| 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 | Psychiatry and Psychology [F] - Psychological processes [F02] |
| 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 |
Assess the efficacy of 2 dose levels of COR388 HCl in Alzheimer’s disease (AD) subjects;
Assess the safety and tolerability of 2 dose levels of COR388 HCl in AD subjects |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
•Cerebrospinal fluid sub-study (subjects who agree to have LP):
- CSF Aβ42, total Tau, and phosphorylated Tau;
- Bacterial DNA in the CSF on quantitative polymerase chain reaction (qPCR); and
- CSF inflammatory markers.
•Magnetic resonance imaging sub-study (subjects who have MRIs done in conjunction with the study):
- Hippocampal volume; and
- Cortical thickness.
•Clinical periodontitis sub-study (subjects enrolled at selected sites):
- Pocket Depth (PD);
- Clinical Attachment Level (CAL) at 6 sites per tooth (distobuccal [DB], buccal, mesiobuccal [MB], distolingual [DL], lingual [L], and mesiolingual [ML]);
- The percentage of sites with Bleeding on Probing (BOP); and
- Biomarkers of P. gingivalis infection and inflammation in subgingival plaque (SGP) and buccal cell swabs. |
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| E.3 | Principal inclusion criteria |
1.Subject has provided full written informed consent prior to the performance of any protocol-specified procedure; or if unable to provide informed consent due to cognitive status, subject has provided assent and a legally authorized representative has provided full written informed consent on behalf of the subject.
2.Caregiver has provided full written informed consent, on a separate informed consent form (ICF), on his/her own behalf prior to the performance of any protocol-specified procedure.
3.Male and female subjects must be 55 years to 80 years of age, at the time of consent.
4.Subject has probable AD dementia according to the NIA-AA criteria (McKhann 2011) with clinical evidence of progressive cognitive decline in the last year. Clinical decline will be determined based on serial cognitive test scores, if available, or subject/caregiver report as documented by the Investigator.
5.Subject has an MMSE score between 12 and 24 inclusive at both screening and Visit 2 and a ≤3-point difference between these visits.
6.Subject has a Modified Hachinski score ≤4 at screening.
7.Subject has brain MRI scan consistent with the diagnosis of AD performed during the screening period. Computed Tomography scan can be used only if the subject has an absolute contraindication for MRI.
8.Subject has a primary caregiver willing to accept responsibility for supervising the treatment (e.g., administering study drug), accompanying the study subject to clinic visits and assessing the condition of the subject throughout the study in accordance with all protocol requirements.
9.Subject is not likely to experience a change in living conditions (e.g., institutionalization, moving to a different city, etc.), or change in primary caregiver, during participation in the trial.
10.Subjects with background symptomatic therapy with acetylcholinesterase inhibitors, and/or memantine, are allowed as long as the dose has been stable for 90 days prior to screening and no changes are planned during the study.
11.Subjects who have occasional use of sedative agents are acceptable, but these agents should not be given within 48 hours prior to cognitive assessments.
12.Subjects who have background medications used for stable chronic illnesses that are not prohibited by the protocol are allowed. The dose of psychoactive drugs must be stable for 30 days prior to screening, and no changes must be planned during the study unless for safety reasons.
13.Subject has body mass index <38 kg/m2 at Screening.
14.Subject must be able to ingest oral medications and can swallow the study drug without breaking or crushing.
15.Subject must be willing to undergo Apolipoprotein E genotype (ApoE) genetic testing (ApoE results may be disclosed after trial completion).
16.Subjects participating in the study must meet one of the following criteria:
a.Females: Surgically sterilized (e.g., hysterectomy, bilateral oophorectomy or tubal ligation) for at least 6 months or postmenopausal (postmenopausal females must have no menstrual bleeding for at least 1 year). If not postmenopausal, agree to use a highly effective method of contraception that can achieve a failure rate of less than 1% per year when used consistently and correctly, such as hormonal contraception or a double barrier method (e.g., intrauterine device plus condom or true abstinence defined as in line with the preferred and usual lifestyle of the subject. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation methods are not acceptable. Declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception) from 30 days prior to dosing until 30 days after last dose and have negative human chorionic gonadotropin (β hCG) test for pregnancy at screening.
