EPOCH

TerminatedPhase 2 / PHASE3Results posted

An Efficacy and Safety Trial of Verubecestat (MK-8931) in Mild to Moderate Alzheimer's Disease (P07738)

A Randomized, Placebo Controlled, Parallel-Group, Double Blind Efficacy and Safety Trial of MK-8931 With a Long Term Double-Blind Extension in Subjects With Mild to Moderate Alzheimer's Disease (Protocol No. MK-8931-017-10)(Also Known as SCH 900931, P07738)

Lead sponsor

Merck Sharp & Dohme LLC

Asset

Verubecestat

Listed sites

Recruiting sites

Enrollment

2,211

actual

Study population

Alzheimer’s disease

Key I/E criteria

•Alzheimer's disease•Study partner/caregiver required

Primary endpoints

•ADAS-Cog•ADCS-Activities of Daily Living (ADCS-ADL)•[Part I (Base Study)] Number of Participants Who Experienced an Adverse Event

Identifiers

Registered as

Registry132229JAPIC-CTI

Eudract number2011-003151-20

Secondary IDMK-8931-017Merck Protocol Number

NCT IDNCT01739348

Org study IDP07738

Timeline

Milestones

Study start2012-11-30actual

Study first posted2012-12-03estimated

Primary completion2017-04-14actual

Study completion2017-04-14actual

Results first posted2018-05-16actual

Last update posted2018-10-24actual

Assets

Drug assets

Verubecestat

Study populations

Who this study enrolls

Alzheimer’s disease

Eligibility

Who can enroll

Minimum age55 Years

Maximum age85 Years

SexAll

Healthy volunteersNot accepted

Inclusion criteria

•Diagnosis of probable AD based on both

a)the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria and

b)the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for AD

•AD is of mild to moderate severity

•Clear history of cognitive and functional decline over at least one year that is either

a)documented in medical records or

b)documented by history from an informant who knows the subject well

•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 participant is receiving an acetylcholinesterase inhibitor, memantine, medical food/supplement (e.g., vitamin E) and/or herbal medications for AD, the dose must have been stable for at least three months before Screening, and the participant must be willing to remain on the same dose for the duration of the trial. Participants may need to be on AD treatments in accordance with local requirements

•Participant must have a reliable and competent trial partner/caregiver who must have a close relationship with the subject

Inclusion Criteria for Extension Period (Part II):

•Tolerated study drug and completed the initial 78-week period of the trial (Part I)

•Participant must have a reliable and competent trial partner who must have a close relationship with the subject

Exclusion criteria

•History of stroke

•Evidence of a neurological disorder other than the disease being studied (i.e., probable AD)

•History of seizures or epilepsy within the last 5 years before Screening

•Evidence of a clinically relevant or unstable psychiatric disorder, excluding major depression in remission

•Participant is at imminent risk of self-harm or of harm to others

•History of alcoholism or drug dependency/abuse within the last 5 years before Screening

•Participant does not have a magnetic resonance imaging (MRI) scan obtained within 12 months of Screening and is unwilling or not eligible to undergo an MRI scan at the Screening Visit. With Sponsor approval, a head computed tomography (CT) scan may be substituted for MRI scan to evaluate eligibility

•History of hepatitis or liver disease that has been active within the six months prior to Screening Visit

•Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of the Screening Visit (e.g., diabetes, hypertension, thyroid or endocrine disease, congestive heart failure, angina, cardiac or gastrointestinal disease, dialysis, or abnormal renal function) other than the condition being studied such that participation in the trial would pose a significant medical risk to the subject. Controlled co-morbid conditions are not exclusionary if stable within three months of the Screening Visit

•History or current evidence of long QT syndrome, corrected QT (QTc) interval ≥470 milliseconds (for male subjects) or ≥480 milliseconds (for female subjects), or torsades de pointes

•History of malignancy occurring within the five years before Screening, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or localized prostate carcinoma; or malignancy which has been treated with potentially curative therapy with no evidence of recurrence for ≥3 year post-therapy

•Clinically significant vitamin B12 or folate deficiency in the six months before Screening Visit

