Evidence map›Paper›PMID 29719179›Full record

Trial reportThe New England journal of medicine2018

Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease.

Michael F Egan, James Kost, Pierre N Tariot, Paul S Aisen, Jeffrey L Cummings, Bruno Vellas, Cyrille Sur, Yuki Mukai, Tiffini Voss, Christine Furtek and 5 more

Registry-linked trialAbstract readClinical Trial, Phase IIIMulticenter StudyRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in The New England journal of medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01739348 (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), which is not on this map. Cited by 323 papers, 7 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
323citing papers in PubMed, 7 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01739348 phase2 / phase3terminatednot on this map

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)

TypeinterventionalSponsorMerck Sharp & Dohme LLCRan2012 to 2017Enrolled2,211ConditionsAlzheimer's DiseaseArmsVerubecestat (Part I and Part II), Placebo (Part I), Verubecestat (Part II)
3 · Its place in the literature

Who cites it

323 citing papers in PubMed, 7 syntheses or guidelines pooled it.

  1. Evaluating the Use of Anxiety Patient-Reported Outcome Measures (PROMs) in Dementia Clinical Trials: A Systematic Review.Health expectations : an international journal of public participation in health care and health policy · 2026
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  8. Regional effects of gantenerumab on neuroimaging biomarkers in the DIAN-TU-001 trial.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
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  16. Association of CSF AβNeurology · 2022
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263 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

15 authors.

Michael F EganFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
James KostFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
Pierre N TariotFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
Paul S AisenFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
Jeffrey L CummingsFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
Bruno VellasFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
Cyrille SurFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
Yuki MukaiFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
Tiffini VossFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
Christine FurtekFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
Erin MahoneyFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
Lyn Harper MozleyFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
Rik VandenbergheFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
Yi MoFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).
David MichelsonFrom Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer's Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, and Neurology, University Hospitals - both in Leuven, Belgium (R.V.).

Funding

Renewal of Centers of Biomedical Research Excellence (COBRE) (Phase 2) CNTN - ResubmissionP20GM109025 · NIGMS · CLEVELAND CLINIC FOUNDATION · PI JESSICA KIRKLAND CALDWELL · 2015 to 2026
$22.8M
NIGMS NIH HHS P20 GM109025
6 · The paper itself

Abstract

backgroundAlzheimer's disease is characterized by the deposition of amyloid-beta (Aβ) plaques in the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein by β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aβ level in the cerebrospinal fluid of patients with Alzheimer's disease.

methodsWe conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function).

resultsA total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group.

conclusionsVerubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer's disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).

Indexed as

Activities of Daily LivingAgedAged, 80 and overAlzheimer DiseaseAmyloid beta-PeptidesAmyloid Precursor Protein SecretasesAspartic Acid EndopeptidasesBiomarkersBrain ChemistryCognitionCyclic S-OxidesDose-Response Relationship, DrugDouble-Blind MethodFemaleHumansMaleAmyloid beta-PeptidesAmyloid Precursor Protein SecretasesAspartic Acid EndopeptidasesBACE1 protein, humanBiomarkersCyclic S-OxidesThiadiazinesverubecestat

Identifiers

PMID29719179
PMCPMC6776074

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.