E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mild to Moderate Alzheimer’s Disease |
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E.1.1.1 | Medical condition in easily understood language |
Mild to Moderate Alzheimer’s Disease |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001896 |
E.1.2 | Term | Alzheimer's disease |
E.1.2 | System Organ Class | 100000004852 |
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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 |
- To evaluate the safety, tolerability, and PK of CT1812 following repeated dosing of CT1812 for 29 days. - To evaluate the efficacy of CT1812 in restoring synaptic function in participants with mild to moderate Alzheimer’s disease through quantitative EEG, as reflected by relative theta power. |
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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) Women of non-childbearing potential and men, aged 50 to 85 years, inclusive, with a diagnosis of mild to moderate Alzheimer’s disease according to the 2018 NIA-AA criteria and at least a 6-month history of decline in cognitive function documented in the medical record. i) Non-childbearing potential for women is defined as postmenopausal (last menses greater than 24 months) or undergone a documented bilateral tubal ligation or hysterectomy. If last menses less than 24 months, a serum follicle stimulating hormone (FSH) value confirming post-menopausal status may be used. ii) Male participants who are sexually active with a woman of child-bearing potential must agree to use condoms during the study and for 3 months after last dose. Female partners should also consider using an acceptable means of birth control, though it is not mandatory. Acceptable forms of birth control include abstinence, birth control pills, or any double combination of: intrauterine device (IUD), male or female condom, diaphragm, sponge, and cervical cap. 2) CSF meets CSF abeta 1‐42 (abeta) and p-tau -181 criteria as defined below. CSF abeta 1‐42 < 1000pg/ml (Elecsys assay) AND CSF p‐tau 181 > 19 pg/ml (Elecsys Assay) OR: CSF abeta 1‐42 < 1000pg/ml (Elecsys assay) AND p‐tau ‐181 / abeta 1‐42 ratio > 0.020 OR: CSF p‐tau 181 > 19 pg/ml (Elcsys Assay) AND p‐tau ‐181 / abeta 1‐42 ratio > 0.020 Historical CSF results will be considered provided the results are consistent with the CSF thresholds required for inclusion and following discussion with the medical monitor; however, a lumbar puncture is still required as part of screening procedures. 3) Neuroimaging (MRI) consistent with the clinical diagnosis of Alzheimer’s disease and without findings of significant exclusionary abnormalities (see exclusion criteria, number 4). A historical MRI, up to 1 year prior to screening, may be used as long as there have been no interval clinical neurologic events which may suggest a change in the MRI scan. 4) MMSE score of 18 to 26, inclusive. 5) No active depression and a GDS ≤ 6 (see exclusion criteria number 6). 6) Formal education of 8 or more years. 7) Participants must have a caregiver/ study partner who in the opinion of the site’s Principal Investigator, has contact with the study participant for a sufficient number of hours per week to provide informative responses on the protocol assessments, oversee the administration of study drug, and is willing and able to participate in all study site visits and some study assessments. The caregiver/study partner must provide written informed consent to participate in the study. 8) Participants living at home or in the community (assisted living acceptable). 9) Participants must have no known history of difficulty swallowing capsules. 10) Stable pharmacological treatment of any other chronic conditions for at least 30 days prior to screening. 11) Must consent to apolipoprotein E (APOE) genotyping. 12) Participants shall be generally healthy with mobility (ambulatory or ambulatory-aided, i.e., walker or cane), vision and hearing (hearing aid permissible) sufficient for compliance with testing procedures. 13) Must be able to complete all screening evaluations. |
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E.4 | Principal exclusion criteria |
1) Hospitalization (except for planned procedures) or change of chronic concomitant medication within 1 month prior to screening 2) Participants living in a continuous care nursing facility 3) Contraindications to the MRI examination for any reason 4) Screening MRI (or historical MRI, if applicable) of the brain indicative of significant abnormality, including, but not limited to, prior hemorrhage or infarct > 1 cm3, > 3 lacunar infarcts, cerebral contusion, encephalomalacia, aneurysm, vascular malformation, subdural hematoma, hydrocephalus, space-occupying lesion 5) Clinical or laboratory findings consistent with: -Other primary degenerative dementia -Other neurodegenerative condition -Seizure disorder -Other infectious, metabolic or systemic diseases affecting the central nervous system 6) A current DSM-V diagnosis of active major depression, schizophrenia or bipolar disorder. Participants with depressive symptoms successfully managed by a stable dose of an antidepressant are allowed entry. 