| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Parkinson's is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Study objectives include assessing buntanetap’ s efficacy and safety in early PD subjects. |
|
| E.2.2 | Secondary objectives of the trial |
| Assess Parkinson's disease related disability and impairment with MDS-UPDRS, PGIC, CGIS, WAIS coding, MMSE, plasma coding. Those will be assessed by clinicians who have successfully completed the requisite certifications/trainings for each assessment. All efforts will be made to ensure subjects will be assessed by the same clinician throughout the study. Participants should stop SOC Parkinson’s medications 12 hrs before clinical visits to ensure clinical OFF-state during visit. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet the following criteria:
1. Diagnosis of idiopathic PD 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 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
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 (L-dopa or dopamine antagonists)
• 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. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be included in the study:
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 ≥ 450 ms for men and 460ms for women, 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 (CKD-EPI <60 mL/min/BSA (body surface area)) or hepatic impairment (ALP > 2.0 ULN and/or total bilirubin > 2.0 ULN).
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. Here are all the inactive ingredients of the IMP:
Silicified Microcrystalline Cellulose
Dibasic Calcium Phosphate Dihydrate
Mannitol
Magnesium Stearate
Hypromellose (capsule shells structure)
Titanium Dioxide (opacifier of the capsule shells)
15. Subject is currently pregnant, breast-feeding and/or lactating
16. Subject is currently taking strong or moderate CYP3A4 inhibitors and/or inducers. See examples below. CYP3A4 inhibitors: Itraconazole, Ketoconazole, Azamulin, Troleandomycin, Verapamil CYP3A4 inducers: Rifampicin
17. Subject is currently receiving deep brain stimulation treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. 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 Unified Parkinson's Disease Rating Scale (UPDRS) (Parts II+III, a UPDRS Subtotal) from Baseline to the End of Trial.
2. Safety and Tolerability
• Adverse Events (AE)
• Severity of AEs
• Drug related AEs
• AEs leading to study discontinuation
• Electrocardiogram findings
• Clinical laboratory test results
• Vital sign measurements
• Physical and neurological examination findings |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From Baseline to the End of Trial. |
|
| E.5.2 | Secondary end point(s) |
1. Change From Baseline to Month 6 in The Sum of MDS-UPDRS Total Score (OFF-state)
The Unified Parkinson's Disease Rating Scale (UPDRS) is a 42-item rating scale designed to assess Parkinson's disease-related disability and impairment.
2. 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.
3. Change From Baseline to Month 6 on Clinical Global Impression of Severity (CGIS) (OFF-state)
The clinical global impressions scale on the severity of movement impairments assessed by the site rater.
Exploratory Endpoints:
1. Changes From Baseline to Month 6 in The Plasma Biomarker Measured
Potential biomarkers to be measured in plasma are Neurofilament Light (NFL), Glial fibrillary acidic protein (GFAP) and TDP43.
2. Change From Baseline to Month 6 in WAIS Coding Test (OFF-state)
In the digital symbol coding test individuals are asked to record associations between different symbols and numbers within time limits. The Total score is the sum of all the correctly coded numbers.
3. Change From Baseline to Month 6 in MMSE (OFF-state)
The Mini-Mental State Exam (MMSE) is a 30-point test, widely used test of cognitive function.
4. Pharmacokinetics
The following PK parameters will be determined, as data permit: Area under the curve (AUC), Cmax, Tmax, t½, and CL.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From Baseline to the End of Trial. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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