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APECS

TerminatedPhase 3Results posted

Efficacy and Safety Trial of Verubecestat (MK-8931) in Participants With Prodromal Alzheimer's Disease (MK-8931-019)

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)

Lead sponsor

Merck Sharp & Dohme LLC

Asset

Verubecestat

Listed sites

Recruiting sites

Enrollment

1,454

actual

Study population

Alzheimer’s disease, MCI / preclinical Alzheimer’s

Key I/E criteria

•prodromal AD•Amyloid biomarker required (PET/CSF)•Tau biomarker required (PET/CSF)

Primary endpoints

•Clinical Dementia Rating-Sum of Boxes (CDR-SB)•Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse•Part 1 (Base Study). Percentage of Participants Who Discontinued From Study

Identifiers

Registered as

Registry142502JAPIC-CTI

Eudract number2012-005542-38

Org study ID8931-019

Secondary IDMK-8931-019Merck Protocol Number

NCT IDNCT01953601

Timeline

Milestones

Study first posted2013-10-01estimated

Study start2013-11-05actual

Primary completion2018-04-17actual

Study completion2018-04-17actual

Last update posted2019-05-17actual

Results first posted2019-05-17actual

Assets

Drug assets

Verubecestat

Study populations

Who this study enrolls

Alzheimer’s diseaseMCI / preclinical Alzheimer’s

Eligibility

Who can enroll

Minimum age50 Years

Maximum age85 Years

SexAll

Healthy volunteersNot accepted

Inclusion criteria

1. Diagnosis of prodromal AD, including the following:

1. History of subjective memory decline with gradual onset and slow progression for at least one year corroborated by an informant,

2. Objective impairment in episodic memory by memory test performed at Screening,

3. Does not meet criteria for dementia, AND

4. Positive Screening amyloid imaging PET scan using [18F]flutametamol tracer or positive Screening CSF tau:amyloid-β42 (Aβ42) ratio (Participants 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)

2. Able to read at a 6th grade level or equivalent

3. If participant is receiving an acetylcholinesterase inhibitor or memantine, the dose must have been stable for at least three months before Screening

4. Must have a reliable and competent trial partner/informant who has a close relationship with the participant and is willing to accompany the participant to all required trial visits, and to monitor compliance of the administration of the trial medication

Inclusion Criteria for Extension Period (Part 2):

1. Tolerated study drug and completed the initial 104-week period of the trial (Part 1)

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

Exclusion criteria

1. History of stroke

2. Evidence of a clinically relevant neurological disorder other than the disease being studied (i.e., prodromal AD)

3. History of seizures or epilepsy within the last 5 years

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

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

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

7. 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

8. History of hepatitis or liver disease that has been active within the 6 months prior to Screening

9. Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of Screening

10. History of malignancy occurring within the 5 years before Screening, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or localized prostate carcinoma

11. Clinically significant vitamin B12 or folate deficiency in the 6 months before Screening

12. Use of any investigational drugs or participation in clinical trials within the 30 days before Screening

13. History of a hypersensitivity reaction to more than three drugs

14. Has human immunodeficiency virus (HIV) by medical history

15. Participant is unwilling or has a contraindication to undergo PET scanning including but not limited to claustrophobia, excessive weight or girth

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

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

Exclusion Criteria for Extension Period (Part 2):

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

2. Has developed a recent or ongoing, uncontrolled, clinically significant medical or psychiatric condition

3. Results of safety assessments (e.g., laboratory tests) performed in participant at end of Part 1 that are clinically unacceptable to the Investigator

4. Has developed a form of dementia that is not AD

5. Has progressed to dementia due to AD per investigator diagnosis in the initial 104-week study (Part 1).

Exclusion Criteria for NFT PET Substudy (Part 2):

1. Had one or two PET scans with MK-6240 in the initial 104-week study.

Endpoints (26)

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

Amyloid biomarkers

Tau biomarkers

Neuroimaging

Global cognition

10 endpoints

Primary/protocol endpoint

Part 1 (Base Study). Least Squares Mean (LSM) Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104

Time frame:Baseline and Week 104 in Part 1

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

change from baseline, improvement

Primary/protocol endpoint

Part 2 (Extension Study). Mean Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130

Time frame:Baseline and Week 130 (i.e., Week 26 of Part 2)

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

change from baseline, improvement

Primary/registry result

Part 1 (Base Study). Least Squares Mean (LSM) Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104

Time frame:Baseline and Week 104 in Part 1

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 1); 12 mg (Part 2)n=465 Participants	1.6	-1.4 - 1.9
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=458 Participants	2.0	-1.8 - 2.3
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=469 Participants	1.6	-1.3 - 1.8

