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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001896 |
E.1.2 | Term | Alzheimer's disease |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10029205 |
E.1.2 | Term | Nervous system disorders |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 |
The primary objectives are to evaluate the safety and efficacy of 2 fixed doses of EVP-6124 (2 or 3 mg daily) compared to placebo for 26 weeks in subjects with mild to moderate dementia due to AD currently receiving stable treatment or previously treated with an AChEI (donepezil, rivastigmine, or galantamine). The primary efficacy response will be an assessment of the change from baseline in cognitive, (ADAS-Cog-13) and functional/global (Disability Assessment for Dementia [DAD]) endpoints. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to assess the effects of EVP-6124 compared with placebo on the following endpoints for 26 weeks:
• Change in activities of daily living using the Disability Assessment for Dementia (DAD)
• Change in psychiatric and behavioral symptoms using the Neuropsychiatric Inventory (NPI)
• Additional assessments of cognition include the Mini-Mental State Examination (MMSE) and the Controlled Oral Word Association Test (COWAT) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible to participate in the study:
1. Informed consent form (ICF) signed by the subject or legally acceptable representative before any study-specific procedures for the subject are performed and an ICF signed by the support person/caregiver before any study-specific procedures for the support person/caregiver are performed
2. Male or female subjects of any race, aged ≥55 and ≤85 years
3. Clinical diagnosis of dementia due to probable AD consistent with criteria established by a workgroup of the National Institute on Aging and the Alzheimer’s Disease Association
4. Clinical decline within 12 months before screening and onset of symptoms at least 12 months or longer before screening, which may include any documented cognition, functional, or other objective assessment or the clinical judgment of the investigator or the subject’s referring physician that the subject has experienced a clinical decline within the last 12 months
5. Magnetic resonance imaging (MRI) or computed tomography (CT) scan performed within 12 months before screening, with findings consistent with the diagnosis of dementia due to AD without any other clinically significant comorbid pathologies. If an MRI or CT scan is unavailable or occurred greater than 12 months before screening, this assessment should be completed and the findings confirmed before the subject enters the run-in period (Day -14) (copy of the report will be available at the study site)
6. Mini-Mental State Examination (MMSE) score ≥14 and ≤24 at screening and confirmed on Day 1 prior to randomization (fluctuations of ±2 points are acceptable on Day 1/baseline)
7. Clinical Dementia Rating Global score (CDR-GS) ≥1 (at least mild dementia) at screening and confirmed on Day 1 prior to randomization
8. Modified Hachinski Ischemic Scale (mHIS) score ≤4 at screening
9. Fertile, sexually active subjects (men and women) must use an effective method of contraception during the study. Female subjects and the female partner of male subjects must be surgically sterile (hysterectomy or bilateral tubal ligation), postmenopausal for at least 1-year, or willing to practice adequate methods of contraception if of childbearing potential (defined as consistent use of combined effective methods of contraception [including at least 1 barrier method])
10. Reliable and capable support person/caregiver, who if not living in the same household, interacts with the subject approximately 4 times per week and will be available to attend clinic visits in person when possible
11. Subject living at home, senior residential setting, or an institutional setting without the need for continuous (ie, 24-hour) nursing care
12. General health status acceptable for participation in a 26-week study
13. Fluency (oral and written) in the language in which the standardized tests will be administered
14. Receiving a stable dose of an AChEI (donepezil, rivastigmine or galantamine) for at least 3 months (90 days) before screening and with continuous dosing for at least 6 months OR not presently receiving an AChEI (at least 30 days before screening), but with a history of previous AChEI treatment (subjects receiving donepezil 23 mg currently or within 3 months before screening are ineligible) |
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria will be excluded from participating in the study:
Exclusion Criteria - General
1. Exposure to an experimental drug, experimental biologic or experimental medical device within 2 months (60 days) before screening
2. Prior participation in an amyloid vaccination clinical study at any time in the past or completion of a passive amyloid vaccination study within 6 months before screening
3. Inability to swallow a tablet
4. In the judgment of the investigator, inability of the subject or the support person/caregiver to complete a 26-week study
5. Inability to be ≥75% compliant with single-blind study drug
6. Inability to adequately cooperate or complete the cognitive testing procedures or any study assessment
7. Residence in a skilled nursing facility
Exclusion Criteria - Medical
8. Untreated vitamin B12 or folate deficiency (if treated, must be stably treated for at least 6 months before screening)
9. Clinically significant (in the judgment of the investigator) abnormal serum electrolytes (sodium, potassium, magnesium) after repeat testing