•Use of any investigational drugs within 30 days (or longer depending on drug) before Screening or participation in studies involving repeated cognitive testing within 30 days before Screening. Participation in an observational study, such as those involving annual cognitive assessments and/or neuroimaging, may be allowed if approved by Sponsor

•History of a hypersensitivity reaction to more than three drugs

•Has tested positive for human immunodeficiency virus (HIV)

•Close family member (including the caregiver, the spouse or any children) who is among the personnel of the investigational or sponsor staff directly involved with this trial

Additional Exclusion Criteria for Safety Cohort:

•History of an ongoing medical condition that has been poorly controlled within 6 months of the Screening Visit (e.g., hypotension, diabetes, hypertension, cerebrovascular disease, thyroid disease, endocrine disturbance, congestive heart failure, cardiac or gastrointestinal disease, dialysis, or abnormal renal function) other than the condition being studied such that a subject's participation in the trial would pose a significant medical risk

•History of congestive heart failure (moderate or greater severity), myocardial infarction, heart surgery, syncope, bradycardia, or clinically significant hypotension within one year before Screening

Exclusion Criteria for Extension Period (Part II):

•Participant is at imminent risk of self-harm or of harm to others

•Has developed a recent or ongoing, uncontrolled, clinically significant medical condition other than AD

•Has 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

•Has developed a form of dementia that is not AD

Endpoints (30)

What's being measured

Protocol endpoints and posted registry outcome measures, grouped into outcome categories. Composite endpoints show their component event types. Standard codes (LOINC, SNOMED CT) are shown where available.

Coverage by outcome category

Global cognition

Safety / tolerability / PK

Function / daily living

Behavior / neuropsychiatric

Amyloid biomarkers

Tau biomarkers

Neuroimaging

Global cognition

10 endpoints

Primary/protocol endpoint

[Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score

Time frame:Baseline and week 78

ADAS-Cog

change from baseline, improvement

Primary/protocol endpoint

[Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score

Time frame:Baseline and week 104

ADAS-Cog

change from baseline, improvement

Primary/registry result

[Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score

Time frame:Baseline and week 78

ADAS-Cog

change from baseline, improvement

Posted result

Group	Value (least_squares_mean), Score on a Scale	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=631 Participants	7.9	-7.2 - 8.6
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=626 Participants	8.0	-7.3 - 8.7
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=644 Participants	7.7	-7.0 - 8.4

Difference in Least Squares Mean0.297.51% CI-0.9 - 1.3p0.6287Longitudinal ANCOVA

Difference in Least Squares Mean0.497.51% CI-0.8 - 1.5p0.4625Longitudinal ANCOVA

Primary/registry result

[Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score

Time frame:Baseline and week 104

ADAS-Cog

change from baseline, improvement

Posted result

Group	Value (mean), Score on a Scale	Standard deviation
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=207 Participants	10.1	9.9
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=208 Participants	8.5	9.5
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=216 Participants	9.6	9.5

Secondary/protocol endpoint

[Part I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score

Time frame:Baseline and week 78

Clinical Dementia Rating-Sum of Boxes (CDR-SB)

change from baseline, improvement

Secondary/protocol endpoint

[Part I (Base Study)] Percentage of Participants Achieving Responder Status

Time frame:Week 78

ADAS-Cog

threshold achievement, improvement

Secondary/protocol endpoint

[Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score

Time frame:Baseline and week 78

Mini-Mental State Examination (MMSE)

change from baseline, improvement

Secondary/registry result

[Part I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score

Time frame:Baseline and week 78

Clinical Dementia Rating-Sum of Boxes (CDR-SB)

change from baseline, improvement

Posted result

Group	Value (least_squares_mean), Score on a Scale	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=611 Participants	2.1	-1.8 - 2.3
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=600 Participants	2.1	-1.9 - 2.4
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=623 Participants	2.1	-1.9 - 2.3

Difference in Least Squares Means0.097.51% CI-0.4 - 0.3p0.8426Longitudinal ANCOVA

