An Efficacy and Safety Trial of MK-8931 in Mild to Moderate AD (EPOCH)

Phase 1

Conditions: mild to moderate Alzheimer's Disease
MedDRA version: 19.0Level: LLTClassification code 10001896Term: Alzheimer's diseaseSystem Organ Class: 100000004852
Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Registration Number: EUCTR2011-003151-20-BE

Lead Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 1960

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.
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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 diab