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 and tolerability of two doses of once-daily oral CT1812, administered for 6 months in participants with mild to moderate Alzheimer’s disease. |
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E.2.2 | Secondary objectives of the trial |
To assess target engagement and identify pharmacodynamic effect of CT1812 on CSF biomarkers.
5.3 5.3 Exploratory Objectives - To evaluate the efficacy of two doses of once-daily oral CT1812, administered for 6 months in participants with mild to moderate Alzheimer’s disease. - To identify and assess metabolites of CT1812 in plasma. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Participants may be included in the study only if they meet all of the following criteria: 1) Men, and women of non-childbearing potential, 50-85 years of age inclusively, with a diagnosis of mild to moderate Alzheimer’s disease according to the 2011 NIA-AA criteria and at least a 6 month decline in cognitive function documented in the medical record. i) Non-childbearing potential for women is defined as postmenopausal (last natural menses greater than 24 months) or undergone a documented bilateral tubal ligation or hysterectomy. If last natural menses less than 24 months, a serum FSH value confirming post-menopausal status can be employed. ii) Male participants who are sexually active with a woman of child-bearing potential must agree to use condoms during the trial and for 3 months after last dose unless the woman is using an acceptable means of birth control. 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) Diagnostic confirmation by amyloid PET with florbetaben or another approved amyloid PET ligand. Previous amyloid imaging study with a positive result will be accepted. If none is available, then amyloid PET will be conducted during screening. Diagnostic confirmation by a CSF sample collected at the screening visit lumbar puncture in place of amyloid PET will also be acceptable. Inclusion via CSF samples requires: low abeta 42 (abeta 42<667 ng/L) OR low abeta 42/40 ratio (abeta 42/40 ratio x 10 < 0.72) AND either increased total-tau (total-tau > 374 ng/L) OR increased phospho-tau (phospho-tau> 78 ng/L). 3) Neuroimaging (MRI) obtained during screening consistent with the clinical diagnosis of Alzheimer’s disease and without findings of significant exclusionary abnormalities (see exclusion criteria, number 4). An historical MRI, up to 1 year prior to screening, may be used as long as there is no history of intervening neurologic disease or clinical events (such as a stroke, head trauma etc.) and the subject is without clinical symptoms or signs suggestive of such intervening events. 4) MMSE 18-26 inclusive. 5) No active depression and a GDS ≤6 (see exclusion criteria number 6). 6) Modified Hachinski ≤4. 7) Formal education of eight or more years. 8) Subjects must have a caregiver/ study partner who in the opinion of the site principal investigator, has contact with the study subject 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 clinic visits and some study assessments. The caregiver/ study partner must provide written informed consent to participate in the study. 9) Subjects living at home or in the community (assisted living acceptable). 10) Ability to swallow CT1812 capsules. 11) Stable pharmacological treatment of any other chronic conditions for at least 30 days prior to screening. 12) Subjects must be capable of providing written informed consent to the study procedures and for use of protected health information [Health Insurance Portability and Accountability Act (HIPAA), if applicable]. Written informed consent also shall be obtained from the responsible caregiver. All consent processes must be undertaken in the presence of a witness and prior to any study procedures. 13) Must consent to apolipoprotein E (ApoE) genotyping for data analysis stratification. 14) Subjects 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. 15) Must be able to complete all screening evaluations. |
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E.4 | Principal exclusion criteria |
Participants will be excluded from the study if any of the following conditions apply: 1) Hospitalization (except for planned procedures) or change of chronic concomitant medication within one month prior to screening. 2) Subjects 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 (e.g. abscess or brain tumor such as meningioma). If a small incidental meningioma is observed, the medical monitor may be contacted to discuss eligibility. 5) Clinical or laboratory findings consistent with: a) Other primary degenerative dementia, (dementia with Lewy bodies, fronto-temporal dementia, Huntington’s disease, Creutzfeldt-Jakob Disease, Down syndrome, etc.). b) Other neurodegenerative condition (Parkinson’s disease, amyotrophic lateral sclerosis, etc.). c) Seizure disorder. d) Other infectious, metabolic or systemic diseases affecting the central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, other laboratory values etc.). 6) A current DSM-V diagnosis of active major depression, schizophrenia or bipolar disorder. Subjects 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: a) 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). b) Respiratory insufficiency. c) Renal insufficiency eGFR < 50 mL/min based on the CKD‐EPI formula, as calculated by the central laboratory. d) Heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy within six months before screening). e) Bradycardia (<50/min.) or tachycardia (>100/min.). f) 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). g) Uncontrolled diabetes defined by HbA1c >7.5 in patients with diabetes, Only those subjects with known diabetes are required to get a HbA1c at screen. 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 (HIV). 10) History of acute/chronic hepatitis B or C and/or carriers of hepatitis B (seropositive for hepatitis B surface antigen [HbsAg] or anti-hepatitis C [HCV] antibody). 11) Clinically significant abnormalities in screening laboratory tests, including: d) 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: i) Hematocrit. ii) Neutrophil count. iii) Platelet count. 12) Disability that may prevent the subject from completing all study requirements (e.g. blindness, deafness, severe language difficulty, etc.). 13) Within 4 weeks of screening visit or during the course of the study, concurrent treatment with antipsychotic agents, antiepileptics, centrally active anti-hypertensive drugs (e.g., clonidine, l-methyl dopa, guanidine, guanfacine, etc.), sedatives, opioids, mood stabilizers (e.g., valproate, lithium); or benzodiazepines, with the following exception: d) Low dose lorazepam may be used for sedation prior to MRI scan for those subjects 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 (e.g. small bowel disease, Crohn’s disease, celiac disease, or liver disease). 15) Nootropic drugs except stable AD meds (acetylcholinesterase inhibitors and memantine. 16) Suspected or known drug or alcohol abuse, i.e. more than approximately 60 g alcohol (approximately 1 liter of beer or 0.5 liter of wine) per day indicated by elevated MCV significantly above normal value at screening. 17) Suspected or known allergy to any components of the study treatments. Please refer to the Investigator’s Brochure for a current listing of study drug ingredients.
Please refer to protocol for remaining exclusion criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety Endpoints - The incidence and severity of adverse events. - The change in usage of concomitant medications. - Changes in vital signs. - Changes in physical exam findings. - Changes in electrocardiogram findings. - Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis). - Changes in the Columbia Suicide Severity Rating Scale (C-SSRS).
Efficacy Endpoints - Mini Mental State Exam (MMSE). - ADAS-cog 11 and ADAS-cog 13 (Delayed Recall and digit cancellation added to ADAS- 11 in the ADAS-13). - Neuropsychological Test Battery (NTB). NTB includes Trails A & B, Digit Span, Letter & Category Fluency (COWAT and CFT). - ADCS-Clinical Global Impression of Change (CGIC). - ADCS-Activities of Daily Living (ADCS-ADL).
Pharmacokinetic/Pharmacodynamic Endpoints - Pharmacokinetics: o CT1812 CSF/plasma concentration ratio (end of study only). o Changes in pre-dose CT1812 plasma concentrations. o Plasma CT1812 metabolites. - Pharmacodynamics: o CSF- abeta, tau, phospho-tau, neurogranin, synaptotagmin, SNAP25 (synaptosomal-associated protein 25), Neuro Filament Light Chain (NFL), Aβ oligomers. Other exploratory target engagement biomarkers may also be evaluated. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety: from screening until end of study Exploratory: from screening until end of study Pharmacokinetic: from baseline until end of 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 | Yes |
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 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 |
Spain |
Czechia |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |