A Study Evaluating the Efficacy and Safety of Crenezumab Versus Placebo in Participants With Prodromal to Mild Alzheimer's Disease (AD). (CREAD)

A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy And Safety Study of Crenezumab in Patients With Prodromal to Mild Alzheimer's Disease.

This randomized, double-blind, placebo-controlled, parallel group study will evaluate the efficacy and safety of crenezumab versus placebo in participants with prodromal to mild AD. Participants will be randomized 1:1 to receive either intravenous (IV) infusion of crenezumab or placebo every 4 weeks (Q4W) for 100 weeks. The final efficacy and safety assessment will be performed 52 weeks after the last crenezumab dose. Participants will then have the option to enter the Open Label Extension (OLE) study if eligible. Participants who do not enter the OLE study will have additional follow-up visits at 16 and 52 weeks after the last dose, primarily for safety and also for limited efficacy assessments.

Study Overview

• Status: Terminated
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: Placebo; Drug: Crenezumab

• Study Type: Interventional
• Enrollment (Actual): 813
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Woodville, South Australia, Australia, 5011
      • The Queen Elizabeth Hospital; Neurology
  • Victoria
    • Caulfield, Victoria, Australia, 3162
      • Caulfield Hospital; Aged Psychiatry Research Unit
    • Heidelberg West, Victoria, Australia, 3081
      • Heidelberg Repatriation Hospital; Medical and Cognitive Research Centre
  • Western Australia
    • West Perth, Western Australia, Australia, 6005
      • Neurodegenerative Disorders Research; Neurology
• Austria
  • Linz, Austria, 4021
    • Konventhospital Barmherzige Brüder; Neurologie I
• Belgium
  • Gent, Belgium, 9000
    • UZ Gent
• Bulgaria
  • Sofia, Bulgaria, 1407
    • ACIBADEM CITY CLINIC TOKUDA HOSPITAL EAD; Clinic of Neurology and Sleep Medicine
  • Sofia, Bulgaria, 1431
    • Alexandrovska hospital; Neurology Department
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Vancouver Hospital - UBC Hospital Site
    • Victoria, British Columbia, Canada, V8R 1J8
      • Vancouver Island Health Authority
  • Ontario
    • London, Ontario, Canada, N6C 5J1
      • Parkwood Hospital; Geriatric Medicine
    • Ottawa, Ontario, Canada, K1N 5C8
      • Bruyere Continuing Care
    • Peterborough, Ontario, Canada, K9H 2P4
      • Kawartha Centre - Redefining Healthy Aging
    • Toronto, Ontario, Canada, M5T 2S8
      • Toronto Western Hospital
    • Toronto, Ontario, Canada, M4G 3E8
      • The Centre for Memory and Aging
    • Woodstock, Ontario, Canada, N4S 5P5
      • Devonshire Clinical Research Inc.
  • Quebec
    • Quebec City, Quebec, Canada, G1J 1Z4
      • CHA Hopital de I enfant-Jesus
• Costa Rica
  • San Jose, Costa Rica, 10108
    • ICIMED Instituto de Investigación en Ciencias Médicas
  • San José, Costa Rica, 10101
    • Hospital Clínica Biblica
• Croatia
  • Zagreb, Croatia, 10000
    • Clinical Hospital Centre Zagreb;Clinic for Neurology
• Czechia
  • Hradec Králové, Czechia, 500 05
    • Charles University, Medical faculty, Hradec Kralove ;Department of Neurology
  • Praha, Czechia, 110 00
    • General Teaching Hospital, Departmetn of Neurology
• Denmark
  • Aarhus N, Denmark, 8200
    • Aarhus Universitetshospital, Neurologisk Afdeling F, Demensklinikken
  • København Ø, Denmark, 2100
    • Rigshospitalet, Hukommelsesklinikken
• Finland
  • Tampere, Finland, 33100
    • Terveystalo Tampere
  • Turku, Finland, 20520
    • CRST Oy
• France
  • Bobigny, France, 93009
    • Hopital Avicenne; Neurologie
  • Bron, France, 69677
    • Hopital neurologique Pierre Wertheimer - CHU Lyon; Neurologie
  • Montpellier, France, 34295
    • Hopital Gui de Chauliac; Neurologie
  • Paris, France, 75475
    • Hôpital Lariboisière
  • Poitiers, France, 86000
    • CHU Poitiers - Hopital La Miletrie
  • Strasbourg, France, 67098
    • Hopital Hautepierre; Centre dInvestigation Clinique
  • Toulouse, France, 31059
    • CHU Toulouse - La Grave
• Germany
  • München, Germany, 80331
    • Neurologische Praxis Dr. Andrej Pauls
