| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Mild Cognitive Impairment or Parkinson’s Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with mild memory problems and patients with Parkinson's disease. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009846 |
| E.1.2 | Term | Cognitive impairment |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061536 |
| E.1.2 | Term | Parkinson's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 |
The primary objectives of this study are:
Part A
To evaluate the effects of CST-139 on cerebral perfusion in healthy subjects.
Part B
To evaluate the effects of multiple doses of CST-139 on cerebral perfusion in subjects with Mild Cognitive Impairment (MCI) or Parkinson’s Disease (PD).
Part C
To evaluate the effects of multiple doses of CST-103 on cerebral perfusion in subjects with MCI or PD. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives include the following:
Part A
1. To examine the effects of CST-139 on cognition in healthy subjects
2. To assess the safety and tolerability of CST-139
3. To characterize the pharmacokinetic (PK) profile of CST-139
Part B
1. To examine the effects of multiple doses of CST-139 on cognition in subjects with MCI or PD
2. To assess the safety and tolerability of CST-139
3. To characterize the PK profile of CST-139
Part C
1. To examine the effects of multiple doses of CST-103 on cognition in subjects with MCI or PD
2. To assess the safety and tolerability of CST-103
3. To characterize the PK profile of CST-103 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part A – healthy subjects
A subject will be considered eligible for enrollment if all of the following criteria are met:
1. Males and females aged 40-75 years (inclusive) at the time of informed consent
2. Body weight ≥ 50 kg and body mass index (BMI) between 18 and 32 kg/m2, inclusive at Screening
3. Unless confirmed to be azoospermic (vasectomized or secondary to medical cause), males must agree to use a male condom from Day 1 throughout the study when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant.
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a condom during each episode of penile-vaginal penetration until after the End of Study Visit
4. Females of childbearing potential (i.e., not postmenopausal or surgically sterile) who have a male partner must have a negative serum pregnancy test result and must agree to one of the following from 30 days prior to Day 1 through 30 days after the last study medication administration:
a. use a reliable method of birth control, or
b. monogamous relationship with a male partner of confirmed sterility, or
c. practice complete abstinence
5. Females of non-childbearing potential may be enrolled if it is documented that they are postmenopausal or have undergone surgical sterilization
6. Subject is free from clinically significant illness or disease as determined by medical and surgical history, physical examination, 12-lead ECG, vital signs, and clinical laboratory assessments conducted at Screening
7. Able to speak, read and understand English
8. Able to understand and sign the written informed consent form (ICF)
9. Willing to follow the protocol requirements and comply with protocol restrictions
Parts B and C – subjects with MCI or PD
MCI or PD subjects must meet the following criteria:
10. Males and females aged 40-75 years (inclusive) at the time of informed consent
11. Montreal Cognitive Assessment (MoCA) score ≥18 and ≤26
12. Unless confirmed to be azoospermic (vasectomized or secondary to medical cause), males must agree to use a male condom from Day 1 throughout the study when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a condom during each episode of penile-vaginal penetration until after the End of Study Visit.
13. Females of childbearing potential (i.e., not postmenopausal or surgically sterile) who have a male partner must have a negative serum pregnancy test result and must agree to one of the following from start of Screening through 30 days after the last study medication administration:
a. use a reliable method of birth control, or
b. monogamous relationship with a male partner of confirmed sterility, or
c. practice complete abstinence
14. Females of non-childbearing potential may be enrolled if it is documented that they are postmenopausal or have undergone surgical sterilization
15. Stable medical conditions for 3 months prior to Screening visit (e.g., diabetes, hypertension, dyslipidemia)
16. If already being administered, vitamin E (up to 400 IU daily), estrogens, aspirin (75-300 mg daily), blood pressure medications (except for adrenergic agents), diabetic medications, and cholesterol-lowering agents for 3 months prior to screening is allowed.
17. In generally good health, in the opinion of the Investigator, based on medical and surgical history, BMI, physical examination, vital signs, 12-lead ECG, and laboratory values, including hematology and chemistry values conducted at Screening.
18. Clinical laboratory values within normal limits or, if abnormal, must be judged to be clinically insignificant by the Investigator
19. Able to speak, read and understand English
20. Able to understand and sign the written ICF
21. Willing to follow the protocol requirements and comply with protocol restrictions. |
|
| E.4 | Principal exclusion criteria |
A subject with any of the following criteria will not be eligible for participation.
