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

• ClinicalTrials.gov Identifier: NCT05357989
• Recruitment Status: Completed
• First Posted: May 3, 2022
• Last Update Posted: February 8, 2024
• Sponsor: Annovis Bio Inc.
• Collaborator: TFS Trial Form Support
• Information provided by (Responsible Party): Annovis Bio Inc.

Tracking Information

• First Submitted Date: April 19, 2022
• First Posted Date: May 3, 2022
• Last Update Posted Date: February 8, 2024
• Actual Study Start Date: August 3, 2022
• Actual Primary Completion Date: December 4, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 6, 2024)

• Change From Baseline to Month 6 in MDS-UPDRS Part II (OFF-state) [ Time Frame: 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.
• Safety and tolerability [ Time Frame: 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

Original Primary Outcome Measures (submitted: April 28, 2022)

• MDS-Unified Parkinson's Disease Rating Scale Part II+III [ Time Frame: From baseline to end of trial (6 months) ]
  The MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a 42-item rating scale designed to assess Parkinson's disease-related disability and impairment. The scale comprises four parts: Part I evaluates mentation, behaviour, 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 (no disability) to 176 (total dependence). This assessment will be based on a change in the sum of the score from the Activities of Daily Living Scale (Part II) and Motor Examination in the Unified Parkinson's Disease Rating Scale (Part III), from Baseline to the End of Trial.
• Safety and tolerability as accessed physical examinations, vital signs, clinical laboratory values, 12-lead ECG, use of concomitant medications, and adverse event (AE) reports [ Time Frame: From consent through up to 30 days after last study visit (up to 8 months) ]
  Safety and tolerability will be assessed with physical examinations, vital signs, clinical laboratory values, 12-lead electrocardiogram (ECG), use of concomitant medications, and adverse event (AE) reports. The frequencies of adverse events, serious adverse events, and laboratory abnormalities between the participants across the treatment groups will be compared.

Current Secondary Outcome Measures (submitted: February 6, 2024)

• Change from Baseline to Month 6 in the sum of MDS-UPDRS Part II+III (OFF-state) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: April 28, 2022)

• MDS-Unified Parkinson's Disease Rating Scale Total Score [ Time Frame: Baseline, 2 months and 6 months visits ]
  The MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a 42-item rating scale designed to assess Parkinson's disease-related disability and impairment. The scale comprises four parts: Part I evaluates mentation, behaviour, 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 (no disability) to 176 (total dependence).
• Percentage of Responders with "minimally improved," "much improved" or "very much improved" on participant global impression of change [ Time Frame: Baseline, 2 months and 6 months visits ]
  The participant global impression of change (PGIC) is a 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Double-blind Study to Investigate Efficacy and Safety of Buntanetap Compared With Placebo in Participants With Early PD
• Official Title: 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

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 Type: Interventional
• Study Phase: Phase 3

Study Design

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

Randomized

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

• Condition: Parkinson's Disease, Idiopathic

Intervention

• Drug: buntanetap/posiphen
  HPMC (vegetarian source) capsule shells
  Other Names:

  • Posiphen Tartrate
  • ANVS401
• Drug: Placebo
  HPMC (vegetarian source) capsule shells

Study Arms

• Experimental: 10 mg buntanetap/posiphen
  Buntanetap/posiphen 10 mg oral capsule with daily administration for a period of 6 months
  Intervention: Drug: buntanetap/posiphen
• Experimental: 20 mg buntanetap/posiphen
  Buntanetap/posiphen 20 mg oral capsule with daily administration for a period of 6 months
  Intervention: Drug: buntanetap/posiphen
• Placebo Comparator: Placebo
  Placebo oral capsule with daily administration for a period of 6 months
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 12, 2023): 523
• Original Estimated Enrollment (submitted: April 28, 2022): 450
• Actual Study Completion Date: December 4, 2023
• Actual Primary Completion Date: December 4, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany, Hungary, Italy, Poland, Spain, United States

Administrative Information

• NCT Number: NCT05357989
• Other Study ID Numbers: ANVS-22001
• Has Data Monitoring Committee: Yes

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

• Plan to Share IPD: Undecided

• Current Responsible Party: Annovis Bio Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Annovis Bio Inc.
• Original Study Sponsor: Same as current
• Collaborators: TFS Trial Form Support
• Investigators: Not Provided
• PRS Account: Annovis Bio Inc.
• Verification Date: February 2024