  • München, Germany, 81675
    • Klinikum rechts der Isar der TU München; Klinik für Psychiatrie und Psychotherapie
  • Münster, Germany, 48149
    • Universitätsklinikum Münster; Klinik und Poliklinik für Neurologie
  • Nürnberg, Germany, 90402
    • Steinwachs Klaus; Arztpraxis fur Neurologie u. Psychiatrie
  • Rostock, Germany, 18147
    • Universitätsklinikum Rostock Zentrum für Nervenheilkunde
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm; Klinik für Neurologie
  • Westerstede, Germany, 26655
    • Studienzentrum Nordwest, Dr. med. Joachim Springub / Herr Wolfgang Schwarz
  • Witten, Germany, 58455
    • Forschungszentrum Ruhr
• Hong Kong
  • Hong Kong, Hong Kong
    • Prince of Wales Hospital; Dept. of Medicine & Therapeutics
  • Hong Kong, Hong Kong
    • Queen Mary Hospital, Division of Geriatric Medicine
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis University; Department of Neurology
  • Nyíregyháza, Hungary, 4400
    • Szabolcs-Szatmár-Bereg Megyei Kórházak - Jósa András Oktatókórház; Pszichiátria
  • Szeged, Hungary, 6725
    • University of Szeged; Department of Psychiatry
  • Tatabánya, Hungary, 2800
    • Szent Borbala Korhaz; Neurologiai es Stroke Osztaly
  • VAC, Hungary, 2600
    • Jávorszky Ödön Kórház, Neurológia és stroke osztály
• Italy
  • Lazio
    • Roma, Lazio, Italy, 00186
      • Ospedale San Giovanni Calibita Fatebenefratell;Neurologia
    • Roma, Lazio, Italy, 00179
      • Fondazione Santa Lucia IRCCS; Neurologia e Riabilitazione Neurologica
  • Liguria
    • Genova, Liguria, Italy, 16128
      • Ente Ospedaliero Ospedali Galliera; Ambulatorio di Neurologia
  • Lombardia
    • Milano, Lombardia, Italy, 20144
      • Casa di Cura Policlinico; Dipartimento di Scienze Neuroriabilitative
    • Milano, Lombardia, Italy, 20148
      • Ospedale S. Maria Nascente; Fondazione Don Gnocchi; Dip. Neurologia Riabilitativa
    • Passirana, Lombardia, Italy, 20017
      • Ospedale Casati Passirana di Rho; Centro Regionale Alzheimer
  • Umbria
    • Perugia, Umbria, Italy, 06129
      • Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia; S.C. Geriatria
• Japan
  • Hiroshima, Japan, 739-0696
    • National Hospital Organization Hiroshima-Nishi Medical Center
  • Hiroshima, Japan, 728-0013
    • Miyoshi Clinic of Neurology, Hananosato
  • Kyoto, Japan, 607-8113
    • Rakuwakai Otowarehabilitation Hospital
  • Mie, Japan, 514-8507
    • Mie University Hospital
  • Nagano, Japan, 399-8701
    • National Hospital Organization Matsumoto Medical Center
  • Niigata, Japan, 949-3193
    • Saigata Medical Center
  • Okayama, Japan, 710-0813
    • Katayama Medical Clinic
  • Tokyo, Japan, 187-8551
    • National Center of Neurology and Psychiatry
  • Tokyo, Japan, 160-0023
    • Tokyo Medical University Hospital
  • Tokyo, Japan, 173-0015
    • Tokyo Metropolitan Geriatric Hospital
• Korea, Republic of
  • Gwangju, Korea, Republic of, 61469
    • Chonnam National University Hospital
  • Incheon, Korea, Republic of, 22332
    • Inha University Hospital
  • Seoul, Korea, Republic of, 05030
    • Konkuk University Medical Center
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 158-710
    • Ewha Womans University Mokdong Hospital; Dept of Neurology
  • Seoul, Korea, Republic of, 130-702
    • KyungHee Medical Center
• Lithuania
  • Vilnius, Lithuania, 08661
    • Vilnius University Hospital Santariskiu Clinic
• Mexico
  • Culiacan, Mexico, 80020
    • Hospital Angeles de Culiacán, Neurociencias Estudios Clínicos SC
  • Monterrey, Mexico, 64710
    • AVIX Investigación Clínica S.C
  • Monterrey, Mexico, 64460
    • Hospital Uni; Dr. Jose E. Gonzalez
  • Saltillo, Mexico, 25000
    • Hospital Universitario de Saltillo
• Poland
  • Białystok, Poland, 15-756
    • Podlaskie Centrum Psychogeriatrii
  • Poznań, Poland, 61-853
    • NZOZ NEURO-KARD Ilkowski i Partnerzy Sp. Partn. Lek
  • Siemianowice Śląskie, Poland, 41-100
    • NEURO-CARE Sp. z o.o. Sp. Komandytowa
  • Warszawa, Poland, 01-684
    • Centrum Medyczne Neuroprotect
  • Warszawa, Poland, 01-231
    • Przychodnia Specjalistyczna PROSEN
  • Warszawa, Poland, 01-785
    • Optimum
• Portugal
  • Amadora, Portugal, 2720-276
    • Hospital Prof. Dr. Fernando Fonseca; Servico de Neurologia
  • Loures, Portugal, 2674-514
    • Hospital Beatriz Angelo; Servico de Neurologia
• Russian Federation
  • Kazan, Russian Federation, 420021
    • State Autonomous Healthcare Institution "Republican Clinical Neurological Center
  • Kazan, Russian Federation, 420101
    • State autonomous institution of healthcare Inter-regional clinical and diagnostic center
  • Moscow, Russian Federation, 115522
    • Institution of RAMS (Mental Health Research Center of RAMS)
  • Moscow, Russian Federation, 119021
    • SBEI of HPI The 1st Moscow State Medical University n.a. I.M. Sechenov of MOH of RF
  • Saratov, Russian Federation, 410028
    • City Clinical Hospital # 2 n.a. V.I. Razumovsky
  • St Petersburg, Russian Federation, 190005
    • SHI City Psychoneurological Dispensary #7
  • St. Petersburg, Russian Federation, 194044
    • Russian Medical Military Academy n.a. S.M.Kirov; Neurology Department
• Slovenia
  • Maribor, Slovenia, 2000
    • University Medical Centre Maribor
• Spain
  • Albacete, Spain
    • Hospital General Universitario de Albacete; Servicio de Neurología
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron; Servicio de Neurología
  • Burgos, Spain, 09006
    • Hospital Universitario de Burgos. Servicio de Neurología
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre; Servicio de Neurologia
  • Madrid, Spain, 28006
    • Clinica Ruber, 4 planta; Servicio de Neurologia
  • Madrid, Spain, 28006
    • Universitario de La Princesa; Servicio de Neurología
  • Malaga, Spain, 29010
    • Hospital Regional Universitario Carlos Haya; Servicio de Neurologia
  • Murcia, Spain
    • Hospital Universitario Virgen de Arrixaca; Servicio de Neurología
  • Valencia, Spain, 46026
    • Hospital Universitario la Fe; Servicio de Neurologia
  • Zaragoza, Spain, 50012
    • Servicio de Neurología Hospital Viamed Montecanal.
  • Barcelona
    • BArcelon, Barcelona, Spain, 08034
      • Fundacio ACE
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Hospital Universitari de Bellvitge; Servicio de Neurologia
    • Manresa, Barcelona, Spain
      • Hospital Sant Joan de Deu; Servicio de Neurología
    • Sant Cugat del Valles, Barcelona, Spain, 8195
      • Hospital General De Catalunya; Servicio de Neurologia
    • Terrassa, Barcelona, Spain, 08222
      • Hospital Mutua De Terrasa; Servicio de Neurologia
  • Caceres
    • Plasencia, Caceres, Spain, 10600
      • Hospital Virgen del Puerto. Servicio de Neurología
  • Cantabria
    • Santander, Cantabria, Spain
      • Hospital Universitario Marques de Valdecilla; Servicio de Neurología
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universitaria de Navarra; Servicio de Neurología
  • Salamanca
    • Salamaca, Salamanca, Spain, 37007
      • Complejo Asistencial Universitario de Salamanca; Servicio de Psiquiatría
• Sweden
  • Malmö, Sweden, 211 46
    • Skånes Universitetssjukhus Malmö, Minneskliniken
  • Mölndal, Sweden, 431 41
    • Sahlgrenska Academy University,Neuroscience and Physiology;Departmt of Psychiatry and Neurochemistry
  • Stockholm, Sweden, 14186
    • Karolinska Uni Hospital, Huddinge; Dept. of Geriatric Med
• Switzerland
  • Basel, Switzerland, 4002
    • Universitäres Zentrum für Altersmedizin und Rehabilitation
• Turkey
  • Ankara, Turkey, 06100
    • Hacettepe University School of Medicine; Neurology
  • Eskişehir, Turkey, 26480
    • Osmangazi University School of Medicine,Neurology Department
  • Istanbul, Turkey, 34093
    • Istanbul University Istanbul School of Medicine; Neurology
  • Samsun, Turkey, 55139
    • Ondokuz Mayis University School of Medicine; Neurology
• Ukraine
  • Kiev, Ukraine, 04112
    • National Medical Academy of Postgraduate Education named after P.L.Shupik; Neurology Department #1
  • Kiev, Ukraine, 04114
    • D.F.Chebotarev Institute of Gerontology NAMS;Depart of Age Physiology&Pathology of Nervous System
  • KIEV Governorate
    • Lviv, KIEV Governorate, Ukraine, 79021
      • Regional mental hospital; Department of psychiatry, psychology and sexology
• United Kingdom
  • Blackburn, United Kingdom, PR2 9HT
    • Royal Preston Hospital
  • Chertsey, United Kingdom, KT16 0AE
    • Surrey and Borders NHS Foundation Trust; Brain Science Research Unit
  • Coventry, United Kingdom, CV6 6NY
    • Coventry and Warwickshire Partnership NHS Trust
  • London, United Kingdom, SW17 0QT
    • St George's Hospital
  • London, United Kingdom, W6 8RF
    • Charing Cross Hospital
  • Manchester, United Kingdom, M13 9WL
    • Manchester Royal Infirmary
  • Newcastle Upon Tyne, United Kingdom, NE4 6BE
    • Campus for Ageing and Vitality
  • Oxford, United Kingdom, OX3 9DU
    • John Radcliffe Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner Alzheimer's Institute
  • California
    • Encino, California, United States, 91316
      • Pharmacology Research Inst
    • Long Beach, California, United States, 90807
      • Alliance for Wellness, dba Alliance for Research
    • Long Beach, California, United States, 90502
      • Collaborative Neuroscience Network Inc.
    • Los Alamitos, California, United States, 90720
      • Pharmacology Research Institute
    • Los Angeles, California, United States, 90033
      • USC Keck School of Medicine
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center, Department of Neurology
    • Newport Beach, California, United States, 92660
      • Pharmacology Research Inst
    • Newport Beach, California, United States, 92663
      • Shankle Clinic
    • Palo Alto, California, United States, 94304
      • Stanford Univ Medical Center
    • Redlands, California, United States, 92374
      • Anderson Clinical Research, Inc.
    • Sacramento, California, United States, 95817
      • University of California, Davis; Alzheimers Disease Center, Department of Neurology
    • San Francisco, California, United States, 94158
      • UCSF - Memory and Aging Center
    • Santa Monica, California, United States, 90404
      • Neurological Research Inst
    • Sebastopol, California, United States, 95472
      • North Bay Neuro Science Institute
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Associated Neurologists PC - Danbury
    • New Haven, Connecticut, United States, 06510
      • Yale University School Of Medicine
    • New Haven, Connecticut, United States, 06510
      • Institute for Neurodegenerative Disorders
    • Norwalk, Connecticut, United States, 06851
      • Research Center for Clinical Studies, Inc.
  • Florida
    • Bradenton, Florida, United States, 34205
      • Bradenton Research Center
    • Deerfield Beach, Florida, United States, 33064
      • Quantum Laboratories
    • Delray Beach, Florida, United States, 33445
      • Brain Matters Research, Inc.
    • Hialeah, Florida, United States, 33016
      • Galiz Research, LLC
    • Jacksonville, Florida, United States, 32216
      • Jacksonville Center for Clinical Research
    • Lake Worth, Florida, United States, 33414
      • Alzheimer's Research and Treatment Center
    • Merritt Island, Florida, United States, 32952
      • Merritt - Island Medical Research
    • Miami, Florida, United States, 33137
      • Miami Jewish Health Systems
    • Ocala, Florida, United States, 34470
      • Renstar Medical Research
    • Orlando, Florida, United States, 32806
      • Bioclinica Research
    • Port Orange, Florida, United States, 32127
      • Progressive Medical Research
    • Tampa, Florida, United States, 33613
      • Stedman Clinical Trials, LLC
    • Tampa, Florida, United States, 33613
      • Johnnie B. Byrd Sr. Alzheimer's Center & Research Institute
    • The Villages, Florida, United States, 32162
      • Compass Research
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University
    • Decatur, Georgia, United States, 30033
      • NeuroStudies.net, LLC
  • Illinois
    • Elk Grove Village, Illinois, United States, 60007
      • Alexian Brothers Neurosci Inst
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University, School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Kansas
    • Prairie Village, Kansas, United States, 66206
      • MidAmerica Neuroscience Institute
  • Maine
    • Auburn, Maine, United States, 04210
      • Maine Research Associates