1. History of any significant cardiovascular, hepatic, renal, pulmonary, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, metabolic, psychological, musculoskeletal disease or malignancies unless deemed not clinically significant by the Principal Investigator.
2. History of malignant disease, including solid tumours and hematologic malignancies (except basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured).
3. A calculated creatinine clearance of ≤70 mL/min according to the Cockcroft-Gault
equation.
4. Uncontrolled hypertension (systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mmHg) at Screening or Day -1.
5. History of drug or alcohol abuse ≤12 months prior to Screening.
6. A positive test for drugs of abuse or alcohol during Screening.
7. Unwilling or unable to abstain from alcohol from 2 days prior to Day 1 until end-of-study assessments.
8. Use of over-the-counter medication (other than paracetamol up to 2 g per day), or herbal supplements/products during Screening or throughout study, unless approved by both the Principal Investigator and the CuraSen Medical Monitor.
9. Subjects on monoamine oxidase type B inhibitors, dopamine agonists or catechol-O-methyltransferase inhibitors are not allowed.
10. Current or prior treatment with any beta agonists or beta blockers within the last month prior to Day 1.
11. Opioid use within 1 month prior to screening or during the study.
12. Use of St. John’s Wort or Ginkgo Biloba within 1 month prior to study enrollment.
13. Positive screening test for hepatitis C antibody (HCV Ab) or current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] at Screening). Subjects with immunity to hepatitis B (defined as negative HBsAg and positive hepatitis B surface antibody [HBsAb]) are eligible to participate in the study.
14. Positive screening test for human immunodeficiency virus (HIV).
15. Positive screening test for or current infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or documented history of prior infection.
16. Clinically significant abnormal clinical laboratory test values, as determined by the Investigator, or any value of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) that is above 1.5 X above the upper limit of normal, or any out-of-range value for serum sodium or potassium. Screening tests may be repeated once at the discretion of the Investigator.
17. Clinically significant laboratory or ECG abnormality that could be a safety issue in the study, including QT using Fredericia’s correction of QT interval (QTcF) >450 msec (males) or >470 msec (females).
18. History of angina, heart failure, coronary insufficiency, cardiac arrythmias, hyperthyroidism, hypothyroidism, or convulsion disorders.
19. Prior treatment with any investigational drug ≤90 days prior to dosing (Day 1), or ≤5 half-lives of the drug (whichever is longer), or current enrolment in any other study treatment or disease study.
20. Donation or loss of ≥500 mL of blood or plasma within 30 days prior to dosing.
21. Inability to undergo a clinical MRI of the brain due to claustrophobia, or other contraindications to undergoing an MRI of the brain including, but not limited to, pacemakers; implantable cardioverter defibrillators; cochlear implants; cerebral aneurysm clips; implanted infusion pumps; implanted nerve stimulators; metallic splinters in the eye; and, other magnetic, electronic or mechanical implants or clinical findings that in the judgment of the investigator would pose a potential hazard in combination with MRI. The inability to lie supine for a prolonged time period.
22. Clinically significant abnormal MRI done at Screening or in the past 6 months
23. Any other reason for which the Principal Investigator considers it is not in the best interest of the participant to undertake the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints are:
Part A
The change in cerebral perfusion after oral administration of CST-139 as measured by Arterial Spin Labeling (ASL) MRI in healthy subjects.
Part B
The change in cerebral perfusion after oral administration of multiple doses of CST-139 as measured by ASL MRI in subjects with MCI or PD.
Part C
The change in cerebral perfusion after oral administration of multiple doses of CST-103 as measured by ASL MRI in subjects with MCI or PD. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to the protocol for details. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
1. CANTAB cognitive assessments, which include the following:
• Reaction Time (RTI)
• Verbal Recognition Memory (VRM) Phase I
• Adaptive Tracking Task (ATT)
• Paired Associates Learning Task (PAL)
• Delayed Verbal Recall
2. Adverse events, ECGs, vitals, laboratory safety tests
3. Plasma PK parameters of CST-103 and CST-139 (including Cmax, tmax, AUCt, AUCinf , t1/2) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to the protocol for details. |
|
| 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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
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