburg, Germany, 14547
      • Kliniken Beelitz GmbH - Neurologisches Frachkrankenhaus fur Bewegungsstoerungen / Parkinson
  • Hesse
    • Kassel, Hesse, Germany, 34128
      • Paracelsus-Kliniken Deutschland GmbH & Co. KGaA - Paracelsus-Elena-Klinik Kassel
  • North Rhine-Westphalia
    • Muenster, North Rhine-Westphalia, Germany, 48149
      • University Hospital Muenster
  • Saxony
    • Dresden, Saxony, Germany, 01307
      • Klinik und Poliklinik fur Neurologie - Universitatsklinikum Carl Gustav Carus an der Techischen Universitat
• Hungary
  • Debrecen, Hungary, H-4032
    • Debreceni Egyetem Klinikai Központ Neurológiai Klinika (Kenézy Gyula Campus, Neurológiai Osztály)
  • Pecs, Hungary, H-7623
    • PTE AOK Neurologiai Klinika
• Italy
  • Campania
    • Baronissi, Campania, Italy, 84081
      • Universita degli Studi di Salerno - Centro per le Malattie Neurodegenerative
  • Lazio
    • Cassino, Lazio, Italy, 3043
      • San Raffaele Cassino - Centro di Cura e Prevenzione per il Parkinson
    • Rome, Lazio, Italy, 163
      • San Raffaele Pisana - Centro per la Cura e la Diagnosi del Parkinson
• Poland
  • Malopolskie
    • Krakow, Malopolskie, Poland, 31-505
      • Krakowska Akademia Neurologil Sp. z o.o. - Centrum Neurologii Klinicznej
    • Kraków, Malopolskie, Poland, 30-727
      • Pratia McM Kraków
    • Kraków, Malopolskie, Poland, 31-271
      • Unicardia Specjalstyczne Centrum Leczenia Chorob Serca I Naczyn&Unimedica Specjalistyczne Centrum Medyczne
  • Mazowieckie
    • Sochaczew, Mazowieckie, Poland, 96-500
      • RCMed Oddzial Sochaczew
    • Warsaw, Mazowieckie, Poland, 02-172
      • MTZ Clinical Research powered by Pratia
  • Silesia
    • Katowice, Silesia, Poland, 40-097
      • Specjalistyczna Praktyka Lekarska Dr. Stanislaw Ochudlo
    • Siemianowice Śląskie, Silesia, Poland, 41-100
      • Neuro-Care Sp. z o.o. Sp. Komandytowa
• Spain
  • Madrid, Spain, 28027
    • Universidad de Navarra - Clinica Universidad de Navarra (CUN) - Madrid
  • Sevilla, Spain, 41015
    • Hospital Universitario Virgen del Rocio (URVR - Instituto de Biomedicina de Sevilla (IBIS)
  • Alicante
    • Elche, Alicante, Spain, 03203
      • Hospital General Universitario de Elche
  • Barcelona
    • Sant Cugat Del Vallès, Barcelona, Spain, 8195
      • Hospital Universitaris General de Catalunya (HGC)
  • Gipuzkoa
    • Donostia-San Sebastian, Gipuzkoa, Spain, 20014
      • Policlinica Gipuzkoa - Centro de Invesigacion Parkinson (CIP)
  • Madrid
    • San Sebastián De Los Reyes, Madrid, Spain, 28701
      • Universidad Complutense de Madrid (UCM) - Hospital Universitario Infanta Sofia
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Universidad de Navarra - Clnica Universidad de Navarra (CUN) - Pamplona
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233-2110
      • University of Alabama at Birmingham (UAB)- The Kirklin Clinic
  • Arizona
    • Sun City, Arizona, United States, 85351-3020
      • Banner Sun Health Research Institute - Cleo Roberts Center for Clinical Research
  • California
    • Fountain Valley, California, United States, 92708
      • Parkinson's & Movement Disorder Institue (PMDI) - Orange County Office
    • San Francisco, California, United States, 94143-2202
      • UCSF Medical Center - Parkinson's Disease and Movement Disorders Clinic
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Rocky Mountain Movement Disorder Center
  • Connecticut
    • Stamford, Connecticut, United States, 06824
      • Ki Health Partners LLC D/B/A New England Institute for Clinical Research
  • Florida
    • Aventura, Florida, United States, 33180
      • Visionary Investigators Network
    • Boca Raton, Florida, United States, 33486-2359
      • Parkinson's Disease and Movement Disorders Center of Boca Raton
    • Coral Springs, Florida, United States, 33067-4640
      • The Neurology Institute - Coral Springs
    • Daytona Beach, Florida, United States, 32114
      • Arrow Clinical Trial
    • DeLand, Florida, United States, 32720
      • Accel Research Sites - DeLand Clinical Research Unit
    • Homestead, Florida, United States, 33032
      • Coral Clinic Reserach LLC
    • Miami, Florida, United States, 33176
      • Visionary Investigators Network
    • Miami, Florida, United States, 33165
      • Reliant Medical Research
    • Miami, Florida, United States, 33032
      • Homestead Associates in Research, Inc
    • Miami, Florida, United States, 33175
      • Ezy Medical Research Co.
    • Miami, Florida, United States, 33165
      • Medical Professional Clinical Research Center, Inc
    • Miami, Florida, United States, 33133
      • Visionary Investigators Networks
    • Ocala, Florida, United States, 34470
      • Renstar Medical Research
    • Pembroke Pines, Florida, United States, 33026
      • Visionary Investigators Network
    • Port Charlotte, Florida, United States, 33952-6705
      • Parkinsons Disease Treatment Center
    • Tampa, Florida, United States, 33613-4808
      • University of South Florida (USF) - University of South Florida College of Medicine- Parkinson's Disease and Movement Disorders Center
    • Viera, Florida, United States, 32940
      • ClinCloud, LLC
    • Winter Park, Florida, United States, 32789
      • Conquest Research, LLC
  • Georgia
    • Decatur, Georgia, United States, 30030
      • CenExel iResearch, LLC
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Hawaii Pacific Neuroscience, LLC
  • Indiana
    • Indianapolis, Indiana, United States, 46256
      • Josephson Wallack Munshower Neurology, P.C.
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University Of Kansas Medical Center
  • Michigan
    • East Lansing, Michigan, United States, 48824-7037
      • Michigan State University (MSU)- Health Team- Neurology and Ophthalmology Clinic
    • Farmington Hills, Michigan, United States, 48334
      • Quest Research Institue
  • New York
    • Commack, New York, United States, 11725-3400
      • Parkinson's Disease and Movement Disorders Center of Long Island
    • New York, New York, United States, 10019-1147
      • Mount Sinai West (Mount Sinai Roosevelt)
  • Ohio
    • Columbus, Ohio, United States, 43211
      • Ohio State University Wexner Medical Center (OSUWMC) - CarePoint Gahanna
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136-6372
      • The Movement Disorder Clinic (MDC) of Oklahoma
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Neurology
    • Philadelphia, Pennsylvania, United States, 19107
      • University of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29401-1189
      • Medical University of South Carolina (MUSC) - The Murray Center for Research on Parkinson's Disease and Related Disorders
  • Tennessee
    • Memphis, Tennessee, United States, 38157
      • Veracity Neuroscience, LLC
  • Texas
    • Round Rock, Texas, United States, 78681
      • Central Texas Neurology Consultants
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia Health System (UVAHS)- Adult Neurology Clinic
  • Washington
    • Spokane, Washington, United States, 99202-1342
      • Inland Northwest Research
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of idiopathic Parkinson Disease according to MDS Clinical Diagnostic Criteria for Parkinson's Disease.
2. H&Y score =1, 2 or 3 during ON-state & OFF-state <2hrs per day.
3. Male or female aged 40 - 85 years.
4. MMSE score between the range of 22-30 during screening visit (ON-state) and subjects can live independently without a caregiver.