b.Males who have not had a vasectomy must use appropriate contraception methods (barrier or true abstinence defined as in line with the preferred and usual lifestyle of the subject. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation methods are not acceptable. Declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception) from 30 days prior to dosing until 90 days after last dose. |
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| E.4 | Principal exclusion criteria |
1.Subject has imaging consistent with other differential dementia diagnoses other than the diagnosis of AD
2.Subject has had an increase or restoration of cognition based on medical history
3.Subjects who meet the following imaging exclusion criteria will not be included in this study:
a.Claustrophobia that will result in significant anxiety and difficulty lying still for MRI or CT scan
b.Severe motor problems or chronic pain indication that prevents the subject from lying still for brain imaging
4.Subject with history of cancer requiring systemic therapy in the last 5 years; except for localized cancer of the skin and in-situ cervical cancer successfully treated with surgical excision. Stable (for at least 90 days) prostate cancer is allowed
5.Subject has a contraindication for LP, such as infected skin over the needle entry site, possible increased intracranial pressure, severe thrombocytopenia or coagulopathy, suspected spinal epidural abscess, or spinal structural abnormalities that would interfere with LP procedures
6.Subject has evidence of clinically significant unstable cardiovascular, pulmonary, renal, hepatic, gastrointestinal, neurologic or metabolic disease within 6 months prior to Screening
7.Subject has any of the following cardiovascular conditions:
a.Unstable angina, uncompensated and/or symptomatic congestive heart failure (Grade 2 or higher on the NYHA scale) or myocardial infarction within 6 months
b.Acute or poorly controlled blood pressure >180 mmHg systolic or >100 mmHg diastolic
c.Current, or recent history of, any of the following that are clinically significant in the investigator's judgment: arrhythmia, hypotension, heart block, any bundle branch block, ventricular pacing, symptomatic ectopy, unstable arrhythmias including atrial fibrillation; stable atrial fibrillation is allowed
d.History of prolonged QT or prolonged QT on screening ECG (QTcF > or = 480 msec)
e.History of prolonged PR interval or prolonged PR interval on screening ECG (PR >210 msec)
f.History of prolonged QRS interval or prolonged QRS interval on screening ECG (QRS >120 msec)
g.Supraventricular or ventricular ectopy on the screening ECG or Brugada pattern on ECG
8.Subject with major stroke, uncontrolled seizure disorder, or other medical illnesses that in the Investigator's opinion will increase the subject's risk of participation in the study or confound study assessments
9.Subject with history or current evidence of major neurological or psychiatric illness such as schizophrenia, bipolar disorder, Parkinson's, etc. Subjects with major depressive disorder that may interfere with the patient's ability to perform the study and all assessments
10.Subject with history of violent or aggressive behavior that requires medication to control
11.Subjects with active suicidal thoughts in the 6 months preceding screening or at baseline; or have a history of a suicide attempt in the previous 2 years, or more than 1 lifetime suicide attempt; or are at serious suicide risk in the Investigator's clinical judgment
12.Subject with history of alcohol or drug use disorder within 12 months of screening as defined by the Diagnostic and Statistical Manual of Mental Disorders-5
13.Subject with previous treatment with investigational vaccine therapy for AD
14.Subject has participated in another Investigational New Drug (IND) research study involving small molecule drugs within 60 days or biological drugs within 90 days prior to the first dose of study drug or 5 half-lives of the investigational drug, whichever is longer
15.Subject has a history of epilepsy or seizure disorder requiring ongoing treatment, or any seizure or loss of consciousness within 6 months prior to enrollment
16.Subject has any of the following laboratory findings at screening:
a.Alanine aminotransferase >3 x upper limit of normal (ULN), aspartate aminotransferase >3 x ULN, or history of clinically significant liver disease in the Investigator's judgment
b.Hemoglobin < or = 10 g/dl
c.INR >1.5 or total bilirubin >1.5 x ULN (unless subject has evidence of Gilbert's disease)
d.Creatinine clearance (CL) of <45 ml/min
e.Poorly controlled diabetes, defined by hemoglobin A1C (HbA1C) >8.
f.Positive blood screen for HIV 1 and 2, HBsAg, or HCV-Ab at Screening
g.Positive urine screen for drugs of abuse that include opiates, cocaine, amphetamines, or barbiturates
17.Subject has abnormal laboratory tests that suggest an alternate etiology for dementia. In these cases, the patient should be re-evaluated to determine if these potential causes of dementia have been addressed. Only if these causes have been ruled out as the cause of the dementia can the patient be enrolled
18.Use of systemic (i.e., oral, intravenous, etc., but not topical) antibiotics in the last 60 days or history of recurrent infection that requires chronic or repeated courses of antibiotics |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The two co-primary endopints are:
- Mean change in Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) from baseline to the end of treatment period.
- Mean change in Alzheimer’s Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) from baseline to the end of treatment period |
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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) |
• Change in Clinical Dementia Rating-Sum of Boxes (CDR-SB)
• Change in Mini-Mental State Examination (MMSE)
• Change in Neuropsychiatric Inventory (NPI) |
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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 | Yes |
| 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 | 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) | Yes |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| France |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
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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 | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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