| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mild to Moderate Alzheimer's Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Mild to Moderate Alzheimer'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 | 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 |
|
| 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. |
|
| 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 characterize the PK profile of CT1812 in plasma.
- To assess the efficacy of CT1812 as a treatment for mild to moderate Alzheimer’s disease. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects 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 subjects 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 birth control pills, or any double combination of:
intrauterine device (IUD), diaphragm, sponge, and cervical cap. Periodic abstinence, coitus interruptus, exclusive use of spermicides and lactational amenorrhea method (LAM) are not acceptable contraceptive methods.
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 optional screening visit lumbar puncture in place of amyloid PET will also be acceptable. Inclusion via CSF samples requires: low Aβ 42
OR low Aβ 42/40 ratio AND either increased total-tau OR increased phospho-tau based on the ranges established by the central lab.
3) Neuroimaging (MRI, or CT scan due to contraindication of MRI is approved by Medical Monitor) 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 (or CT scan), up to 1 year prior to screening, may be used if 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). Subjects with a GDS >6 may be allowed to enroll if the investigator does not believe the subject is clinically depressed. Investigators must contact the Medical Monitor to discuss eligibility.
6) Modified Hachinski ≤4.
7) Formal education of eight or more years.
8) Participants 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) Participants 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) Participants 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), and European General Data Protection Regulation (GDPR) 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) 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.
15) Must be able to complete all screening evaluations. |
|
| 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) Participants living in a continuous care nursing facility.
3) Contraindications to the MRI examination for any reason. CT scan may be substituted for an MRI if a subject is unable to tolerate an MRI or an MRI is contraindicated for medical reasons. The proposed CT scan will be approved by the Medical Monitor on a case-by-case basis.
4) Screening MRI (or historical MRI, or CT scan due to contraindication of MRI if approved by medical monitor) 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 dementias such as dementia with Lewy bodies, frontotemporal 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 or antipsychotic would be allowed to enroll.
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 beats/min or tachycardia (>100 beats/min.). If the hear rate is below 50 beats/min the subject may be eligible to enroll if the Investigator has determined that the heart rate < 50 beats/min is stable and not clinically significant. If the heart rate is above 100 beats/min, the heart rate assessment may be repeated to assess eligibility.
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 participants 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). Subjects who have evidence of resolved Hepatitis C infection (HCV RNA negative) may be considered following discussion with the Medical Monitor.
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 < 1500/uL (with the exception of a documented history of a chronic benign neutropenia), ), absolute lymphocyte count <900/ul 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) Lymphocyte count.
iv) Platelet count.
v) PT/INR.
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 exceptions:
.....
Please refer to protocol for remaining exclusion criteria. |
|
| 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- Aβ, 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. |
|
| 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 |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 |
|
| 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 |
| Czechia |
| Netherlands |
| Spain |
|
| 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 | 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 |
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