Difference in Least Squares Means0.097.51% CI-0.3 - 0.4p0.8264Longitudinal ANCOVA

Secondary/registry result

[Part I (Base Study)] Percentage of Participants Achieving Responder Status

Time frame:Week 78

ADAS-Cog

threshold achievement, improvement

Posted result

Group	Value (number), Percentage of Participants	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=652 Participants	20.1	-
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=652 Participants	19.6	-
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=653 Participants	19.3	-

Secondary/registry result

[Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score

Time frame:Baseline and week 78

Mini-Mental State Examination (MMSE)

change from baseline, improvement

Posted result

Group	Value (least_squares_mean), Score on a Scale	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=610 Participants	-3.9	--4.3 - -3.6
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=600 Participants	-3.6	--4.0 - -3.3
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=628 Participants	-4.1	--4.5 - -3.8

Difference in Least Squares Means0.295% CI-0.3 - 0.7p0.4721Longitudinal ANCOVA

Difference in Least Squares Means0.595% CI0.0 - 1.0p0.0599Longitudinal ANCOVA

Function / daily living

4 endpoints

Primary/protocol endpoint

[Part I (Base Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score

Time frame:Baseline and week 78

ADCS-Activities of Daily Living (ADCS-ADL)

change from baseline, improvement

Primary/protocol endpoint

[Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score

Time frame:Baseline and week 104

ADCS-Activities of Daily Living (ADCS-ADL)

change from baseline, improvement

Primary/registry result

[Part I (Base Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score

Time frame:Baseline and week 78

ADCS-Activities of Daily Living (ADCS-ADL)

change from baseline, improvement

Posted result

Group	Value (least_squares_mean), Score on a Scale	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=627 Participants	-8.4	--9.5 - -7.4
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=622 Participants	-8.2	--9.2 - -7.1
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=636 Participants	-8.9	--9.9 - -8.0

Difference in Least Squares Means0.597.51% CI-1.1 - 2.1p0.4925Longitudinal ANCOVA

Difference in Least Squares Means0.797.51% CI-0.9 - 2.3p0.3221Longitudinal ANCOVA

Primary/registry result

[Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score

Time frame:Baseline and week 104

ADCS-Activities of Daily Living (ADCS-ADL)

change from baseline, improvement

Posted result

Group	Value (mean), Score on a Scale	Standard deviation
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=207 Participants	-10.7	13.7
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=209 Participants	-9.2	12.7
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=216 Participants	-9.3	12.0

Behavior / neuropsychiatric

2 endpoints

Secondary/protocol endpoint

[Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score

Time frame:Baseline and week 78

Neuropsychiatric Inventory (NPI)

change from baseline, improvement

Secondary/registry result

[Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score

Time frame:Baseline and week 78

Neuropsychiatric Inventory (NPI)

change from baseline, improvement

Posted result

Group	Value (least_squares_mean), Score on a Scale	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=632 Participants	3.4	-2.5 - 4.4
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=631 Participants	3.8	-2.8 - 4.8
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=639 Participants	2.7	-1.7 - 3.7

Difference in Least Squares Means0.795% CI-0.6 - 2.1p0.2949Longitudinal ANCOVA

Difference in Least Squares Means1.195% CI-0.4 - 2.6p0.1372Longitudinal ANCOVA

Amyloid biomarkers

2 endpoints

Secondary/protocol endpoint

[Part I (Base Study)] Change From Baseline in Cortical Amyloid Load Assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR)

Time frame:Baseline and week 78

change from baseline, improvement

Secondary/registry result

[Part I (Base Study)] Change From Baseline in Cortical Amyloid Load Assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR)

Time frame:Baseline and week 78

change from baseline, improvement

Posted result

Group	Value (least_squares_mean), SUVR	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=20 Participants	-0.02	--0.04 - -0.01
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=10 Participants	-0.04	--0.06 - -0.03
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=14 Participants	0.00	--0.01 - 0.01

Difference in Least Squares Means-0.0395% CI-0.05 - 0.00p0.0066Longitudinal ANCOVA

Difference in Least Squares Means-0.0495% CI-0.06 - -0.02p<0.0001Longitudinal ANCOVA

