Clinical trial NCT01739348: An Efficacy and Safety Trial of Verubecestat (MK-8931) in Mild to Moderate Alzheimer's Disease (P07738)
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Alzheimer's Disease
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2012-12-03
Enrollment: 2211
Sex: ALL
Minimum age (years): 55
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: [Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
timeFrame: Baseline and week 78
measure: [Part I (Base Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score
timeFrame: Baseline and week 78
measure: [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
timeFrame: Baseline and week 104
measure: [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score
timeFrame: Baseline and week 104
measure: [Part I (Base Study)] Number of Participants Who Experienced an Adverse Event
timeFrame: Up to week 80 (up to 2 weeks following cessation of study treatment in Part I)
measure: [Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event
timeFrame: From week 78 (end of treatment in Part I) up to week 262 of Part II
measure: [Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event
timeFrame: Up to week 78
measure: [Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event
timeFrame: From week 78 (end of treatment in Part I) up to week 260 of Part II
Secondary outcomes:
measure: [Part I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score
timeFrame: Baseline and week 78
measure: [Part I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV)
timeFrame: Baseline and week 78
measure: [Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau
timeFrame: Baseline and week 78
measure: [Part I (Base Study)] Change From Baseline in Cortical Amyloid Load Assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR)
timeFrame: Baseline and week 78
measure: [Part I (Base Study)] Percentage of Participants Achieving Responder Status
timeFrame: Week 78
measure: [Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score
timeFrame: Baseline and week 78
measure: [Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score
timeFrame: Baseline and week 78
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.