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    Summary
    EudraCT Number:2012-005542-38
    Sponsor's Protocol Code Number:MK-8931-019-06
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-10-14
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2012-005542-38
    A.3Full title of the trial
    A Phase III, Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Clinical Trial to Study the Efficacy and Safety of MK-8931 (SCH 900931) in Subjects with Amnestic Mild Cognitive Impairment Due to Alzheimer’s Disease (Prodromal AD).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Safety and Efficacy Study for Alzheimer's Disease (Prodromal AD)
    A.3.2Name or abbreviated title of the trial where available
    A Safety and Efficacy Study for Alzheimer's Disease (Prodromal AD)
    A.4.1Sponsor's protocol code numberMK-8931-019-06
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co.,
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co.,
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme Corp., a subsidiary of Merck
    B.5.2Functional name of contact pointGlobal Clinical Trials Operations
    B.5.3 Address:
    B.5.3.1Street AddressOne Merck Drive, P.O. Box 100
    B.5.3.2Town/ cityWhitehouse Station, NJ
    B.5.3.3Post code08889-0100
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1267305-7678
    B.5.5Fax number+1267305-6440
    B.5.6E-mailmichael.egan@merck.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMK-8931
    D.3.2Product code MK-8931
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMK-8931
    D.3.9.2Current sponsor codeMK-8931, SCH900931
    D.3.9.3Other descriptive nameSCH 900931
    D.3.9.4EV Substance CodeSUB31364
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMK-8931
    D.3.2Product code MK-8931
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMK-8931
    D.3.9.2Current sponsor codeMK-8931, SCH900931
    D.3.9.3Other descriptive nameSCH 900931
    D.3.9.4EV Substance CodeSUB31364
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    prodromal Alzheimer's Disease
    E.1.1.1Medical condition in easily understood language
    early Alzheimer’s Disease
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level HLT
    E.1.2Classification code 10001897
    E.1.2Term Alzheimer's disease (incl subtypes)
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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.
    E.3Principal 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]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.)
    • 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
    (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.)
    • 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).
    • 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.
    E.4Principal 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. (Notes: Determination of QTc interval at Screening will be based on the average of three measurements, using the Fridericia formula for correction.Subjects with stable bundle branch block who exceed these limits for QTc interval are eligible for the trial if judged by an expert in cardiology not to be at increased risk for Torsades.
    • 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.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline and Week 104
    E.5.2Secondary 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

    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA55
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1470
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    patients with mild cognitive impairment who may progress to dementia during the trial
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 462
    F.4.2.2In the whole clinical trial 1500
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects who have completed the trial, demonstrated acceptable compliance with trial medication, and have not initiated acetylcholinesterase inhibitors or memantine during the trial will be eligible for enrollment in the separate extension protocol (if approved locally). In the extension study, all subjects, including those who initially received placebo in the current protocol, will receive active drug.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-12-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-04-17
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