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

NCT01953601 | Terminated Phase 3 Results DMC

• 4 other identifiers: 8931-0192012-005542-38142502MK-8931-019
• Study Type: interventional
• Target: 1,454
• Locations: 0 countries
• Sites: N/A

Brief 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. 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.

Conditions

Amnestic Mild Cognitive Impairment; Alzheimer's Disease; Prodromal Alzheimer's Disease

Outcome Measures

Primary Outcomes (6)

• 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.

  Baseline and Week 104 in Part 1

• 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.

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

• 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.

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

• 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.

  Up to Week 104 in Part 1

• 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.

  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)

• 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.

  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)

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

  Up to Week 104 in Part 1

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

  Week 13 and Week 104 in Part 1

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

  Baseline and Week 104 in Part 1

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

  Baseline and Week 104 in Part 1

• 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

  Baseline and Week 104 in Part 1

Study Arms (3)

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.

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.

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.

Drug: Verubecestat 40 mg (Parts 1 and 2); Other: Placebo (Part 1)

Interventions

Verubecestat 12 mg (Parts 1 and 2) DRUG

Verubecestat 12 mg oral tablet, given once daily.

Also known as: MK-8931

Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)

Verubecestat 40 mg (Parts 1 and 2) DRUG

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

Also known as: MK-8931

Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2); Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)

Placebo (Part 1) OTHER

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

Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (5)

• 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.

  PMID: 36744336 DERIVED

• 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.

  PMID: 35384522 DERIVED

• 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.

  PMID: 33049114 DERIVED

• 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.

  PMID: 30970186 DERIVED

• 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.

  PMID: 27807285 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Interventions

verubecestat

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 25, 2013
• First Posted: October 1, 2013
• Study Start: November 5, 2013
• Primary Completion: April 17, 2018
• Study Completion: April 17, 2018
• Last Updated: May 17, 2019
• Results First Posted: May 17, 2019

Record last verified: 2019-05