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

Phase 3

Completed

• Conditions: Parkinson's Disease, Idiopathic
• Interventions: Drug: Placebo; Drug: buntanetap/posiphen

• Registration Number: NCT05357989
• Lead Sponsor: Annovis Bio Inc.

Brief Summary

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

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 Timeline

• Study First Submitted: 2022-04-19
• Study First Submitted QC: 2022-04-28
• Study First Posted: 2022-05-03
• Study Start: 2022-08-03
• Primary Completion: 2023-12-04
• Study Completion: 2023-12-04
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-06
• Last Update Posted: 2024-02-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 523

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo oral capsule with daily administration for a period of 6 months
10 mg buntanetap/posiphen	buntanetap/posiphen	Buntanetap/posiphen 10 mg oral capsule with daily administration for a period of 6 months
20 mg buntanetap/posiphen	buntanetap/posiphen	Buntanetap/posiphen 20 mg oral capsule with daily administration for a period of 6 months

Primary Outcome Measures

Name	Time	Method
Safety and tolerability	From consent to end of trial (up to 8 months)	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
Change From Baseline to Month 6 in MDS-UPDRS Part II (OFF-state)	Baseline and 6 months visits	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.

Secondary Outcome Measures

Name	Time	Method
Change from Baseline to Month 6 in the sum of MDS-UPDRS Part II+III (OFF-state)	Baseline and 6 months visits	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.
Change from Baseline to Month 6 in the MDS-UPDRS Part III (OFF-state)	Baseline and 6 months visits	MDS-UPDRS Part III (motor examination) has 18 items and ranges from 0-132, with higher scores reflecting greater severity
Change From Baseline to Month 6 in The Sum of MDS-UPDRS Total Score (OFF-state)	Baseline and 6 months visits	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.
Percentage of Responders with "Much Improved" or "Very Much Improved" on Participant Global Impression of Change (PGIC) (ON-state)	1 month, 2 months, 3 months and 6 months visits	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).
Change From Baseline to Month 6 on Change on Clinical Global Impression of Severity (CGIS) (OFF-state)	Baseline and 6 months visits	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.

Trial Locations

Locations (67)

Medical Professional Clinical Research Center, INC; 🇺🇸 Miami, Florida, United States

Josephson Wallack Munshower Neurology, P.C.; 🇺🇸 Indianapolis, Indiana, United States

Ohio State University Wexner Medical Center (OSUWMC) - CarePoint Gahanna; 🇺🇸 Columbus, Ohio, United States

Central Texas Neurology Consultants; 🇺🇸 Round Rock, Texas, United States

Pratia MCM Krakow; 🇵🇱 Kraków, Malopolskie, Poland

Hawaii Pacific Neuroscience, LLC; 🇺🇸 Honolulu, Hawaii, United States

Unicardia Specjalstyczne Centrum Leczenia Chorob Serca I Naczyn&Unimedica Specjalistyczne Centrum Medyczne; 🇵🇱 Kraków, Malopolskie, Poland

Curiositas-ad-sanum GmbH; 🇩🇪 Haag, Bavaria, Germany

Specjalistyczna Praktyka Lekarska Dr. Stanislaw Ochudlo; 🇵🇱 Katowice, Silesia, Poland

Hospital Universitaris General de Catalunya (HGC); 🇪🇸 Sant Cugat Del Vallès, Barcelona, Spain

Klinik und Poliklinik fur Neurologie - Universitatsklinikum Carl Gustav Carus an der Techischen Universitat; 🇩🇪 Dresden, Saxony, Germany

Banner Sun Health Research Institute - Cleo Roberts Center for Clinical Research; 🇺🇸 Sun City, Arizona, United States

Parkinson's & Movement Disorder Institue (PMDI) - Orange County Office; 🇺🇸 Fountain Valley, California, United States

Ki Health Partners LLC D/B/A New England Institute for Clinical Research; 🇺🇸 Stamford, Connecticut, United States

Rocky Mountain Movement Disorder Center; 🇺🇸 Englewood, Colorado, United States

Visionary Investigators Network; 🇺🇸 Pembroke Pines, Florida, United States

Parkinson's Disease and Movement Disorders Center of Boca Raton; 🇺🇸 Boca Raton, Florida, United States

The Neurology Institute - Coral Springs; 🇺🇸 Coral Springs, Florida, United States

Arrow Clinical trial; 🇺🇸 Daytona Beach, Florida, United States

Visionary Investigators Networks; 🇺🇸 Miami, Florida, United States

Mount Sinai West (Mount Sinai Roosevelt); 🇺🇸 New York, New York, United States

Parkinsons Disease Treatment Center; 🇺🇸 Port Charlotte, Florida, United States

University of South Florida (USF) - University of South Florida College of Medicine- Parkinson's Disease and Movement Disorders Center; 🇺🇸 Tampa, Florida, United States

