| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Sponsor is developing an oral formulation of CT1812 fumarate to treat AD and mild cognitive impairment.
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| E.1.1.1 | Medical condition in easily understood language |
| The sponsor is performing research on patients with cognitive impairment related to Alzheimer's Disease at a mild stage. |
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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 target engagement of CT1812 treatment by measuring the displacement of Aβ oligomers into cerebrospinal fluid (CSF) and
to evaluate the safety and tolerability of 100 mg of once-daily oral CT1812, administered for 6 months in participants with mild to moderate Alzheimer’s disease (AD). |
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| E.2.2 | Secondary objectives of the trial |
Secondary:
To evaluate the effect of CT1812 on Plasma and CSF proteomics and biomarkers known to be affected in AD patients through measurement of CSF Aβ40, Aβ42, tau, phospho-tau, neurogranin, NFL and SNAP25
To evaluate the pharmacokinetics of CT1812 through measurement of plasma and CSF concentrations of CT1812 in AD patients
To evaluate the safety and tolerability of CT1812 in AD patients
Exploratory:
To correlate cognitive measures at screening with CSF oligomer concentrations collected at baseline.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men, and women of non-childbearing potential, 50-85 years of age inclusively, with a diagnosis of mild to moderate Probable Alzheimer’s Disease Dementia according to the 2011 NIA-AA criteria and at least a 6 month decline in cognitive function documented in the medical record.
a. Non-childbearing potential for women is defined as postmenopausal [last natural menses greater than 24 months; in women under age 55, menopausal status will be documented with serum follicle stimulating hormone (FSH) test] or undergone a documented bilateral tubal ligation or hysterectomy
b. 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 participation, 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. 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
3. MMSE 18-26 inclusive. Subjects must, in the opinion of the investigator, be able to comply with study procedures and must understand the consent process. The investigator will use his or her clinical judgment in conjunction with the cognitive screening assessments to determine whether the subject meets these criteria in a manner that is consistent with local clinical practice and standards. Subjects with borderline low MMSE at screening may undergo repeat MMSE administration if extenuating circumstances were present at original assessment.
4. A positive amyloid scan (florbetaben F18, florbetapir F18, or flutametamol F18) at screening or within prior 12 months, as read by the certified, site-designated PET scan reader.
5. Must consent to apolipoprotein E (ApoE) genotyping
6. Subjects must have a caregiver or study partner who can participate in all clinic visits.
7. Patients living at home or in the community (assisted living acceptable)
8. Able to swallow CT1812 capsules.
9. Stable pharmacological treatment of any other chronic conditions for at least 30 days prior to screening.
10. Subjects must be capable of providing either written informed consent to the study procedures and for use of protected health information [Health Insurance Portability and Accountability Act (HIPAA) Authorization, if applicable]. Written informed consent also shall be obtained from the responsible caregiver or study partner. All consent processes must be undertaken in the presence of a witness and prior to any study procedures.
11. 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.
12. Must be able to complete all screening evaluations.
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| E.4 | Principal exclusion criteria |
1 Hospitalization or change of chronic concomitant medication within one month prior to screening
2 Patients living in a continuous care nursing facility
3 Screening MRI of the brain indicative of significant abnormality, inter alia, 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)
4 Clinical or laboratory findings consistent with:
a Other primary degenerative dementia
b Other neurodegenerative condition
c Seizure disorder; or
d Other infectious, metabolic or systemic diseases affecting the central nervous system
5 A current DSM-V diagnosis that would interfere with the subject’s ability to participate in the study
6 Any prior history of suicidal thoughts or behavior that are believed by the investigator to represent a current safety risk
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, > 1.5 ULN);
b Respiratory insufficiency;
c Renal insufficiency, defined as eGFR < 40 mL/min based on the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula, Heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy within six months before screening)
d Bradycardia (<50 beats/min.) or tachycardia (>100 beats/min.)
