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Amnestic Mild Cognitive ImpairmentPhase 3APECSNCT01953601

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

A Phase 3 study testing Verubecestat 12 mg (Parts 1 and 2) and Verubecestat 40 mg (Parts 1 and 2) in people with Amnestic Mild Cognitive Impairment and Alzheimer's Disease, run by Merck Sharp & Dohme LLC.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This study consists of two parts, Part 1 and Part 2. Part 1 assesses the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 104 weeks in the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer's Disease (AD), also known as prodromal AD. Read more about this study

Who is it for?
Ages 50 to 85 years
What is being tested?
Verubecestat 12 mg (Parts 1 and 2) and Verubecestat 40 mg (Parts 1 and 2)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
1,454 participants
Where
No sites listed yet
Study dates
5 Nov 2013to 17 Apr 2018
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 50 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Diagnosis of prodromal AD, including the following:
  • History of subjective memory decline with gradual onset and slow progression for at least one year corroborated by an informant,
  • Objective impairment in episodic memory by memory test performed at Screening,
  • Does not meet criteria for dementia, AND
  • 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)
  • Able to read at a 6th grade level or equivalent
Show all 10Show fewer
  • If participant is receiving an acetylcholinesterase inhibitor or memantine, the dose must have been stable for at least three months before Screening
  • 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
  • Tolerated study drug and completed the initial 104-week period of the trial (Part 1)
  • Participant must have a reliable and competent trial partner who must have a close relationship with the subject

Who cannot join

  • History of stroke
  • Evidence of a clinically relevant neurological disorder other than the disease being studied (i.e., prodromal AD)
  • History of seizures or epilepsy within the last 5 years
  • 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
Show all 23Show fewer
  • 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 6 months prior to Screening
  • Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of Screening
  • 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
  • Clinically significant vitamin B12 or folate deficiency in the 6 months before Screening
  • Use of any investigational drugs or participation in clinical trials within the 30 days before Screening
  • History of a hypersensitivity reaction to more than three drugs
  • Has human immunodeficiency virus (HIV) by medical history
  • Participant is unwilling or has a contraindication to undergo PET scanning including but not limited to claustrophobia, excessive weight or girth
  • 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
  • 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
  • Participant is at imminent risk of self-harm or of harm to others
  • Has developed a recent or ongoing, uncontrolled, clinically significant medical or psychiatric condition
  • Results of safety assessments (e.g., laboratory tests) performed in participant at end of Part 1 that are clinically unacceptable to the Investigator
  • Has developed a form of dementia that is not AD
  • Has progressed to dementia due to AD per investigator diagnosis in the initial 104-week study (Part 1).
  • 1. Had one or two PET scans with MK-6240 in the initial 104-week study.

About this study

Official title: 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)

This study consists of two parts, Part 1 and Part 2. Part 1 assesses the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 104 weeks in the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer's Disease (AD), also known as prodromal AD. Participants are randomized to receive placebo, or 12 mg or 40 mg verubecestat, once daily. The primary study hypothesis for Part 1 is that ≥1 verubecestat dose is superior to placebo with respect to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score at 104 weeks. Participants completing Part 1 may choose to participate in Part 2, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks. In Part 2, all participants receive either 12 mg or 40 mg verubecestat, once daily.

Read the detailed description

As a result of protocol amendment, Study Part 2 will contain a Positron Emission Tomography (PET) imaging substudy to assess regional neurofibrillary tangle (NFT) expression.

Being tested
Verubecestat 12 mg (Parts 1 and 2), Verubecestat 40 mg (Parts 1 and 2), Placebo (Part 1)
Medical subject headings
Alzheimer Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Verubecestat 12 mg (Parts 1 and 2)Drug

    Also called MK-8931

    Verubecestat 12 mg oral tablet, given once daily.

  • Verubecestat 40 mg (Parts 1 and 2)Drug

    Also called MK-8931

    Verubecestat 40 mg oral tablet, given once daily. Verubecestat 40 mg given to participants in Arm C continuing to study Part 2.

  • Placebo (Part 1)Other

    Placebo matching verubecestat, given once daily as an oral tablet.