Difference in Least Squares Mean (LSM)0.197.51% CI-0.3 - 0.4p0.6734Longitudinal ANCOVA

Difference in Least Squares Means (LSM)0.497.51% CI0.0 - 0.8p0.0141Longitudinal ANCOVA

Primary/registry result

Part 2 (Extension Study). Mean Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130

Time frame:Baseline and Week 130 (i.e., Week 26 of Part 2)

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

change from baseline, improvement

Posted result

Group	Value (mean), Score on a Scale	Standard deviation
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)n=120 Participants	2.0	2.5
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=113 Participants	1.9	2.2
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=124 Participants	1.5	2.1

Secondary/protocol endpoint

Part 1 (Base Study). Event-Rate Per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia

Time frame:Up to Week 104 in Part 1

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

event count, event

Secondary/protocol endpoint

Part 1 (Base Study). Estimated Least Squares Mean Difference Between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment

Time frame:Week 13 and Week 104 in Part 1

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

descriptive

Secondary/protocol endpoint

Part 1 (Base Study). Least Squares Mean Change From Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104

Time frame:Baseline and Week 104 in Part 1

change from baseline, improvement

Secondary/registry result

Part 1 (Base Study). Event-Rate Per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia

Time frame:Up to Week 104 in Part 1

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

event count, event

Posted result

Group	Value (number), Event-Rate / 100 Participant-Years	Reported bounds
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)n=480 Participants	24.5	-
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=481 Participants	25.5	-
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=481 Participants	19.3	-

Hazard Ratio (HR)1.30197.51% CI1.005 - 1.684p0.0222Regression, Cox

Hazard Ratio (HR)1.38297.51% CI1.067 - 1.790p0.0050Regression, Cox

Secondary/registry result

Part 1 (Base Study). Estimated Least Squares Mean Difference Between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment

Time frame:Week 13 and Week 104 in Part 1

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

descriptive

Posted result

Group	Value (least_squares_mean), Score on a Scale	Reported bounds
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)n=465 Participants	1.5	-1.3 - 1.7
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=458 Participants	1.8	-1.5 - 2.0
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=469 Participants	1.5	-1.3 - 1.7

Difference in Least Squares Mean (LSM)0.097.51% CI-0.3 - 0.4p0.9109Longitudinal ANCOVA

Difference in Least Squares Mean (LSM)0.397.51% CI-0.1 - 0.7p0.0824Longitudinal ANCOVA

Secondary/registry result

Part 1 (Base Study). Least Squares Mean Change From Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104

Time frame:Baseline and Week 104 in Part 1

change from baseline, improvement

Posted result

Group	Value (least_squares_mean), Z-score	Reported bounds
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)n=441 Participants	0.8	-0.7 - 0.9
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=424 Participants	0.8	-0.7 - 0.9
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=440 Participants	0.8	-0.7 - 0.9

Difference in Least Squares Mean (LSM)0.097.51% CI-0.2 - 0.2p0.9510Longitudinal ANCOVA

Difference in Least Squares Mean (LSM)0.097.51% CI-0.2 - 0.2p0.9392Longitudinal ANCOVA

Function / daily living

2 endpoints

Secondary/protocol endpoint

Part 1 (Base Study). Least Squares Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL MCI) Score at Week 104

Time frame:Baseline and Week 104 in Part 1

ADCS-Activities of Daily Living (ADCS-ADL)

change from baseline, improvement

Secondary/registry result

Time frame:Baseline and Week 104 in Part 1

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 1); 12 mg (Part 2)n=469 Participants	-5.2	--6.1 - -4.3
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=462 Participants	-5.8	--6.8 - -4.8
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=472 Participants	-4.1	--5.0 - -3.3

Difference in Least Squares Mean (LSM)-1.097.51% CI-2.4 - 0.4p0.0960Longitudinal ANCOVA

Difference in Least Squares Mean (LSM)-1.797.51% CI-3.2 - -0.2p0.0110Longitudinal ANCOVA

Amyloid biomarkers

2 endpoints

Secondary/protocol endpoint

Part 1 (Base Study). Least Squares Mean Change From Baseline in Composite Cortical Amyloid Standard Uptake Value Ratio (SUVR) Assessed With Amyloid Tracer [18F]Flutemetamol Using Positron Emission Tomography (PET) Imaging at Week 104

Time frame:Baseline and Week 104 in Part 1

change from baseline, improvement

Secondary/registry result

Time frame:Baseline and Week 104 in Part 1

change from baseline, improvement

Posted result

Group	Value (least_squares_mean), Standard Uptake Value Ratio (SUVR)	Reported bounds
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)n=63 Participants	-0.03	--0.04 - -0.03
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=59 Participants	-0.04	--0.05 - -0.04
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=65 Participants	0.02	-0.02 - 0.03