CenExel iResearch, LLC; 🇺🇸 Decatur, Georgia, United States

Conquest Research, LLC; 🇺🇸 Winter Park, Florida, United States

ClinCloud, LLC; 🇺🇸 Viera, Florida, United States

Michigan State University (MSU)- Health Team- Neurology and Ophthalmology Clinic; 🇺🇸 East Lansing, Michigan, United States

The Movement Disorder Clinic (MDC) of Oklahoma; 🇺🇸 Tulsa, Oklahoma, United States

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

Inland Northwest Research; 🇺🇸 Spokane, Washington, United States

Alexianer St. Joseph-Krankenhaus Berlin-Weissensee; 🇩🇪 Berlin, Germany

Veracity Neuroscience, LLC; 🇺🇸 Memphis, Tennessee, United States

University Hospital Muenster; 🇩🇪 Muenster, North Rhine-Westphalia, Germany

Paracelsus-Kliniken Deutschland GmbH & Co. KGaA - Paracelsus-Elena-Klinik Kassel; 🇩🇪 Kassel, Hesse, Germany

Debreceni Egyetem Klinikai Központ Neurológiai Klinika (Kenézy Gyula Campus, Neurológiai Osztály); 🇭🇺 Debrecen, Hungary

San Raffaele Pisana - Centro per la Cura e la Diagnosi del Parkinson; 🇮🇹 Rome, Lazio, Italy

Krakowska Akademia Neurologil Sp. z o.o. - Centrum Neurologii Klinicznej; 🇵🇱 Krakow, Malopolskie, Poland

RCMed Oddzial Sochaczew; 🇵🇱 Sochaczew, Mazowieckie, Poland

MTZ Clinical Research Powered by Pratia; 🇵🇱 Warsaw, Mazowieckie, Poland

NEURO-CARE Sp. z o.o. Sp. Komandytowa; 🇵🇱 Siemianowice Śląskie, Silesia, Poland

Hospital General Universitario de Elche; 🇪🇸 Elche, Alicante, Spain

Policlinica Gipuzkoa - Centro de Invesigacion Parkinson (CIP); 🇪🇸 Donostia-San Sebastian, Gipuzkoa, Spain

Universidad de Navarra - Clnica Universidad de Navarra (CUN) - Pamplona; 🇪🇸 Pamplona, Navarra, Spain

University of Alabama at Birmingham (UAB)- The Kirklin Clinic; 🇺🇸 Birmingham, Alabama, United States

UCSF Medical Center - Parkinson's Disease and Movement Disorders Clinic; 🇺🇸 San Francisco, California, United States

Coral Clinic Reserach LLC; 🇺🇸 Homestead, Florida, United States

Homestead Associates in Research, Inc; 🇺🇸 Miami, Florida, United States

Ezy Medical Research Co.; 🇺🇸 Miami, Florida, United States

Renstar Medical Research; 🇺🇸 Ocala, Florida, United States

Reliant Medical Research; 🇺🇸 Miami, Florida, United States

Parkinson's Disease and Movement Disorders Center of Long Island; 🇺🇸 Commack, New York, United States

Quest Research Institue; 🇺🇸 Farmington Hills, Michigan, United States

Abington Neurology; 🇺🇸 Abington, Pennsylvania, United States

Kliniken Beelitz GmbH - Neurologisches Frachkrankenhaus fur Bewegungsstoerungen / Parkinson; 🇩🇪 Beelitz, Brandenburg, Germany

University of Virginia Health System (UVAHS)- Adult Neurology Clinic; 🇺🇸 Charlottesville, Virginia, United States

San Raffaele Cassino - Centro di Cura e Prevenzione per il Parkinson; 🇮🇹 Cassino, Lazio, Italy

PTE AOK Neurologiai Klinika; 🇭🇺 Pecs, Hungary

Universita degli Studi di Salerno - Centro per le Malattie Neurodegenerative; 🇮🇹 Baronissi, Campania, Italy

Universidad Complutense de Madrid (UCM) - Hospital Universitario Infanta Sofia; 🇪🇸 San Sebastián De Los Reyes, Madrid, Spain

Universidad de Navarra - Clinica Universidad de Navarra (CUN) - Madrid; 🇪🇸 Madrid, Spain

Hospital Universitario Virgen del Rocio (URVR - Instituto de Biomedicina de Sevilla (IBIS); 🇪🇸 Sevilla, Spain

Medical University of South Carolina (MUSC) - The Murray Center for Research on Parkinson's Disease and Related Disorders; 🇺🇸 Charleston, South Carolina, United States

Neurologie Berlin - Gemeinschaftspraxis Dr. Ehret / Dr. von Pannwitz; 🇩🇪 Berlin, Germany

Accel Research Sites - DeLand Clinical Research Unit; 🇺🇸 DeLand, Florida, United States

University of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States

Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States