10. Clinically significant untreated hypothyroidism (if treated, thyroid-stimulating hormone level and thyroid supplementation dose must be stable for at least 6 months before screening)
11. Insufficiently controlled diabetes mellitus (in the judgment of the investigator) or requiring insulin
12. Renal insufficiency (serum creatinine >2.0 mg/dL)
13. Malignant tumor within 3 years before screening (except squamous and basal cell carcinoma or cervical carcinoma in situ or brachytherapy for localized prostate cancer)
14. Unstable medical condition that is clinically significant in the judgment of the investigator
15. Female subjects who are pregnant, nursing, or planning to become pregnant during the study
16. Alanine transaminase (ALT) or aspartate transaminase (AST) >2.5 times the upper limit of normal
Exclusion Criteria - Cardiovascular
17. History of myocardial infarction or unstable angina within 6 months before screening
18. History of more than 1 myocardial infarction within 5 years before screening
19. Clinically significant (in judgment of the investigator) cardiac arrhythmia (including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (subjects with a pacemaker are acceptable)
20. Symptomatic hypotension or hypertension (supine diastolic blood pressure >95 mmHg) (in the judgment of the investigator)
21. Clinically significant abnormality on screening or baseline ECG, including but not necessarily limited to a confirmed QTc value ≥450 msec for males or ≥470 msec for females
Exclusion Criteria - Psychiatric
22. Diagnosis of severe major depressive disorder with psychotic features, delusions or hallucinations, which is either recurrent (Diagnostic and Statistical Manual of Mental Disorders 4th Edition Text Revision [DSM-IV-TR] 296.34) or single episode (DSM-IV-TR 296.24) within 5 years before screening (American Psychiatric Association, 2000)
23. Geriatric Depression Scale (GDS) score (15-item scale) >5 at screening or baseline
24. History or current diagnosis of psychosis (American Psychiatric Association, 2000)
25. History within 2 years before screening or current evidence of substance abuse as defined by the DSM-IV-TR
26. Significant suicide risk as defined by 1) suicidal ideation as endorsed on items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) within the past year, at screening or baseline; 2) suicidal behaviors within 1-year before screening
Exclusion Criteria - Neurological
27. Stroke within 18 months before screening, or history of a stroke concomitant with onset of dementia
28. History of brain tumor, subdural hematoma, or other clinically significant (in the judgment of the investigator) space-occupying lesion on CT or MRI
29. Head trauma with clinically significant (in the judgment of the investigator) loss of consciousness within 12 months before screening or concurrent with the onset of dementia
30. Onset of dementia secondary (in the judgment of the investigator) to cardiac arrest, surgery with general anesthesia, or resuscitation
31. Specific degenerative CNS disease diagnosis other than AD (eg, Huntington’s disease, Creutzfeld-Jacob disease, Down’s syndrome, Fronto-Temporal Dementia, Parkinson’s disease)
32. Wernicke’s encephalopathy
33. Active acute or chronic CNS infection
Exclusion Criteria – Prohibited Prior and Concomitant Medications
34. Subjects with no history of prior treatment with an AChEI (donepezil, rivastigmine, or galantamine)
35. Memantine currently or within 30 days before screening
For the reamining list of exclusion criteria, please refer to page 36-37 of the Protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
The co-primary efficacy endpoints for this study include the mean change from baseline to Day 182 in the cognitive (Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13-item [ADAS-Cog-13]) and functional/global (Disability Assessment for Dementia [DAD]) endpoints. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
ADAS-Cog-13: Day -14 (run-in), baseline (predose on Day 1) and Days 84, 140, and 182 or early termination.
DAD: Day 1 (predose), and days 84, 140, and 182 or early termination.
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E.5.2 | Secondary end point(s) |
ADAS-Cog-11 (derived from the ADAS-Cog-13), Alzheimer’s Disease Assessment Scale, Cognitive Subscale-11,
MMSE (Mini-Mental State Examination)
COWAT (Controlled Oral Word Association Test),
DAD (Disability Assessment for Dementia),
NPI (Neuropsychiatric Inventory) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
ADAS-Cog-11 (derived from the ADAS-Cog-13):
Day -14 (run-in), baseline (predose on Day 1) and Days 84, 140, and 182 or early termination.
MMSE (Mini-Mental State Examination):
Pre-Run-in and Days 1 (predose), 28, 84, and 182 or early termination.
COWAT (Controlled Oral Word Association Test):
(Day -14) Run-in and Day 1 (predose), and days 84 and 182 or early termination
DAD (Disability Assessment for Dementia):
Day 1 (predose), and days 84, 140, and 182 or early termination.
NPI (Neuropsychiatric Inventory):
Days 1 (predose), 84, and 182 or early termination.
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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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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) | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
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 |
Belgium |
Canada |
France |
Italy |
Japan |
Argentina |
Australia |
Germany |
Korea, Republic of |
Spain |
Mexico |
Poland |
South Africa |
United Kingdom |
United States |
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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 | 8 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |