| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| prodromal Alzheimer's Disease |
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| E.1.1.1 | Medical condition in easily understood language |
| early 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 | 18.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10001897 |
| E.1.2 | Term | Alzheimer's disease (incl subtypes) |
| 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 assess the efficacy of two doses of MK-8931 based on overall clinical progression in subjects with prodromal Alzheimer's Disease (AD).
• To assess the safety and tolerability of two doses of MK-8931 in the treatment of subjects with prodromal AD.
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| E.2.2 | Secondary objectives of the trial |
| • To assess the efficacy of two doses of MK-8931 in slowing clinical decline and disease progression in subjects with prodromal AD. |
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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 main objectives are as follows:
• To assess the effect of MK-8931 on CSF total tau in subjects included in the CSF substudy.
• To assess the effect of MK-8931 on the composite cortical amyloid standard uptake value ratio (SUVR) assessed with amyloid tracer [18F]Flutemetamol using PET imaging in subjects included in the PET substudy.
• To support the development of a CSF based companion diagnostic. |
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| E.3 | Principal inclusion criteria |
Each subject must:
• Be ≥ 50 and ≤ 85 years of age at the Screening Visit.
• Meet the following criteria for a diagnosis of prodromal AD:
o Each subject must report a history of subjective memory decline with gradual onset and slow progression for at least one year before Screening, that is either corroborated by an informant who knows the subject well or is documented in medical records.
o Each subject must have objective impairment in episodic memory at Screening that is ≥1.0 SD below the appropriate population mean as measured by the screening memory test [Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]. An RBANS delayed memory index score of ≤85 is required for entry. (Note: the proportion of subjects with RBANS delayed memory index scores ranging from 79 to 85 (approximately 1.5 to 1.0 SD below the appropriate population mean), inclusive, will not exceed 15-30% of the total number randomized).
o Each subject must have general cognitive function and activities of daily living sufficiently intact, based on clinical assessment, so as not to meet criteria for mild AD dementia (based on DSM-IV-TR and NINCDS-ADRDA criteria).
o Each subject must have a positive amyloid imaging PET scan using [18F]flutametamol at Screening or positive CSF tau:Aβ42 ratio at Screening (see Trial Manuals for details). PET is the primary inclusion tool for the trial. Subjects who fail to meet inclusion criteria based on PET but qualify based on CSF will be enrolled in a separate CSF subgroup of the trial. (Refer to Protocol Section 7.1.3.4 for direction regarding initiation of CSF collection in the trial.)
• Have an MMSE score ≥ 24 at Screening.
• 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 receiving an acetylcholinesterase inhibitor, memantine, medical food/supplement, and/or herbal medications for AD, be on a stable dose for at least the 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 that the subject is receiving at Screening must not be changed during the trial unless medically necessary. Additional treatments [including herbal medications] for AD that are not specified in the protocol must not be initiated during the trial. The subject and trial partner must agree that they do not plan to discontinue treatment or initiate additional AD treatments during the trial unless medically necessary. (See Protocol Section 5.5.2 for additional details regarding use of other AD therapy.)
• Have a reliable and competent trial partner/informant who must have a close relationship with the subject, have face to face contact at least three days a week for a minimum of six waking hours a week, 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/informant should understand the nature of the trial and adhere to trial requirements (e.g., dose, visit schedules, receive phone calls, and evaluations).
• 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.
• Have results of a physical examination, vital signs, and ECG within normal limits or clinically acceptable to the investigator at Screening.
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| E.4 | Principal exclusion criteria |
The subject must be excluded from participating in the trial if the subject:
• Has a Rosen modified Hachinski Ischemia Score > 4 at Screening (i.e., evidence of vascular dementia).
• Has a known history of stroke or evidence from screening MRI scan that is clinically important in the investigator's opinion.
• Meets the criteria for a diagnosis of dementia, including probable or possible AD, based on DSM IV TR or NINCDS ADRDA criteria at Screening or Baseline.
• Has evidence of a clinically relevant neurological disorder other than the disease being studied (i.e., prodromal 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.
• 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.
• Has evidence of a current episode of major depression based on investigator's judgment. A score on the 15-item Geriatric Depression Scale (GDS) of 5 or more requires an assessment by an appropriate health care professional to evaluate for the presence of major depression. Subjects with a score of 5 or more who are not diagnosed with major depression following such an assessment may be included in the trial.
• Has an MRI scan obtained at Screening that shows evidence of a neurological disorder other than prodromal 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 over 10 mm each, any cortical infarct over 10 mm, or any other clinically significant finding (e.g., any lesion that may account for their cognitive impairment, including but not limited to brain tumor, severe white matter disease with a rating of 3 on the age-related white matter changes (ARWMC) scale, arteriovenous malformation, cavernous hemangioma, or any infarct in a strategic subcortical location).
• Has a history of hepatitis or liver disease that, in the opinion of the investigator, has been active within the six months prior Screening.
• Has a recent or ongoing, uncontrolled, clinically significant medical condition within three months of the Screening Visit (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 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. Controlled co-morbid conditions (including diabetes, hypertension, heart disease, etc.) are not exclusionary if stable within three months of the Screening Visit. All concomitant medications, supplements, or other substances must be kept as stable as medically possible during the trial. Note: urinary tract infections at screening are not exclusionary if adequately treated (as documented by repeat urinalysis) prior to baseline.
• Has a history or current evidence of long QT syndrome, QTC interval 470 milliseconds (for male subjects) or ≥ 480 milliseconds (for female subjects), or torsades de pointes. (Note: Determination of QTc interval at Screening will be based on the average of three measurements, using the Fridericia formula for correction.)
• Has a history of malignancy occurring within the five years immediately before Screening, except for a subject who has been adequately treated for
o basal cell or squamous cell skin cancer,
o in situ cervical cancer, or
o localized prostate carcinoma; or
o who has undergone potentially curative therapy with no evidence of recurrence for ≥ 3 year post therapy, and who is deemed at low risk for recurrence by her/his treating physician.
• Has one of the following:
o clinically significant vitamin B12 or folate deficiency in the six months immediately before Screening, or
o vitamin B12 or folate deficiency in addition to increased serum homocysteine or methylmelonic acid levels at Screening as determined by central laboratory normal values.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the change from Baseline in the Clinical Dementia Rating Sum of Boxes (CDR SB) score at Week 104. |
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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) |
Secondary efficacy endpoints are:
• the time to progression to probable AD dementia
• the mean difference between the last (Week 104) and first (Week 13) postdose timepoint in CDR-SB
• the change from Baseline at Week 104 in the 3-domain composite cognition score (CCS-3D)
• the change from Baseline at Week 104 in total hippocampal volume
• the change from Baseline at Week 104 in CSF total tau
• the change from Baseline at Week 104 in composite cortical amyloid SUVR assessed with amyloid tracer [18F]Flutemetamol using PET imaging
• the change from Baseline at Week 104 in the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory (mild cognitive impairment [MCI] version) (ADCS ADLMCI) score
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• progression to probable AD dementia: Weeks 2, 6, 13, 26, 39, 52, 65, 78, 91, 104
• Mean difference in CDR-SB: Weeks 13 and 104
• CCS-3D: Baseline, Week 104
• Total hippocampal volume: Screening, Week 104
• CSF total tau: Screening, Week 104
• Cortical amyloid SUVR: Screening, Week 104
• ADCS-ADLMCI: Screening, Week 104 |
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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 | No |
| 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) | 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 | 55 |
| 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 |
| Finland |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Norway |
| Spain |
| Switzerland |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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