Tau biomarkers

2 endpoints

Secondary/protocol endpoint

[Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau

Time frame:Baseline and week 78

change from baseline, improvement

Secondary/registry result

[Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau

Time frame:Baseline and week 78

change from baseline, improvement

Posted result

Group	Value (least_squares_mean), Fold Change	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=32 Participants	1.02	-0.96 - 1.08
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=46 Participants	1.04	-0.99 - 1.09
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=33 Participants	1.07	-1.01 - 1.13

Ratio of Fold Change from Baseline0.9595% CI0.87 - 1.04p0.2138Longitudinal ANCOVA

Ratio of Fold Change from Baseline0.9795% CI0.90 - 1.05p0.4330Longitudinal ANCOVA

Neuroimaging

2 endpoints

Secondary/protocol endpoint

[Part I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV)

Time frame:Baseline and week 78

percent change from baseline, improvement

Secondary/registry result

[Part I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV)

Time frame:Baseline and week 78

percent change from baseline, improvement

Posted result

Group	Value (least_squares_mean), Percent Change	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=308 Participants	-5.6	--5.9 - -5.4
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=281 Participants	-5.7	--5.9 - -5.4
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=308 Participants	-5.0	--5.2 - -4.7

Difference in Least Squares Means-0.697.51% CI-1.0 - -0.2p0.0005Longitudinal ANCOVA

Difference in Least Squares Means-0.797.51% CI-1.1 - -0.3p0.0002Longitudinal ANCOVA

Safety / tolerability / PK

8 endpoints

Primary/protocol endpoint

[Part I (Base Study)] Number of Participants Who Experienced an Adverse Event

Time frame:Up to week 80 (up to 2 weeks following cessation of study treatment in Part I)

event count, event

Primary/protocol endpoint

[Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event

Time frame:From week 78 (end of treatment in Part I) up to week 262 of Part II

event count, event

Primary/protocol endpoint

[Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event

Time frame:Up to week 78

event count, event

Primary/protocol endpoint

[Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event

Time frame:From week 78 (end of treatment in Part I) up to week 260 of Part II

event count, event

Primary/registry result

[Part I (Base Study)] Number of Participants Who Experienced an Adverse Event

Time frame:Up to week 80 (up to 2 weeks following cessation of study treatment in Part I)

event count, event

Posted result

Group	Value (count_of_participants), Participants	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=702 Participants	630	-
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=700 Participants	646	-
Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]n=103 Participants	90	-
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=705 Participants	579	-

Primary/registry result

[Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event

Time frame:From week 78 (end of treatment in Part I) up to week 262 of Part II

event count, event

Posted result

Group	Value (count_of_participants), Participants	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=379 Participants	240	-
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=365 Participants	230	-
Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]n=61 Participants	51	-
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=394 Participants	264	-

Primary/registry result

[Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event

Time frame:Up to week 78

event count, event

Posted result

Group	Value (count_of_participants), Participants	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=702 Participants	57	-
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=700 Participants	64	-
Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]n=103 Participants	12	-
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=705 Participants	42	-

Primary/registry result

[Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event

Time frame:From week 78 (end of treatment in Part I) up to week 260 of Part II

event count, event

Posted result

Group	Value (count_of_participants), Participants	Reported bounds
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]n=379 Participants	10	-
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]n=365 Participants	9	-
Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]n=61 Participants	6	-
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]n=394 Participants	29	-

Publications (7)

Bibliography

Records linked to this trial through ClinicalTrials.gov references, PubMed NCT search, and curated study seeds. 'Canonical' marks design/result papers; others are registry references or candidates.

Registry references + supporting bibliography

Provenance

Sources

Trial identity, design, statusClinicalTrials.gov API v2

Snapshot dateJuly 21, 2026

Endpoint classificationDelfa ADRD endpoint taxonomy

Results tableClinicalTrials.gov results section

Trial facts come from public ClinicalTrials.gov records. Endpoint categories are Delfa's classification of those records, not a ClinicalTrials.gov field. All figures reflect the July 21, 2026 snapshot.