| 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 | 20.0 |
| 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 |
Merck will conduct Future Biomedical Research on DNA (blood) and CSF specimens collected during this clinical trial. This research may include genetic analyses (DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the measurement of other analytes. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
CSF substudy- A Companion Diagnostic Clinical Study of Luminex xMAP Tau/Amyloid Assay in Subjects with Amnestic Mild Cognitive Impairment due to Alzheimer's Disease (Prodromal AD) who are enrolled into Merck MK-8931 Pivotal Phase III Clinical Trial (Study No. MK-8931-019).
The xMAP Tau/Amyloid Assay is a quantitative immunoassay used on the FLEXMAP 3D instrument for the detection of total Tau protein and amyloid beta (1-42) peptide from cerebrospinal fluid samples of patients with amnestic mild cognitive impairment (aMCI). The xMAP Tau/Amyloid Assay is intended to aid in the identification of prodromal AD patients for whom it is appropriate to treat with MK-8931 based on a the ratio of total Tau protein concentration to amyloid beta 1-42 peptide concentration in the CSF.
The CSF substudy has two distinct objectives: 1) to evaluate change from baseline in AD biomarkers at Week 104 and 2) to support development of a CSF companion or standalone diagnostic.
Amyloid PET Substudy: Only subjects randomized in this trial with both a new [18F]-flutemetamol PET scan and new MRI at screening will be allowed to participate in the PET substudy. For patients participating in the PET substudy to evaluate change from baseline in brain [18F]- flutemetamol tracer standard uptake value ratio at 104 weeks of treatment (N = 100 patients/treatment arm), an End of Treatment PET scan should be performed within 4 weeks before the clinical visit (Visit 12) and before trial medication is discontinued. All Visit 12 PET scans will be acquired using [18F]-flutemetamol.
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| E.3 | Principal inclusion criteria |
In order to be eligible for participation in this trial, the subject must:
1. Be ≥ 50 and ≤ 85 years of age at the Screening Visit.
Meet the following criteria (2-5) for a diagnosis of prodromal AD
2. 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.
3. 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 RBANS (Repeatable Battery for the Assessment of Neuropsychological Status). To meet this criterion, 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 10-30% of the total number randomized).
4. 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).
5. Each subject must have a positive amyloid imaging PET scan using [18F]flutemetamol 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.)
*Subjects with a prior positive amyloid imaging PET scan or a Screening PET scan with florbetaben or florbetapir may be enrolled without a Screening flutemetamol scan with Sponsor approval (see Section 7.1.2.5.7).
6. Have an MMSE score ≥ 24 at Screening.
7. 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.
8. If receiving an acetylcholinesterase inhibitor, memantine, medical food/supplement (e.g., vitamin E), 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 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. 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 Section 5.5.2 for additional details regarding use of other AD therapy.)
9. 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 (or more in accordance with 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/informant should understand the nature of the trial and adhere to trial requirements (e.g., dose, visit schedules, receive phone calls, and evaluations).
10. 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.
11. Have results of a physical examination, vital signs, and ECG within normal limits or clinically acceptable to the investigator at Screening.
(read rest in the protocol) |
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| E.4 | Principal exclusion criteria |
1. Has a Rosen-modified Hachinski Ischemia Score > 4 at Screening (i.e., evidence of vascular dementia).
2. Has a known history of stroke or evidence from screening imaging scan (e.g., MRI or CT) that is clinically important in the investigator's opinion.
3. Meets the criteria for a diagnosis of AD dementia, including probable or possible AD, based on DSM-IV-TR or NINCDS-ADRDA [21] criteria at Screening or Baseline.
4. 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.
5. Has a history of seizures or epilepsy within the last five years before Screening.
6. 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 remiss ion is not exclusionary.
7. 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.
8. Is at imminent risk of self-harm, based on clinical interview and responses on the Columbia Suicide 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 or method (e.g., positive response to items 4 or 5 in assessment of suicidal ideation on the C-SSRS) in the past two months or suicidal behavior in the past six months.
9. Has a history of alcoholism or drug dependency/abuse within the last five years before Screening.
10. Does not have an MRI scan obtained within 12 months before Screening available for central review and is unwilling or not eligible to undergo an MRI scan (e.g., metal implants, obesity) at the Screening Visit (see MRI Procedure Manual and Imaging Charter for details). Exception: A head CT scan obtained at Screening or within 12 months before Screening may be accepted for evaluation of the eligibility criteria on a case-by-case basis, as approved by the Sponsor (e.g., when MRI is contraindicated for the subject). The head CT must be suitable for central review.
Note: Once 20% of subjects have been randomized based on historical MRI or CT scans, no further historical MRIs or CT scans will be accepted.
11. Has an MRI scan obtained at Screening that shows evidence of a neurological disorder other than prodromal AD or:
- evidence of a prior macrohemorrhage,
- symptomatic vasogenic edema in the investigator´s judgment,
- > 3 lacunar infarcts over 10 mm each, or
- any other clinically significant finding that may account for their 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 obtained at Screening or within 12 months before Screening may be accepted instead of MRI on a case-bycase basis, as approved by the Sponsor (e.g., when MRI is contraindicated for the subject).
(read rest in the protocol) |
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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 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) |
- 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 CCS-3D
- the change from Baseline at Week 104 in total hippocampal volumen
- the change from Baseline at Week 104 in composite cortical amyloid standard uptake value ratio assessed with amyloid tracer [18F]Flutemetamol using PET imaging
- the change from Baseline at Week 104 in ADCS-ADLMCI score
- the change from Baseline at Week 104 in CSF total tau |
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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
-Cortical amyloid SUVR: Screening, Week 104
-ADCS-ADLMCI: Screening, Week 104
-CSF total tau: 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| 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 |
| Finland |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Norway |
| Poland |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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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