    • Scarborough, Maine, United States, 04074
      • MMP Neurology
  • Massachusetts
    • Springfield, Massachusetts, United States, 01104
      • Springfield Neurology Associates
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Precise Research Centers
  • New Jersey
    • Springfield, New Jersey, United States, 07081
      • The Cognitive and Research Center of New Jersey
    • Toms River, New Jersey, United States, 08755
      • Advanced Memory Research Institute of NJ
  • New York
    • Albany, New York, United States, 12208
      • Neurological Associates of Albany, PC
    • Albany, New York, United States, 12206
      • Albany Medical Faculty Physicians COmmunity Division. The Neurology Group
    • Amherst, New York, United States, 14226
      • Dent Neurological Institute
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Patchogue, New York, United States, 11772
      • South Shore Neurologic Associates P.C.
  • North Carolina
    • Charlotte, North Carolina, United States, 28211
      • Behavioral Health Research
    • Greensboro, North Carolina, United States, 27401
      • Guilford Neurologic Associates
  • Ohio
    • Centerville, Ohio, United States, 45459
      • Valley Medical Primary Care
    • Shaker Heights, Ohio, United States, 44122
      • Insight Clinical Trials LLC
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73116
      • Cutting Edge Research Group
    • Oklahoma City, Oklahoma, United States, 73112
      • Oklahoma Clinical Research
    • Tulsa, Oklahoma, United States, 74136
      • Central States Research
  • Oregon
    • Portland, Oregon, United States, 97210
      • Summit Research Network Inc.
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel Univ College of Med; Clinical Research Group
    • Willow Grove, Pennsylvania, United States, 19090
      • Abington Neurological Associates
  • Texas
    • Austin, Texas, United States, 78757
      • Senior Adults Specialty Research
    • Dallas, Texas, United States, 75231
      • Kerwin Research Center, LLC
    • Fort Worth, Texas, United States, 76107
      • University of North Texas Health Science Center; Fort Worth Patient Care Center
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Sentara Medical Group
    • Richmond, Virginia, United States, 23294
      • National Clinical Research Inc.-Richmond
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Weight between 40 and 120 kilograms (Kg) inclusive
• Availability of a person (referred to as the "caregiver") who in the investigator's judgment:
• Has frequent and sufficient contact with the participant to be able to provide accurate information regarding the participant's cognitive and functional abilities, agrees to provide information at clinic visits (which require partner input for scale completion), signs the necessary consent form, and has sufficient cognitive capacity to accurately report upon the participant's behavior and cognitive and functional abilities
• Fluency in the language of the tests used at the study site
• Adequate visual and auditory acuity, in the investigator's judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted)
• Evidence of the AD pathological process, by a positive amyloid assessment either on cerebrospinal fluid (CSF) amyloid beta 1-42 levels as measured on the Elecsys beta-amyloid(1-42) test system or amyloid PET scan by qualitative read by the core/central PET laboratory
• Demonstrated abnormal memory function at screening (up to 4 weeks before screening begins) or screening (FCSRT cueing index =<0.67 AND free recall =<27)
• Screening mini mental state examination (MMSE) score of greater than or equal to (>=) 22 points and Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 or 1.0
• Meets National Institute on Aging/Alzheimer's Association (NIAAA) core clinical criteria for probable AD dementia or prodromal AD (consistent with the NIAAA diagnostic criteria and guidelines for mild cognitive impairment (MCI)
• If receiving symptomatic AD medications, the dosing regimen must have been stable for 3 months prior to screening
• Participant must have completed at least 6 years of formal education after the age of 5 years