7) Clinically significant, advanced or unstable disease that may interfere with outcome evaluations, such as: -Chronic liver disease, liver function test abnormalities or other signs of hepatic insufficiency (ALT, AST, alkaline phosphatase > 1.5 ULN, lactate dehydrogenase (LDH) > 1.5 x ULN). -Respiratory insufficiency. -Renal insufficiency eGFR < 50 mL/min based on the CKD-EPI formula, https://www.mdcalc.com/ckd-epi-equations-glomerular-filtration-rate-gfr -Heart disease. -Bradycardia (< 50/min.) or tachycardia (> 100/min.). -Poorly managed hypertension (systolic > 160 mm Hg and/or diastolic > 95 mm Hg) or hypotension (systolic < 90 mm Hg and/or diastolic < 60 mm Hg) -Uncontrolled diabetes in known diabetics, as defined by hemoglobin A1c > 7.5 8) History of cancer within 3 years of screening with the exception of fully excised nonmelanoma skin cancers or non-metastatic prostate cancer that has been stable for at least 6 months 9) Seropositive for human immunodeficiency virus 10) History of acute/chronic hepatitis B or C and/or carriers of hepatitis B 11) Clinically significant abnormalities in screening laboratory tests, including: Hematocrit less than 35% for males and less than 32% for females, absolute neutrophil cell count of <1500/uL (with the exception of a documented history of a chronic benign neutropenia), or platelet cell count of < 120,000/uL; INR > 1.4 or other coagulopathy, confirmed by repeat assessment of: -Hematocrit -Neutrophil count -Platelet count 12) Disability that may prevent the participant from completing all study requirements 13) Within 4 weeks of screening visit or during the study, concurrent treatment with antipsychotic agents, antiepileptics, centrally active anti-hypertensive drugs, sedatives, opioids, mood stabilizers; or benzodiazepines, with the following exception: -Low dose lorazepam may be used for sedation prior to MRI scan for those participants requiring sedation. At the discretion of the Investigator, 0.5 to 1 mg may be given orally prior to scan with a single repeat dose given if the first dose is ineffective. No more than a total of 2 mg lorazepam may be used for the MRI scan 14) Any disorder that could interfere with the absorption, distribution, metabolism or excretion of drugs 15) Nootropic drugs except stable AD meds (acetylcholinesterase inhibitors and memantine) 16) Suspected or known drug or alcohol abuse, ie, more than approximately 60 g alcohol per day 17) Suspected or known allergy to any components of the study treatments 18) Enrollment in another investigational study or intake of investigational drug within the previous 30 days or 5 half-lives of the investigational drug, whichever is longer 19) Intake of drugs or substances potentially involved in clinically significant induction or inhibition of CYP3A4 or P-gp mediated drug interactions with CT1812, within 4 weeks or 5 half-lives of the interacting drug prior to administration of CT1812 and throughout the study. Grapefruit juice should be avoided in the 2 weeks prior to dosing and throughout the study 20) Exposure to immunomodulators, anti Aβ vaccines, passive immunotherapies for AD within the past 180 days and/or exposure to BACE inhibitors within the past 30 days 21) Anticipated use of nonsteroidal anti-inflammatory drugs on more than 14 days from Baseline/Day 1 to Day 182. Contraindication to undergoing an LP including, but not limited to: inability to tolerate an appropriately flexed position for the time necessary to perform an LP; international normalized ratio > 1.4 or other coagulopathy; platelet count of < 120,000/μL; infection at the desired LP site; taking anti-coagulant medication within 90 days of screening; degenerative arthritis of the lumbar spine; suspected non-communicating hydrocephalus or intracranial mass; prior history of spinal mass or trauma
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E.5 End points |
E.5.1 | Primary end point(s) |
Exploratory Efficacy Endpoints: • EEG spectral measures, specifically relative theta (4-8 Hz) power • ADAS-Cog-14 • ADCS-CGIC • A-IADL-Q • NTB, which includes: o CFT o COWAT o TMT A & B o VMDS • CSF protein concentration (AB42 and AB40 monomers, total tau, phospho-tau, neurogranin, and SNAP-25)
Safety Endpoints • The incidence and severity of adverse events. • The change in usage of concomitant medications. • Changes in vital signs. • Changes in physical examination findings. • Changes in ECG findings. • Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis). • Changes in the Columbia Suicide Severity Rating Scale (C-SSRS).
Pharmacokinetic Endpoints: o CT1812 CSF/plasma concentration ratio (end-of-study [EOS] only). o Changes in predose CT1812 plasma concentrations. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Exploratory Efficacy Endpoints: From screening until the end of study. Safety Endpoints: From screening until the end of study. Pharmacokinetic Endpoints: From baseline until the end of the study. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | 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 | No |
E.8.1.6 | Cross over | Yes |
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 | 2 |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |