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

Study Results

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Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE2/PHASE3

Total Enrollment

2211 participants

Study Classification

INTERVENTIONAL

Study Start Date

2012-11-30

Study Completion Date

2017-04-14

Brief Summary

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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.

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Detailed Description

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Two substudies are included in Part I of the study: 1) a medical imaging substudy to evaluate changes in brain amyloid protein load using positron emission tomography (PET) and an amyloid tracer (\[18F\]flutemetamol); and 2) a cerebrospinal fluid (CSF) biomarker substudy to evaluate changes in CSF concentrations of amyloid-β related peptides, total tau, and phosphorylated tau (p-tau). The substudies will be conducted only at designated investigational sites. Participants are not required to take part in a substudy in order to take part in the larger trial.

Conditions

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Alzheimer's Disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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

\[Part I\] 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.

Group Type EXPERIMENTAL

Verubecestat (Part I and Part II)

Intervention Type DRUG

Single 12 mg verubecestat tablet once daily, taken orally

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

\[Part I\] 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.

Group Type EXPERIMENTAL

Verubecestat (Part I and Part II)

Intervention Type DRUG

Single 40 mg verubecestat tablet once daily, taken orally

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

\[Part I\] 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.

Group Type EXPERIMENTAL

Verubecestat (Part I and Part II)

Intervention Type DRUG

Single 60 or 40 mg verubecestat tablet once daily, taken orally

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

\[Part I\] 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.

Group Type PLACEBO_COMPARATOR

Placebo (Part I)

Intervention Type DRUG

Single placebo tablet matching verubecestat treatment once daily, taken orally

Verubecestat (Part II)

Intervention Type DRUG

Single 40 mg verubecestat tablet once daily, taken orally

Interventions

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Verubecestat (Part I and Part II)

Single 12 mg verubecestat tablet once daily, taken orally

Intervention Type DRUG

Verubecestat (Part I and Part II)

Single 40 mg verubecestat tablet once daily, taken orally

Intervention Type DRUG

Verubecestat (Part I and Part II)

Single 60 or 40 mg verubecestat tablet once daily, taken orally

Intervention Type DRUG

Placebo (Part I)

Single placebo tablet matching verubecestat treatment once daily, taken orally

Intervention Type DRUG

Verubecestat (Part II)

Single 40 mg verubecestat tablet once daily, taken orally

Intervention Type DRUG

Other Intervention Names

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SCH 900931 SCH 900931 SCH 900931 SCH 900931

Eligibility Criteria

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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

* 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

* 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

* 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

Minimum Eligible Age

55 Years

Maximum Eligible Age

85 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No