Exclusion Criteria:

• Any evidence of a condition other than AD that may affect cognition such as other dementias, stroke, brain damage, autoimmune disorders (e.g. multiple sclerosis) or infections with neurological sequelae.
• History of major psychiatric illness such as schizophrenia or major depression (if not considered in remission)
• At risk of suicide in the opinion of the investigator
• Any abnormal MRI findings, such as presence of cerebral vascular pathology, cortical stroke, etc or inability to tolerate MRI procedures or contraindication to MRI
• Unstable or clinically significant cardiovascular (e.g., myocardial infarction), kidney or liver disease
• Uncontrolled hypertension
• Screening hemoglobin A1c (HbA1C) >8%
• Poor peripheral venous access
• History of cancer except:

If considered to be cured or If not being actively treated with anti-cancer therapy or radiotherapy

- Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Drug: Placebo; Placebo was administered by intravenous (IV) infusion at 60mg/kg as per the dosing schedule described above.
Experimental: Crenezumab; Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.	Drug: Crenezumab; Crenezumab was administered by intravenous (IV) infusion at 60mg/kg as per the dosing schedule described above.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score	The CDR-SB rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment = 0, questionable impairment = 0.5 and mild, moderate and severe impairment = 1, 2 and 3 respectively. The score range is from 0 to 18 with a high score indicating a high disease severity. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline for this primary endpoint. Data after 29 January 2019 are censored for the primary and secondary efficacy analyses to avoid potential biases due to investigators, participants, raters, etc. being potentially influenced by early closure of the study due to lack of efficacy.	Baseline, Week 105