Difference in Least Squares Mean (LSM)-0.0597.51% CI-0.06 - -0.04p<0.0001Longitudinal ANCOVA

Difference in Least Squares Mean (LSM)-0.0697.51% CI-0.07 - -0.05p<0.0001Longitudinal ANCOVA

Tau biomarkers

2 endpoints

Secondary/protocol endpoint

Part 1 (Base Study). Mean Percent Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau Concentration at Week 104

Time frame:Baseline and Week 104 in Part 1

percent change from baseline, improvement

Secondary/registry result

Part 1 (Base Study). Mean Percent Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau Concentration at Week 104

Time frame:Baseline and Week 104 in Part 1

percent change from baseline, improvement

Posted result

Group	Value (mean), Percent Change	Standard deviation
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)n=5 Participants	33.2	44.3
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=6 Participants	42.8	39.7
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=6 Participants	10.2	27.9

Neuroimaging

2 endpoints

Secondary/protocol endpoint

Part 1 (Base Study). Least Squares Mean Percent Change From Baseline in Total Hippocampal Volume (THV) at Week 104

Time frame:Baseline and Week 104 in Part 1

percent change from baseline, improvement

Secondary/registry result

Part 1 (Base Study). Least Squares Mean Percent Change From Baseline in Total Hippocampal Volume (THV) at Week 104

Time frame:Baseline and Week 104 in Part 1

percent change from baseline, improvement

Posted result

Group	Value (least_squares_mean), Percent Change	Reported bounds
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)n=168 Participants	-6.5	--6.9 - -6.2
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=181 Participants	-6.7	--7.1 - -6.3
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=191 Participants	-6.1	--6.5 - -5.7

Difference in Least Squares Mean (LSM)-0.497.51% CI-1.0 - 0.2p0.1133Longitudinal ANCOVA

Difference in Least Squares Mean (LSM)-0.697.51% CI-1.2 - 0.0p0.0310Longitudinal ANCOVA

Safety / tolerability / PK

8 endpoints

Primary/protocol endpoint

Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)

Time frame:Up to Week 106 (up to 2 weeks following cessation of study treatment in Part 1)

threshold achievement, event

Primary/protocol endpoint

Part 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)

Time frame:Up to Week 104 in Part 1

threshold achievement, event

Primary/protocol endpoint

Part 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)

Time frame:From Week 104 (start of treatment in Part 2) up to Week 210 (up to 2 weeks following cessation of study treatment in Part 2)

threshold achievement, event

Primary/protocol endpoint

Part 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)

Time frame:From Week 104 (start of treatment in Part 2) up to Week 208 (i.e., up to Week 104 in Part 2)

threshold achievement, event

Primary/registry result

Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)

Time frame:Up to Week 106 (up to 2 weeks following cessation of study treatment in Part 1)

threshold achievement, event

Posted result

Group	Value (number), Percentage of Participants	Reported bounds
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)n=483 Participants	91.3	-
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=484 Participants	92.1	-
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=484 Participants	87.0	-

Difference in % vs Placebo4.3295% CI0.40 - 8.31

Difference in % vs Placebo5.1795% CI1.33 - 9.09

Primary/registry result

Part 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)

Time frame:Up to Week 104 in Part 1

threshold achievement, event

Posted result

Group	Value (number), Percentage of Participants	Reported bounds
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)n=483 Participants	6.6	-
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=484 Participants	10.1	-
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=484 Participants	4.5	-

Difference in % vs Placebo2.0895% CI-0.84 - 5.10

Difference in % vs Placebo5.5895% CI2.35 - 8.99

Primary/registry result

Part 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)

Time frame:From Week 104 (start of treatment in Part 2) up to Week 210 (up to 2 weeks following cessation of study treatment in Part 2)

threshold achievement, event

Posted result

Group	Value (number), Percentage of Participants	Reported bounds
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)n=197 Participants	59.4	-
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=191 Participants	55.5	-
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=204 Participants	66.2	-

Difference in % vs Placebo-6.7995% CI-16.16 - 2.68

Difference in % vs Placebo-10.6895% CI-20.16 - -1.04

Primary/registry result

Part 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)

Time frame:From Week 104 (start of treatment in Part 2) up to Week 208 (i.e., up to Week 104 in Part 2)

threshold achievement, event

Posted result

Group	Value (number), Percentage of Participants	Reported bounds
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)n=197 Participants	1.0	-
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)n=191 Participants	1.0	-
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)n=204 Participants	3.4	-

Difference in % vs Placebo-2.4295% CI-6.03 - 0.61

Difference in % vs Placebo-2.3895% CI-6.01 - 0.71

Publications (5)

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.