5. Female subjects of childbearing potential* must have a negative serum or 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 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.

6. Male subjects 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 6. Female participants will be given a urine pregnancy test at the screening visit for which they should test negative.
7. General cognition and functional performance sufficiently preserved that the subject can provide written informed consent.
8. No evidence of current suicidal ideation or previous suicide attempt in the past month as evaluated in the Columbia Suicide Severity Rating Scale.
9. Stability of permitted medications prior to screening for at least 4 weeks.

10. At screening subjects do not need to but may be on the following medication:

    • Standard of Care anti-parkinsonian medication
    • Anticonvulsant medications used for epilepsy or mood stabilization, neuropathic pain indications
    • Mood-stabilizing psychotropic agents, including, but not limited to, lithium.
11. Adequate visual and hearing ability (physical ability to perform all the study assessments).
12. Good general health with no disease expected to interfere with the study.
13. Subjects 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 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 SSRI or SNRI medication at a stable dose is acceptable.
2. History of a seizure disorder, if stable on medication is acceptable.
3. Has a history or current evidence of long QT syndrome, Fridericia's formula corrected QT (QTcF) interval ≥ 475ms, or torsades de pointes.
4. Has bradycardia (<50 bpm) or tachycardia (>100 bpm) on the ECG at screening.
5. 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.
6. Has clinically significant renal or hepatic impairment.
7. Has any clinically significant abnormal laboratory values. Subjects with liver function tests (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) greater than twice the upper limit of normal will be excluded.
8. 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. Subjects 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.
9. Has cancer or has had a malignant tumor within the past year, except subjects who underwent potentially curative therapy with no evidence of recurrence. (Subjects with stable untreated prostate cancer or skin cancers are not excluded).
10. Alcohol / Substance use disorder, moderate to severe, in the last 5 years according to the most current version DSM.
11. Participation in another clinical trial with an investigational agent and have taken at least one dose of study medication, unless unblinded on placebo, within 60 days prior to the start of screening. The end of a previous investigational trial is the date the last dose of an investigational agent was taken, or five half-lives of the investigational drug, whichever is greater.
12. Subjects with learning disability or developmental delay.
13. Subjects whom the site PI deems to be otherwise ineligible.
14. Subjects with a known allergy to the investigational drug or any of its components.
15. Subject is currently pregnant, breast-feeding and/or lactating.
16. Subject is currently taking CYP3A4 inhibitors and/or inducers.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo oral capsule with daily administration for a period of 6 months	Drug: Placebo; HPMC (vegetarian source) capsule shells
Experimental: 10 mg buntanetap/posiphen; Buntanetap/posiphen 10 mg oral capsule with daily administration for a period of 6 months	Drug: buntanetap/posiphen; HPMC (vegetarian source) capsule shells; Other Names: Posiphen Tartrate; ANVS401
Experimental: 20 mg buntanetap/posiphen; Buntanetap/posiphen 20 mg oral capsule with daily administration for a period of 6 months	Drug: buntanetap/posiphen; HPMC (vegetarian source) capsule shells; Other Names: Posiphen Tartrate; ANVS401