Study groups in NCT01953601
Study groupRoleWhat they receive
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)Experimental[Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.
Receives: Drug: Verubecestat 12 mg (Parts 1 and 2)
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)Experimental[Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
Receives: Drug: Verubecestat 40 mg (Parts 1 and 2)
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)Placebo comparator[Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
Receives: Drug: Verubecestat 40 mg (Parts 1 and 2); Other: Placebo (Part 1)

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    LSM change from baseline at week 104 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant's caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score.

    Measured: Baseline and Week 104 in Part 1

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

    Mean change from baseline at week 130 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant's caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score. Per protocol, baseline refers to the baseline measurement obtained in Part 1.

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

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

    The percentage of participants experiencing an AE in Part 1 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.

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

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

    The percentage of participants who discontinued from study drug due to an AE in Part 1 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.

    Measured: Up to Week 104 in Part 1

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

    The percentage of participants experiencing an AE in Part 2 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.

    Measured: 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)

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

    The percentage of participants who discontinued from study drug due to an AE in Part 2 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.

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

Secondary outcomes (7)

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

    The event-rate per 100 participant-years for progression to a clinical diagnosis of probable AD dementia was calculated. Adjudication of a potential case was triggered if either: 1) in the investigator's own expert judgment, they think the participant may have progressed to dementia and/or 2) the participant's CDR-SB score is ≥2 points higher compared to baseline. Cases of progression to probable AD dementia confirmed by an external adjudication committee were counted as events in the analysis. The event-rate was calculated as the number of events divided by total follow-up time (participant-years) x 100; unit of measure is event-rate / 100 participant-years.

    Measured: Up to Week 104 in Part 1

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

    LSM difference between weeks 104 and 13 was estimated for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment / problem solving; community affairs; home / hobbies; and personal care. For each domain, degree of impairment is scored by a semi-structured interview of the participant and the participant's caregiver (domain score range: 0 [no impairment] to 3 [severe impairment]). Domain scores sum to a total CDR-SB score (range: 0-18); higher scores indicate more severe cognitive impairment. Further, increased cognitive impairment is reflected by higher CDR-SB scores; larger differences between week 104 and week 13 scores indicates accelerated AD progression.

    Measured: Week 13 and Week 104 in Part 1

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

    CCS-3D is composed of individual cognitive tests, grouped into 3 domains: 1) episodic memory; 2) executive function; and 3) attention/processing speed. For each cognitive test, a z-score (Z) is calculated at each time point [Z = (observed value - study population mean at baseline) / study population standard deviation at baseline]. These individual Zs are first combined into domain-specific Zs, and then into a composite Z, (i.e. CCS-3D). Theoretically, 99.9% of CCS-3D will be ± 3; more positive CCS-3D indicate greater cognitive impairment relative to the total study population at baseline. Further, negative changes in CCS-3D over time indicate improved cognition relative to the total study population at baseline.

    Measured: Baseline and Week 104 in Part 1

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

    Least squares mean percent change from baseline at week 104 was calculated for THV as measured by volumetric magnetic resonance imaging (vMRI). Negative percent changes from baseline indicate decreases in THV (i.e. increased hippocampal atrophy).

    Measured: Baseline and Week 104 in Part 1

  5. 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

    [18F]Flutemetamol PET SUVR measures brain cortical amyloid load. The PET tracer [18F]Flutemetamol was given intravenously (IV). After 90 minutes, participants were scanned for 20 minutes. Using the PET scan images, SUVRs, the ratio of tracer signal in a specific region compared to a reference region (RR; subcortical white matter) are calculated for brain regions of interest (ROIs). SUVRs from a selected set of brain regions are averaged to compute a composite SUVR. Higher composite SUVR values indicate increased amyloid load in selected brain regions, with negative changes in composite cortical SUVR over time indicating decreases in brain amyloid load.

