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 |
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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 | 19.0 |
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 |
Part I (initial 78 week treatment period)
1. To assess the efficacy of two doses of MK-8931 on cognition in subjects with mild to moderate AD.
2. To assess the efficacy of two doses of MK-8931 on functional ability in activities of daily living in subjects with mild to moderate AD.
3. To assess the safety and tolerability of three doses of MK-8931 in the treatment of subjects with mild to moderate AD.
Part II:
1. To evaluate the safety an tolerability of MK-8931 in the long term treatment of mild to moderate Alzheimer’s Disease
2. To compare the efficacy of MK-8931 on cognition and functional ability in activities of daily living in subjects with mild to moderate AD in subjects administered MK-8931 for 24 months to that of subjects administered placebo for 18 months followed by MK-8931 for 6 months.
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E.2.2 | Secondary objectives of the trial |
Part I:
- To assess the overall clinical response, as reflected by global assessment, of two doses of MK-8931 in subjects with mild to moderate AD.
Part II: no secondary objectives |
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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 |
The substudies are embedded in the main-study protocol. The objectives are as follows:
• To assess the effect of two doses of MK-8931 on CSF total tau in subjects with mild to moderate AD included in the CSF substudy.
• To assess the effect of two doses of MK-8931 on cortical amyloid load assessed using an amyloid tracer and PET imaging in subjects with mild to moderate AD included in the PET substudy.
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E.3 | Principal inclusion criteria |
Part I:
- Each subject must be ≥ 55 to ≤ 85 years of age.
- Each subject must meet the criteria for a diagnosis of probable AD based on both a) the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS ADRDA) criteria and b) the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM IV TR) criteria for AD.
- Each subject must have a Mini Mental State Examination (MMSE) score ≥ 15 and ≤ 26 at Screening.
- Each subject must have a clear history of cognitive and functional decline over at least 1 year that is either a) documented in medical records or b) documented by history from an informant who knows the subject well.
- Each subject must have a Magnetic Resonance Imaging (MRI) scan at the Screening Visit that is consistent with a diagnosis of AD.
- Each subject must be able to read at a 6th grade level or equivalent, as determined by the investigator, and must have a history of academic achievement and/or employment sufficient to exclude mental retardation.
- If a subject is receiving an acetylcholinesterase inhibitor, memantine and/or herbal medications for AD, the dose must have been stable for at least 3 months before Screening, and the subject must be willing to remain on the same dose for the duration of the trial.
- Each subject must have a trial partner who is reliable and competent. The trial partner must have a close relationship with the subject, have face to face contact at least 3 days/wk for a minimum of 6 waking hours/wk, be willing to accompany the subject to all trial visits, and be willing to monitor compliance of the administration of the trial medication. The trial partner should understand the nature of the trial and adhere to trial requirements (eg, dose, visit schedules, and evaluations).
- Each subject must have results of clinical laboratory tests (complete blood count [CBC], blood chemistries, thyroid stimulating hormone [TSH], and urinalysis) within normal limits or clinically acceptable to the investigator at Screening.
- Each subject must have results of a physical examination, vital signs, and electrocardiogram (ECG) within normal limits or clinically acceptable to the investigator at Screening.
Part II:
- Each subject must have tolerated study medication and completed the initial 78-week period of the trial.
- Each subject must have a trial partner who is reliable and competent. The trial partner must have a close relationship with the subject, have face to face contact at least 3 days/wk for a minimum of 6 waking hours/wk (or more, based on local requirements), be willing to accompany the subject to all trial visits, and be willing to monitor compliance of the administration of the trial medication.
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E.4 | Principal exclusion criteria |
Part I:
- The subject has a Rosen modified Hachinski Ischemia Score > 4 at Screening (ie, evidence of vascular dementia).
- The subject has a known history of stroke or evidence from screening MRI scan that is clinically important in the investigator's opinion.
- The subject has evidence of a clinically relevant neurological disorder other than the disease being studied (ie, probable AD) at Screening, including but not limited to: vascular dementia, parkinsonism, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive supranuclear palsy, neurosyphilis, dementia with Lewy bodies, other types of dementia, mental retardation, hypoxic cerebral damage, cognitive impairment due to other disorders, or head trauma with loss of consciousness that led to persistent cognitive deficits.
