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

NCT01739348 | Terminated Phase 2 Results DMC

• 4 other identifiers: P07738MK-8931-0172011-003151-20132229
• Study Type: interventional
• Target: 2,211
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study consists of two parts, Part I and Part II. The purpose of Part I of the study is to assess the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 78 weeks in the treatment of Alzheimer's Disease (AD). The primary study hypotheses for Part I are that at least one verubecestat dose is superior to placebo at 78 weeks of treatment with respect to change from baseline in Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) score and that at least one verubecestat dose is superior to placebo at 78 weeks of treatment with respect to change from baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) score. The first approximately 400 participants entering Part I of the study are identified as the Safety Cohort. Participants who complete Part I of the study may choose to participate in Part II, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks.

Conditions

Alzheimer's Disease

Outcome Measures

Primary Outcomes (8)

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

  Least squares mean change from baseline at week 78 was assessed for the ADAS-Cog score. ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog score.

  Baseline and week 78

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

  Least squares mean change from baseline at week 78 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. 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.

  Baseline and week 78

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

  Mean change from baseline at week 104 was assessed for the ADAS-Cog score. ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog score. Per study protocol, the baseline measurement to be used was the baseline measurement obtained in Part I.

  Baseline and week 104

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

  Mean change from baseline at week 104 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. 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. Per study protocol, the baseline measurement to be used was the baseline measurement obtained in Part I.

  Baseline and week 104

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

  The number of participants experiencing an adverse event (AE) in Part I 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 80 (up to 2 weeks following cessation of study treatment in Part I)

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

  The number of participants experiencing an adverse event (AE) in Part II 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 78 (end of treatment in Part I) up to week 262 of Part II

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

  The number of participants discontinuing from study drug due to an AE in Part I 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 78

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

  The number of participants discontinuing from study drug due to an AE in Part II 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 78 (end of treatment in Part I) up to week 260 of Part II

Secondary Outcomes (7)

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

  Baseline and week 78

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

  Baseline and week 78

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

  Baseline and week 78

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

  Baseline and week 78

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

  Week 78

Study Arms (4)

Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]

EXPERIMENTAL

\[Part I\] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). \[Part II\] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.

Drug: Verubecestat (Part I and Part II)

Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]

EXPERIMENTAL

\[Part I\] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). \[Part II\] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

Drug: Verubecestat (Part I and Part II)

Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]

EXPERIMENTAL

\[Part I\] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). \[Part II\] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

Drug: Verubecestat (Part I and Part II)

Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]

PLACEBO COMPARATOR

\[Part I\] Placebo once daily for 78 weeks in Study Part I (Base Study). \[Part II\] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

Drug: Placebo (Part I); Drug: Verubecestat (Part II)

Interventions

Verubecestat (Part I and Part II) DRUG

Single 12 mg verubecestat tablet once daily, taken orally

Also known as: SCH 900931

Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]

Placebo (Part I) DRUG

Single placebo tablet matching verubecestat treatment once daily, taken orally

Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]

Verubecestat (Part II) DRUG

Single 40 mg verubecestat tablet once daily, taken orally

Also known as: SCH 900931

Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]

Eligibility Criteria

• Age: 55 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (7)

• Sur C, Adamczuk K, Scott D, Kost J, Sampat M, Buckley C, Farrar G, Newton B, Suhy J, Bennacef I, Egan MF. Evaluation of 18F-flutemetamol amyloid PET image analysis parameters on the effect of verubecestat on brain amlyoid load in Alzheimer's disease. Mol Imaging Biol. 2022 Dec;24(6):862-873. doi: 10.1007/s11307-022-01735-z. Epub 2022 Jul 7.

  PMID: 35794343 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

• Sur C, Kost J, Scott D, Adamczuk K, Fox NC, Cummings JL, Tariot PN, Aisen PS, Vellas B, Voss T, Mahoney E, Mukai Y, Kennedy ME, Lines C, Michelson D, Egan MF. BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain. Brain. 2020 Dec 1;143(12):3816-3826. doi: 10.1093/brain/awaa332.

  PMID: 33253354 DERIVED

• Sergott RC, Raji A, Kost J, Sur C, Jackson S, Locco A, Patel A, Furtek C, Mattson B, Egan MF. Retinal Optical Coherence Tomography Metrics Are Unchanged in Verubecestat Alzheimer's Disease Clinical Trial but Correlate with Baseline Regional Brain Atrophy. J Alzheimers Dis. 2021;79(1):275-287. doi: 10.3233/JAD-200735.

  PMID: 33252075 DERIVED

• Egan MF, Mukai Y, Voss T, Kost J, Stone J, Furtek C, Mahoney E, Cummings JL, Tariot PN, Aisen PS, Vellas B, Lines C, Michelson D. Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer's disease. Alzheimers Res Ther. 2019 Aug 7;11(1):68. doi: 10.1186/s13195-019-0520-1.

  PMID: 31387606 DERIVED

• Egan MF, Kost J, Tariot PN, Aisen PS, Cummings JL, Vellas B, Sur C, Mukai Y, Voss T, Furtek C, Mahoney E, Harper Mozley L, Vandenberghe R, Mo Y, Michelson D. Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease. N Engl J Med. 2018 May 3;378(18):1691-1703. doi: 10.1056/NEJMoa1706441.

  PMID: 29719179 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 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 29, 2012
• First Posted: December 3, 2012
• Study Start: November 30, 2012
• Primary Completion: April 14, 2017
• Study Completion: April 14, 2017
• Last Updated: October 24, 2018
• Results First Posted: May 16, 2018

Record last verified: 2018-09

Data Sharing

• IPD Sharing: Will share