| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 |
The primary objective of this study is to evaluate the pharmacodynamics (PD) (apolipoproteins/lipid particles and cholesterol efflux) of obicetrapib in cerebrospinal fluid (CSF) and plasma (apolipoproteins/lipid particles) in patients with early Alzheimer’s Disease (AD) (hetero/homozygote APOE4 carriers).
The exploratory objectives of this study are to evaluate:
• other PD markers of obicetrapib (additional lipoproteins, neurodegeneration, and inflammation) in patients with early AD.
• the cognitive effects of obicetrapib in patients with early AD.
• the pharmacokinetics (PK) of obicetrapib in patients with early AD.
The safety objective of this study is to evaluate the safety and tolerability of obicetrapib in patients with early AD. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age range: 50-75 years of age at the Screening Visit.
2. Males, or females who are post-menopausal or otherwise not of child-bearing potential.
a. Women are not considered to be of childbearing potential if they meet 1 of the following criteria as documented by the Investigator:
i. They have had a hysterectomy or tubal ligation at a minimum of 1 cycle prior to signing the ICF; or
ii. They are postmenopausal, defined as ≥1 year since their last menstrual period for women ≥55 years of age or ≥1 year since their last menstrual period and have a follicle stimulating hormone (FSH) level in the postmenopausal range for women <55 years of age
b. Men whose partners are of childbearing potential must agree to use an effective method of avoiding pregnancy from screening to 90 days after the last visit. Effective methods of avoiding pregnancy are contraceptive methods with a Pearl index of <1 used consistently and correctly (including implantable contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, intrauterine devices, diaphragm with spermicide, male or female condoms with spermicide, or cervical cap) or a sterile sexual partner;
3. Diagnosis of AD based on the NIA-AA Research Framework criteria:
Biomarker classification A+T+N+ or A+T+N- based upon:
a. CSF profile consistent with AD (an Aβ42 concentration of <1000 pg/mL AND phosphorylated tau (p-Tau) >19 pg/mL, or a ratio of p-Tau/Aβ42 of ≥0.020 taken during the Screening period prior to the day of the first dose of study medication or,
b. Documented evidence of a CSF profile consistent with AD obtained within the previous 12 months, or
c. Documented amyloid positron emission tomography (PET) scan evidence acquired within the previous 12 months.
4. AD Clinical Stage 3 or 4 based on the NIA-AA Research Framework criteria
a. Clinical Dementia Rating scale global score ≥0.5 and ≤1
b. Mini-mental state examination (MMSE) score at Screening and baseline ≥20
5. Able to speak, read and write the local language fluently.
6. Have an APOE genotype of E4/E4 or E3/E4.
7. Patients should either be:
a. Not treated with any approved treatments for AD with a reasonable expectation that, based on the course of illness, need for treatment is not imminent and the patient should not be initiated on treatment for the length of the study, or
b. Stabilized on an approved medication(s) for the treatment of AD for at least 3 months prior to baseline. The dose of the AD treatment should remain the same after entering the study.
8. Patient and study partner are willing to consent to all study procedures. |
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| E.4 | Principal exclusion criteria |
1. Other than AD, neurologic or medical disorder which may impair cognition including: head trauma, seizure disorder, neurodegenerative disease, hydrocephalus, cerebral/spinal hematoma, inflammatory disease, central nervous system infection (eg, encephalitis or meningitis), neoplasm, toxic exposure, metabolic disorder (including hypoxic or hypoglycemic episodes), or endocrine disorder, or any significant medical conditions that would prohibit their participation in the study.
2. Any contra-indication to undergo magnetic resonance imaging (MRI)
3. MRI of the brain indicative of significant abnormality, including, but not limited to, prior hemorrhage or infarct >1 cm3, >3 lacunar infarcts, deep white matter lesions corresponding to a Fazekas score of 3, cerebral contusion, encephalomalacia, aneurysm, vascular malformation, subdural hematoma, hydrocephalus, space-occupying lesion (eg, abscess or brain tumor such as meningioma). Small incidental meningiomas may be allowed if discussed and approved by the Principal Investigator (PI).