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Month 6 in MDS-UPDRS Part II (OFF-state)	Change in the Score from the MDS- Unified Parkinson's Disease Rating Scale (UPDRS) Parts II from Baseline to the End of Trial. MDS-UPDRS Part II (Motor experiences of daily living) has 13 items and the score ranges from 0-52, with higher score reflecting greater severity.	Baseline and 6 months visits
Safety and tolerability	Safety and tolerability assessed by adverse events (AEs), severity of AEs, drug related AEs, AEs leading to study discontinuation, electrocardiogram findings, clinical laboratory test results, vital sign measurements, and physical and neurological examination findings	From consent to end of trial (up to 8 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline to Month 6 in the sum of MDS-UPDRS Part II+III (OFF-state)	Change in the Sum of the Score from the Activities of Daily Living (ADL) Scale and Motor Examination in the MDS-UPDRS (Parts II+III) from Baseline to the End of Trial. MDS-UPDRS Part II (Motor experiences of daily living) has 13 items and the score ranges from 0-52, with higher score reflecting greater severity MDS-UPDRS Part III (motor examination) has 18 items and ranges from 0-132, with higher scores reflecting greater severity. The sum of Part II+III will be 0-184, with higher scores reflecting greater severity.	Baseline and 6 months visits
Change from Baseline to Month 6 in the MDS-UPDRS Part III (OFF-state)	MDS-UPDRS Part III (motor examination) has 18 items and ranges from 0-132, with higher scores reflecting greater severity	Baseline and 6 months visits
Change From Baseline to Month 6 in The Sum of MDS-UPDRS Total Score (OFF-state)	The MDS-Unified Parkinson's Disease Rating Scale (UPDRS) is a 50-item rating scale designed to assess Parkinson's disease-related disability and impairment. The scale comprises four parts: Part I evaluates mentation, behavior, and mood symptoms; Part II evaluates activities of daily living (ADL); Part III evaluates motor function; and Part IV evaluates complications of dopaminergic therapy. The Total score is the sum of the subscale scores for Parts I to III and ranges from 0 to 236, with higher scores reflecting greater severity.	Baseline and 6 months visits
Percentage of Responders with "Much Improved" or "Very Much Improved" on Participant Global Impression of Change (PGIC) (ON-state)	The PGIC is the participant-reported outcome. The qualitative assessment of meaningful change will be determined by the participant in response to the question, "Compared to your condition at the beginning of treatment, how much has your condition changed?" Scores are: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; and 7=very much worse. Percentage of responders with much improved and very much improved on PGIC scale will be assessed. PGIC will be taken at home while the subject is during ON-state (with their SOC for Parkinson disease).	1 month, 2 months, 3 months and 6 months visits
Change From Baseline to Month 6 on Change on Clinical Global Impression of Severity (CGIS) (OFF-state)	The Clinical Global Impressions Scale on the severity of movement impairment as assessed by the site rater. Site raters will be asked: Considering your total clinical experience with the Parkinson disease population, how ill is the patient at this time? Answers were based on a 7-point scale, with 1=not assessed, 2= very mild, 3= mild, 4= moderate, 5= moderate severe, 6= severe, 7=extremely severe.	Baseline and 6 months visits

Collaborators and Investigators

• Sponsor: Annovis Bio Inc.
• Collaborators: TFS Trial Form Support

Study record dates

Study Major Dates

• Study Start (Actual): August 3, 2022
• Primary Completion (Actual): December 4, 2023
• Study Completion (Actual): December 4, 2023

Study Registration Dates

• First Submitted: April 19, 2022
• First Submitted That Met QC Criteria: April 28, 2022
• First Posted (Actual): May 3, 2022

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Parkinson's
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Enzyme Inhibitors; Cholinesterase Inhibitors; Phenserine
• Other Study ID Numbers: ANVS-22001

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