Overview

This trial is active, not recruiting.

Condition alzheimer's disease
Treatments verubecestat (part i and part ii), placebo (part i), verubecestat (part ii)
Phase phase 2/phase 3
Sponsor Merck Sharp & Dohme Corp.
Start date November 2012
End date June 2017
Trial size 2221 participants
Trial identifier NCT01739348, 132229, 2011-003151-20, MK-8931-017, P07738

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking double blind (subject, investigator)
Primary purpose treatment
Arm
(Experimental)
Verubecestat 12 mg once daily for 78 weeks (Part I). Participants who complete Part I may continue to receive verubecestat 12 mg once daily for up to an additional 260 weeks (Part II).
verubecestat (part i and part ii) SCH 900931
Single 12 mg verubecestat tablet once daily, taken orally
(Experimental)
Verubecestat 40 mg once daily for 78 weeks (Part I). Participants who complete Part I may continue to receive verubecestat 40 mg once daily for up to an additional 260 weeks (Part II).
verubecestat (part i and part ii) SCH 900931
Single 40 mg verubecestat tablet once daily, taken orally
(Experimental)
Verubecestat 60 mg once daily until the first interim analysis in Part 1 of study. Based on results of the first interim analysis, conducted when the first 200 participants in all study treatment groups combined reach 13 weeks of treatment or discontinue study before 13 weeks, participants in this group will be switched to verubecestat 40 mg once daily, for remainder of Part I (total dosing period of 78 weeks). Participants who complete Part I may continue to receive verubecestat 40 mg once daily for up to an additional 260 weeks (Part II).
verubecestat (part i and part ii) SCH 900931
Single 60 or 40 mg verubecestat tablet once daily, taken orally
(Placebo Comparator)
Placebo once daily for 78 weeks (Part I). Participants who complete Part I may receive verubecestat 40 mg once daily for up to 260 weeks (Part II).
placebo (part i)
Single placebo tablet matching verubecestat treatment once daily, taken orally
verubecestat (part ii) SCH 900931
Single 40 mg verubecestat tablet once daily, taken orally

Primary Outcomes

Measure
Change from baseline in ADAS-Cog score
time frame: Baseline and week 78
Change from baseline in ADCS-ADL score
time frame: Baseline and week 78
Extension period (Part II): Change from baseline in ADAS-Cog score
time frame: Baseline and week 104
Extension period (Part II): Change from baseline in ADCS-ADL score
time frame: Baseline and week 104

Secondary Outcomes

Measure
Change from baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) score
time frame: Baseline and week 78
Change from baseline in total hippocampal volume
time frame: Baseline and week 78
Change from baseline in cerebrospinal fluid (CSF) total tau
time frame: Baseline and week 78
Change from baseline in brain amyloid load
time frame: Baseline and week 78
Percentage of Responders
time frame: Week 78
Change from baseline in Neuropsychiatric Inventory (NPI) score
time frame: Baseline and week 78
Change from baseline in Mini-Mental State Examination (MMSE) score
time frame: Baseline and week 78

Eligibility Criteria

Male or female participants from 55 years up to 85 years old.

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 Inclusion Criteria for Extension Period (Part II): - 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 Additional Exclusion Criteria for Safety Cohort: - 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 Exclusion Criteria for Extension Period (Part II): - 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

Additional Information

Official title A Randomized, Placebo Controlled, Parallel-Group, Double Blind Efficacy and Safety Trial of MK-8931 With a Long Term Double-Blind Extension in Subjects With Mild to Moderate Alzheimer's Disease (Protocol No. MK-8931-017-10)(Also Known as SCH 900931, P07738)
Description 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.
Trial information was received from ClinicalTrials.gov and was last updated in October 2016.
Information provided to ClinicalTrials.gov by Merck Sharp & Dohme Corp..