- The subject has evidence of a clinically relevant or unstable psychiatric disorder, based on DSM IV TR criteria, including schizophrenia or other psychotic disorder, bipolar disorder, major depression, or delirium. Major depression in remission is not exclusionary.
- The subject has evidence of a current episode of major depression based on investigator's judgment.
- The subject’s MRI scan obtained at Screening shows evidence of a neurological disorder other than probable AD or > 4 cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as "possible" or "definite"), a single area of superficial siderosis, evidence of a prior macrohemorrhage, > 3 lacunar infarcts, any cortical infarct over 10 mm, or any other clinically significant finding (eg, any lesion that may account for their cognitive impairment, including but not limited to brain tumor, severe white matter disease, arteriovenous malformation, cavernous hemangioma, or any infarct in a strategic subcortical location).
- The subject has exudative (wet) age-related macular degeneration, active proliferative diabetic retinopathy, myopia or hyperopia > 8 diopters, pigment dispersion syndrome, pseudo-exfoliation syndrome, pigmentary glaucoma, glaucoma that requires > 2 classes of medications, intraocular pressure (IOP) > 21 mmHg (at the Screening Visit), clinically significant macula edema with diabetic retinopathy or advanced cataract to the degree that does not allow spectral-domain optical coherence tomography (SD-OCT) measurement, nystagmus, or other significant retinal diseases causing such significant distortion that baseline measurements would be too greatly abnormal to allow reasonable detection of possible change.
- The subject has a history of hepatitis or liver disease that, in the opinion of the investigator, has been active within the 6 months prior to Screening.
- The subject has a recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of the Screening Visit other than the condition being studied such that, in the judgment of the investigator, participation in the trial would pose a significant medical risk to the subject.
- The subject has a history or current evidence of long QT syndrome, QTC interval ≥ 470 ms (for male subjects) or ≥ 480 ms (for female subjects), or torsades de pointes.
- The subject has a history of malignancy occurring within the 5 years immediately before Screening, except for a subject who has been adequately treated for a.) basal cell or squamous cell skin cancer, b.) in situ cervical cancer, or c.) localized prostate carcinoma; or d.) who has undergone potentially curative therapy with no evidence of recurrence for ≥ 3 years post therapy, and who is deemed at low risk for recurrence by her/his treating physician.
- The subject has a.) a history of clinically significant Vit B12 or folate deficiency in the 6 months immediately before Screening, or b.) Vit B12 or folate deficiency in addition to increased serum homocysteine or methylmelonic acid levels at Screening as determined by central laboratory normal values.
Part II:
- The subject is at imminent risk of self-harm, based on clinical interview or on the Columbia Suicidality Severity Rating Scale (C-SSRS), or of harm to others in the opinion of the investigator.
- The subject has developed a recent or ongoing, uncontrolled, clinically significant medical condition other than Alzheimer’s disease such that, in the judgment of the investigator, participation in the trial would pose a significant medical risk to the subject.
The subject has a history of, or has developed during Part I evidence of long QT syndrome, QTC interval ≥ 470
ms (for male subjects) or ≥ 480 ms (for female subjects), or torsades de pointes.
- The subject anticipates receiving any of the treatments listed in Table 13 of the protocol.
- The subject has developed a form of dementia that is not Alzheimer's disease. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The two Coprimary Efficacy Endpoints in Part I of the trial are the following ones:
1. change from Baseline score in the ADAS-Cog at Week 78 and
2. change from Baseline score in the ADCS-ADL at Week 78.
Part II:
The two Coprimary Efficacy Endpoints for the extension part (Part II) trial are the following ones:
1. change from Baseline score in the ADAS-Cog at Week 104 (Visit 13) and
2. change from Baseline score in the ADCS-ADL at Week 104.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
ADAS-Cog: Screening, Baseline, Week 13, 26, 39, 52, 65 and 78 for Part I and Week 104 for Part II
ADCS-ADL: Baseline, Week 13, 26, 39, 52, 65 and 78 for Part I and Week 104 for Part II
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E.5.2 | Secondary end point(s) |
The Key Secondary Efficacy Endpoint in Part I is the change from Baseline score in the CDR-SB at Week 78.
There are no secondary endpoints in Part II. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening, Week 26, 52 and 78 |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
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) | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Italy |
Japan |
Korea, Republic of |
Netherlands |
New Zealand |
Portugal |
Spain |
Turkey |
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 | 6 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 6 |