4. History of any of the following:
a. large vessel stroke
b. myocardial infarction or unstable angina within the previous 12 months
c. Type 1 diabetes and uncontrolled type 2 diabetes (hemoglobin A1c [HbA1c] >8%)
d. Systemic blood pressure >150/90 mmHg on 3 separate determinations
e. hyperaldosteronism
f. Significant renal or hepatic dysfunction
g. Current or previous hepatitis B infection (defined as positive test for hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (anti-HBc). Subjects with immunity to hepatitis B (if due to natural infection defined as negative HBsAg, positive hepatitis B antibody [anti-HBs] and positive anti-HBc; if due to vaccination defined as negative HBsAg, negative anti-HCV and positive anti-HBs) are eligible to participate in the study
h. History or positive test at Screening for hepatitis C virus antibody (anti-HCV)
i. History or positive test at Screening for human immunodeficiency virus (HIV)
j. Diagnosed with cancer with metastatic potential within the last 5 years other than carcinoma in situ of the breast or cervix, or basal cell carcinoma of the skin that has been completely excised
k. Major depressive episode requiring initiation of medication or hospitalization within the previous 90 days
l. Presence of hallucinations or delusions
m. Surgery within 12 weeks of Screening
5. Any of the following laboratory abnormalities at Screening
a. Clinically significant (as determined by a cardiologist or local PI) 12-lead ECG abnormalities
b. Any serum chemistry value (eg, aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, creatine kinase [CK], total bilirubin etc) >2x the upper limit of normal (ULN) on 2 successive determinations less than 2 weeks apart
c. Serum creatinine above the ULN or estimated glomerular filtration rate (eGFR) <60 mL/min
d. Platelet count, international normalized ratio (INR), prothrombin time (PT) or partial thromboplastin time (PTT) not within the normal range or other risk for increased or uncontrolled bleeding
e. Not carrying an APOE4 allele (eg, E3/E3; E3/E2/ E2/E2).
6. Contraindication to lumbar puncture.
7. Any other significant medical conditions that would prohibit participation.
8. Taking any of the following medications
a. Antipsychotic agents
b. Stimulant medications
c. Antidepressant medications whose dose has not been stable for at least 90 days
d. Immunosuppressant medications
e. Injected or infused antibody therapies
f. Anticoagulant or anti-platelet medications including warfarin, heparanoids and direct coagulation factor inhibitors (eg, apixaban, dagibatran, rivaroxaban); either aspirin at a dose of ≤100 mg/day or clopidogrel at a dose of 75 mg/day, but not both in combination is permitted.
g. Any lipid-altering therapies
9. Participation in any other interventional clinical trial, or treatment with any investigational drug or investigational use of an approved therapy within 30 days (or 5 half-lives of such agent) prior to the first Screening visit.
10. Regular use of cannabis or cannabis products, including non-prescription products containing cannabidiol.
11. History of drug or alcohol abuse within the last 5 years.
12. Known CETP inhibitor allergy or intolerance.
13. Has an active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
a. Note: A subject being screened for this study who had a documented, positive polymerase chain reaction (PCR) or serology test for SARS-CoV-2 may be enrolled provided the subject has:
i. Recovered from COVID-19 ie, all COVID-19 related symptoms and major clinical findings which could potentially affect the safety of the subject should be resolved to baseline, and
ii. A negative result from a health authority-authorized nucleic acid amplification (PCR) test for SARS-CoV-2 taken. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary PD endpoint is the change from baseline in levels of ApoA-I, ApoE, small HDL particles, in both CSF as well as plasma and ABCA1-driven cholesterol efflux in CSF measured at Day 168. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. Changes From Baseline Levels in Lipoproteins and Apolipoproteins in Plasma (LDL-C, Total cholesterol, Non-HDL-C, TG, ApoB)
2. Changes From Baseline Levels in Lipoproteins and Apolipoproteins in CSF and Plasma (HDL-C, HDL-ApoE, ApoA-II)
3. Change From Baseline Levels in AD Biomarkers in CSF (p-Tau 181, Aβ1-42, Aβ1-40, Aβ1-42/Aβ1-40 ratio, neurogranin, NfL, GFAP, sTREM2, YKL40, Inflammatory markers (eg, interferon [IFN]-γ, IL-10, IL-12p70, IL-17A, IL-6, TNF-α))
4. Change From Baseline Levels in AD Biomarkers in Plasma (Tau and p-Tau epitopes, Aβ1-42, Aβ1-40, Aβ1-42/Aβ1-40 ratio, NfL)
5. Correlation Between the Change From Baseline Levels in CSF p-Tau 181 and CSF ApoA-I, ApoE, and Cholesterol Efflux Capacity
6. Change From Baseline Levels in 24-Hydroxycholesterol and 27-Hydroxycholesterol in CSF and Plasma
7. Disease Progression Measured With the Cognitive-Functional Composite
8. Mini-Mental State Examination
9. Mean Plasma Levels of Obicetrapib at Steady State in CSF and Plasma |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 and 6. At Baseline (Visit 2), at Day 84 (Visit 4), and the End of Treatment (Day 168, Visit 6)
2. At Screening (Visit 1) or Baseline (Visit 2), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6)
3. At Screening (Visit 1), at Day 84 (Visit 4), and at the End of Treatment (Day 168, Visit 6)
4. At Baseline (Visit 2), at Day 84 (Visit 4), and the End of Treatment (Day 168, Visit 6)
5. At Screening (Visit 1) and at the End of Treatment (Day 168, Visit 6)
7 . At Baseline (Visit 2) and the End of Treatment (Day 168, Visit 6)
8. At Screening (Visit 1), Baseline (Visit 2) and the End of Treatment (Day 168, Visit 6)
9. At Day 84 (Visit 4) and the End of Treatment (Day 168, Visit 6) |
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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 | 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.8.3 |
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
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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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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