e 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); or
f Uncontrolled diabetes defined by HbA1c >7.5
8 History of cancer within 3 years of screening exception: fully excised non-melanoma skin cancers or non-metastatic prostate cancer (stable for at least 6 months)
9 History of acute/chronic hepatitis B or C and/or carriers of hepatitis B
10 Clinically significant abnormalities in screening laboratory tests, including:
a hematocrit <35% for males and < 32% for females,
b platelet cell count of < 120,000/uL, or
c INR >1.4 or other coagulopathy, confirmed by repeat analysis
d lymphocyte count less than 1200/ul
11 Disability that may prevent the patient from completing all study requirements
12 Women who are of childbearing potential
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, exceptions:
a benzodiazepines must not be administered within 5 half-lives of cognitive testing;
b administration of selective serotonin re-uptake inhibitors (SSRI) may be continued if stable for 60 days prior to Screening;
c low dose lorazepam may be used for sedation prior to MRI scan for those patients requiring sedation. Max. 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 for AD meds (acetylcholinesterase inhibitors and memantine) stable for at least 30 days
16 Suspected or known drug or alcohol abuse, i.e. more than approximately 60 g alcohol per day indicated by elevated MCV significantly above normal value at screening
17 Suspected or known allergy to any components of the study treatments
18 Enrolment in another investigational study or intake of investigational drug within the previous 30 days or five half lives of the investigational drug, whichever is longer
19 Intake of drugs or substances potentially involved in clinically significant inhibition or induction of CYP3A4, or P-gp mediated drug interactions with CT1812, within 4 weeks or five half-lives of the interacting drug prior to administration of CT1812 and throughout the course of the study. Grapefruit juice should be avoided in the two weeks prior to dosing. See Appendix A and Appendix B for a complete list of prohibited substances.
20 Previous exposure to anti Aβ vaccines
21 Exposure to passive immunotherapies for AD (e.g. monoclonal antibodies), or BACE inhibitors within the previous 180 days.
22 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 (INR) >1.4 or other coagulopathy; platelet count of <120,000/μL; infection at the desired lumbar puncture site; taking anti-coagulant medication within 90 days of screening (Note: low dose aspirin is permitted); degenerative arthritis of the lumbar spine; suspected non-communicating hydrocephalus or intracranial mass; prior history of spinal mass or trauma
23 Positive assay for Lyme disease if a screening lumbar puncture is conducted
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the change from the baseline CSF Aβ oligomer concentration after dosing with CT1812 versus placebo. The change from baseline will be measured through a number of exploratory endpoints as indicated below. For each subject, the baseline CSF oligomer concentration will be computed as the average of the measurements from hours -4, -3, -2 and -1 and 0.
CSF Aβ Oligomer pharmacodynamic endpoints will include:
Cmax
Mean relative and absolute change from baseline to each sample collection time point
AUC
The time to peak Aβ oligomer concentration (Tmax)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Pharmacokinetic and Pharmacodynamic Endpoints: Day 1 to Day 2. |
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| E.5.2 | Secondary end point(s) |
Safety Endpoints
• The incidence and severity of adverse events (AE)
• The incidence of serious adverse events (SAE)
• Changes in vital signs
• Changes in physical and neurological exam findings
• Changes in body mass
• Changes in electrocardiogram (ECG) findings
• Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)
• Changes in the Columbia Suicide Severity Rating Scale (C-SSRS)
Pharmacokinetic and Pharmacodynamic Endpoints
The following CT1812 pharmacokinetic parameters will be determined in plasma and CSF:
• Maximum concentration (Cmax)
• Time to maximum concentration (Tmax)
• Area under the curve (AUClast and AUCinf)
• apparent drug clearance (CL/F) (plasma only)
• apparent volume of distribution in the terminal phase (Vz/F) (plasma only)
• Terminal half life (t1/2)
Pharmacodynamic endpoints include the effect of CT1812 on the following biomarkers in CSF:
• Total-Tau
• Phospho -Tau
• Aβ40
• Aβ42
• NFL
• Neurogranin
• SNAP25 (synaptosomal-associated protein 25)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety Endpoints: From screening until the end of study.
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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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| A double blind Pilot Study followed by a Open Label Ext. with a 100mg single daily dose of CT1812 |
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| 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 | 4 |
| 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 | 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 |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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