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 (main cohort) - Primary Trial Objectives:
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 (extension) - Primary Extension Trial Objectives:
1. To evaluate the safety and 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 (main cohort) - Secondary Trial Objective:
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 (extension) - Exploratory Extension Trial Objective:
To compare the efficacy of MK-8931 administered to subjects for 18 months to that of subjects administered placebo for 18 months in Part I followed by long term treatment of MK-8931 in Part II on cognition, function, disease progression, and health economic burden at multiple time points |
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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 (main cohort) - Principal Inclusion Criteria:
-Each subject must be ≥ 55 to ≤ 85 years of age at the first visit.
-Each subject must meet the criteria for a diagnosis of probable AD based on both a) NINCDS-ADRDA criteria (see Appendix 3) and b) DSM-IV-TR criteria for AD.
-Each subject must have an MMSE score ≥ 15 and ≤ 26 at Screening
-Each subject must have a clear history of cognitive and functional decline over at least one year
-Each subject must have an MRI scan at the Screening Visit that is consistent with a diagnosis of AD.MRI scans or head CT (with Sponsor approval) obtained within 12 months are acceptable alternatives and must be submitted for central review.
-Each subject must be able to read at a 6th grade level or equivalent 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, medical food/supplement, and/or herbal medications for AD, the dose must have been stable for at least three months before Screening, and the subject must be willing to remain on the same dose for the duration of the trial. (The treatment and dose at Screening must not be changed during the trial unless medically necessary to ensure subject safety. Additional treatments [including herbal medications] for AD that are not specified in the protocol must not be initiated during 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 required 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). It is recommended that the trial partner accompany the subject to all trial visits.
-Each subject must have results of clinical laboratory tests within normal limits or clinically acceptable to the investigator at Screening.
-Each subject must have results of a physical examination, vital signs, and ECG within normal limits or clinically acceptable to the investigator at Screening.
-Each subject must be willing to provide a blood sample for APOE and HLA genotyping.
-Based on the investigator's judgement, each subject is able to speak, read, hear,and understand the language of the trial staff and the informed consent form, and possess the ability to respond verbally to questions, follow instructions, and complete questionnaires. Each subject must also be able and willing to adhere to dose and visit schedules and to consent to audio recording of selected interviews.
Subjects who agree to participate in pharmacogenetic testing must give written informed consent for pharmacogenetic testing. Subjects who are unwilling to sign the informed consent for pharmacogenetic testing may be included into the trial, however, pharmacogenetic samples must not be obtained.
Part II (extension) - Principal Inclusion Criteria:
Each subject must
- have tolerated study medication and completed the initial 78-week period of the trial.
Subjects who did not complete the initial 78 weeks of treatment but continued in the trial may be permitted to continue in the extension at the discretion of the Sponsor.
- have a trial partner who is reliable, competent, and meets the same criteria outlined for Part I. |
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E.4 | Principal exclusion criteria |
Part I (main cohort) - Principal Exclusion Criteria:
The subject
- has a Rosen MHIS > 4 at Screening.
- has a known history of stroke or evidence from screening imaging scan (e.g. MRI scan or CT) that is clinically important in the investigator's opinion.
- has evidence of a clinically relevant neurological disorder other than the disease being studied (ie, probable AD) at Screening.
- 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.
- has evidence of a current episode of major depression based on investigator's judgment.
- MRI scan obtained at Screening shows evidence of a neurological disorder other than probable AD or
• evidence of a prior macrohemorrhage,
• symptomatic vasogenic edema in the investigator’s judgment,
• > 3 lacunar infarcts over 10 mm each, or
cognitive impairment, including but not limited to: brain tumor, large or strategically located cortical or subcortical infarct, or severe white matter disease equaling a rating of 3 on the age-related white matter changes (ARWMC) scale.An MRI that was done within 12 months before the Screening visit that is available for review by the central MRI reading vendor is also acceptable for evaluation of the eligibility criteria. A head CT scan may be accepted instead of MRI on a case-by-case basis, as approved by the Sponsor (e.g., when MRI is contraindicated for the subject).
- has a history of hepatitis or liver disease that has been active within the 6 months prior to Screening.
- 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. All concomitant substances must be kept as stable as medically possible during the trial.
- has a history or current evidence of long QT syndrome, QTC interval or torsades de pointes.
- has a history of malignancy occurring within the 5 years immediately before Screening.
-has 1. a history of clinically significant vitamin B12 or folate deficiency in the 6 months immediately before Screening, or 2. vitamin 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 (extension) - Principal Exclusion Criteria:
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. Subjects must be excluded if they report suicidal ideation with intent, with or without a plan (ie, suicidal ideation Type 4 or 5 on the C-SSRS) in the past 1 month or suicidal behavior in the past 6 months.
- has developed a recent or ongoing, uncontrolled, clinically significant medical condition (such as, but not limited to, diabetes, hypertension, thyroid or endocrine disease, congestive heart failure, angina, cardiac or gastrointestinal disease, dialysis, or abnormal renal function with estimated creatinine clearance < 30 mL/min ) 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. Controlled co-morbid conditions (including diabetes, hypertension, heart disease, etc) are not exclusionary if stable. All concomitant medications, supplements, or other substances must be kept as stable as medically possible during the trial. Note: urinary tract infections at Visit 10B are not exclusionary if adequately treated (as documented by repeat urinalysis).
- has a history of, or has developed during Part I evidence of long QT syndrome, QTC interval ≥ 470 milliseconds (for male subjects) or ≥ 480 milliseconds (for female subjects), or torsades de pointes.
- anticipates receiving any of the prohibited treatments listed in Table 13 during Part II.
- has developed a form of dementia that is not Alzheimer's disease, including but not limited to, dementia due to HIV infection, head trauma, vascular disease, Parkinson's disease, frontotemporal dementia, or Huntington's disease, as determined by the investigator. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part I (main cohort) - The two Coprimary Efficacy Endpoints for the trial are the:
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.
The primary Part II (extension) endpoint is the 24-Month (6 months after the primary
timepoint from Part I) change-from-baseline treatment difference on ADAS-Cog and ADCS-ADL. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part I (main cohort) :
ADAS-Cog: Screening, Baseline, Week 13, 26, 39, 52, 65 and 78
ADCS-ADL: Baseline, Week 13, 26, 39, 52, 65 and 78
Part II (extension) :
ADAS-Cog: Week 91, 104, 130, 182, 234, 286 and 338
ADCS-ADL: Week 91, 104, 130, 182, 234, 286 and 338 |
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E.5.2 | Secondary end point(s) |
Part I (main cohort):
The Key Secondary Efficacy Endpoint is the change from Baseline score in the CDR-SB at Week 78.
Part II (extension): none - only exploratory end point |
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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 | 5 |
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 | 5 |
E.8.9.1 | In the Member State concerned months | 5 |
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 |