    Measured: Baseline and Week 104 in Part 1

  6. 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

    Least squares mean change from baseline at week 104 was assessed for the ADCS-ADL MCI score. The ADCS-ADL MCI is an 18-item assessment of recent, observed performance of activities of daily living administered to participants' trial partners in an interview format. For the 18 items, scores range from 0 (no independence) to (depending on the item) either 2 (5 items), 3 (9 items), or 4 (4 items), with higher scores indicating greater independence in activity performance. Scores from individual items sum to a total ADCS-ADL score (range: 0-53). Lower scores indicate less independence in activity performance and, as a result, greater AD severity. Further, increases in AD severity over time would be reflected by decreases in ADCS-ADL score.

    Measured: Baseline and Week 104 in Part 1

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

    Mean percent change from baseline at week 104 was calculated for Total Tau concentration in CSF, a measure of brain tau pathology. Per protocol, CSF Total Tau concentration was analyzed as part of a substudy in Part 1, with testing occurring only at select trial sites.

    Measured: Baseline and Week 104 in Part 1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Oct 2013 (estimated)
  2. Study start5 Nov 2013
  3. Primary completion17 Apr 2018
  4. Study completion17 Apr 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
1,454 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01953601
Sponsor's protocol ID
8931-019
Other IDs
2012-005542-38, 142502, MK-8931-019
Acronym
APECS
Status last verified
May 2019
First submitted
25 Sep 2013
Last updated
17 May 2019
Data monitoring committee
Yes

Publications

  • Voss T, Kost J, Mercer SP, Furtek C, Randolph C, Lines C, Egan MF, Cummings JL. Progression from Prodromal Alzheimer's Disease to Mild Alzheimer's Disease Dementia in the Verubecestat APECS Study: Adjudicating Diagnostic Transitions. J Alzheimers Dis. 2023;92(1):341-348. doi: 10.3233/JAD-220836.

    PubMed 36744336

  • Dockendorf MF, Jaworowicz D, Humphrey R, Anderson M, Breidinger S, Ma L, Taylor T, Dupre N, Jones C, Furtek C, Kantesaria B, Bateman KP, Woolf E, Egan MF, Stone JA. A Model-Based Approach to Bridging Plasma and Dried Blood Spot Concentration Data for Phase 3 Verubecestat Trials. AAPS J. 2022 Apr 6;24(3):53. doi: 10.1208/s12248-022-00682-5.

    PubMed 35384522

  • Wessels AM, Lines C, Stern RA, Kost J, Voss T, Mozley LH, Furtek C, Mukai Y, Aisen PS, Cummings JL, Tariot PN, Vellas B, Dupre N, Randolph C, Michelson D, Andersen SW, Shering C, Sims JR, Egan MF. Cognitive outcomes in trials of two BACE inhibitors in Alzheimer's disease. Alzheimers Dement. 2020 Nov;16(11):1483-1492. doi: 10.1002/alz.12164. Epub 2020 Oct 13.

    PubMed 33049114

  • Egan MF, Kost J, Voss T, Mukai Y, Aisen PS, Cummings JL, Tariot PN, Vellas B, van Dyck CH, Boada M, Zhang Y, Li W, Furtek C, Mahoney E, Harper Mozley L, Mo Y, Sur C, Michelson D. Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease. N Engl J Med. 2019 Apr 11;380(15):1408-1420. doi: 10.1056/NEJMoa1812840.

    PubMed 30970186

  • Kennedy ME, Stamford AW, Chen X, Cox K, Cumming JN, Dockendorf MF, Egan M, Ereshefsky L, Hodgson RA, Hyde LA, Jhee S, Kleijn HJ, Kuvelkar R, Li W, Mattson BA, Mei H, Palcza J, Scott JD, Tanen M, Troyer MD, Tseng JL, Stone JA, Parker EM, Forman MS. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS beta-amyloid in animal models and in Alzheimer's disease patients. Sci Transl Med. 2016 Nov 2;8(363):363ra150. doi: 10.1126/scitranslmed.aad9704.

    PubMed 27807285

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Verubecestat 12 mg (Parts 1 and 2) and Verubecestat 40 mg (Parts 1 and 2) in people with Amnestic Mild Cognitive Impairment and Alzheimer's Disease, run by Merck Sharp & Dohme LLC.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 17 May 2019. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 May 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01953601, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 May 2019.

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