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 105 on Cognition, as Assessed by Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) (Subscale) 13 (ADAS-Cog-13)	The ADAS-Cog-13 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 further items: delayed word recall and total digit cancellation. The score range for ADAS-Cog-13 is from 0 to 85 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline, Week 105
Change From Baseline to Week 105 on Cognition, as Assessed by Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) (Subscale) 11 (ADAS-Cog-11)	The ADAS-Cog-11 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The score range for ADAS-Cog-11 is from 0 to 70 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline, Week 105
Change From Baseline to Week 105 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS)	The CDR-GS represents a semi-structured interview which rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care) on a 5-point scale in which CDR 0 = no dementia and CDR 0.5, 1, 2 or 3 = questionable, mild, moderate or severe dementia respectively. The range in scores for the CDR-GS is from 0 to 3 and a high score on the CDR-GS would indicate a high disease severity. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline, Week 105
Change From Baseline to Week 105 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE)	The MMSE is a set of standardized questions used to evaluate possible cognitive impairment and help stage the severity level of this impairment. The questions target 6 areas: orientation, registration, attention, short-term recall, language and constructional praxis/visuospatial abilities. The scores on the MMSE range from 0 to 30, with higher scores indicating better function. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline, Week 105
Change From Baseline to Week 105 on Function as Assessed by the ADCS-ADL Total Score	The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline, Week 105
Change From Baseline to Week 105 on Function as Assessed by the ADCS-instrumental (ADCS-iADL) Subscore	The ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) measures activities such as using the telephone, managing finances and preparing a meal. The ADCS-iADL consists of 16 questions with a score range of 0 to 56 where a higher score represents better function. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline, Week 105
Change From Baseline to Week 105 on a Measure of Dependence Derived From the ADCS-ADL Score	The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline, Week 105
Change From Baseline to Week 105 Assessed Using the Neuropsychiatric Inventory Questionnaire (NPI-Q)	The NPI-Q is an informant-based instrument that evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavioral disturbances and appetite and eating abnormalities. The severity of each neuropsychiatric symptom is rated on a 3-point scale (mild, moderate and marked). The total severity score range is from 0 to 36 with higher scores representing higher severity. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline, Week 105
Quality of Life-Alzheimer's Disease (QoL-AD) Scale Score	The QoL-AD (Quality of Life - Alzheimer's Disease) scale assesses QoL in participants who have dementia. The QoL-AD consists of 13 items covering aspects of participants' relationships with friends and family, physical condition, mood, concerns about finances and overall assessment of QoL. Items are rated on 4-point Likert-type scales ranging from 1 [poor] to 4 [excellent]. The score range is from 13 to 52, with higher scores indicating a better QoL. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline up to Week 105
Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) Scale Score	The ZCI-AD is a modified version of the Zarit Burden Interview, which was originally designed to reflect the stresses experienced by caregivers of people with dementia. This modified version includes slight modifications in item and title wording (e.g., removal of "your relative" to refer directly to the patient, removal of "burden" from title) and the use of 11-point numerical rating scales. The ZCI-AD scale consists of a total of 30 items. Total scores will be calculated with a total score range from 0 to 300 (higher scores indicate a higher burden on the caregiver). The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline up to Week 105
EQ-5D Questionnaire Domain Score for Participants	The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline up to Week 105
EQ-5D Questionnaire Domain Score for Caregivers	The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline up to Week 105
Percentage of Participants With Adverse Event (AEs) and Serious Adverse Event (SAEs)	An Adverse Event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	Baseline up until 16 weeks after the last dose of study drug (up to 117 weeks).
Percentage of Participants With Anti-Crenezumab Antibodies	Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for Crenezumab and Placebo groups. The prevalence of ADA at baseline was calculated as the proportion of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the proportion of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis.	Baseline up to Week 105
Serum Concentration of Crenezumab	Serum concentration data for Crenezumab will be tabulated and summarized. Descriptive summary statistics will include the arithmetic mean and SD. Since a sparse PK sampling design is being used, population (non-linear mixed-effects) modeling will be used to analyze the dose concentration-time data of crenezumab. Information from other clinical studies may be incorporated to establish the PK model. Please note that Post-dose samples were not collected at Weeks 37 and 105.	Pre-infusion (0 hour), 60-90 minutes post-infusion on Day 1 Week 1 and on Week 25; Weeks 13, 37 (Pre-dose), 53, 77 and 105 (infusion length = as per the Pharmacy Manual)
Plasma Amyloid Beta (Abeta) 40 Concentrations	Plasma Abeta 40 concentrations will be measured over time and descriptive summary statistics will include the arithmetic mean and SD. Please note that a Post-dose sample was only collected at Week 13.	Week 1 Day 1; Weeks 13, 25, 53, 77 and 105
Plasma Amyloid Beta (Abeta) 42 Concentrations	Plasma Abeta 42 concentrations will be measured over time and descriptive summary statistics will include the arithmetic mean and SD. Please note that a Post-dose sample was only collected at Week 13.	Week 1 Day 1; Weeks 13, 25, 53, 77 and 105
Percentage Change From Baseline to Week 105 in Whole Brain Volume as Determined by Magnetic Resonance Imaging (MRI)	Percentage Change in Whole Brain Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline, Week 105
Percentage Change From Baseline to Week 105 in Ventricle Volume as Determined by Magnetic Resonance Imaging (MRI)	Percentage Change in Ventricle Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline, Week 105
Percentage Change From Baseline to Week 105 in Hippocampal Volume as Determined by Magnetic Resonance Imaging (MRI)	Percentage Change in Hippocampal Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.	Baseline, Week 105

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Ostrowitzki S, Bittner T, Sink KM, Mackey H, Rabe C, Honig LS, Cassetta E, Woodward M, Boada M, van Dyck CH, Grimmer T, Selkoe DJ, Schneider A, Blondeau K, Hu N, Quartino A, Clayton D, Dolton M, Dang Y, Ostaszewski B, Sanabria-Bohorquez SM, Rabbia M, Toth B, Eichenlaub U, Smith J, Honigberg LA, Doody RS. Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials. JAMA Neurol. 2022 Nov 1;79(11):1113-1121. doi: 10.1001/jamaneurol.2022.2909.

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2016
• Primary Completion (Actual): May 31, 2019
• Study Completion (Actual): May 31, 2019

Study Registration Dates

• First Submitted: January 28, 2016
• First Submitted That Met QC Criteria: January 28, 2016
• First Posted (Estimate): February 1, 2016

Study Record Updates

• Last Update Posted (Actual): July 16, 2020
• Last Update Submitted That Met QC Criteria: July 1, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: BN29552; 2015-003034-27 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No