A Study Evaluating the Efficacy and Safety of Crenezumab Versus Placebo in Participants With Prodromal to Mild Alzheimer's Disease (AD).
- Registration Number
- NCT02670083
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 813
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks. Crenezumab Crenezumab Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
- Primary Outcome Measures
Name Time Method Change From Baseline to Week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score Baseline, Week 105 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.
- Secondary Outcome Measures
Name Time Method Change From Baseline to Week 105 on Cognition, as Assessed by Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) (Subscale) 11 (ADAS-Cog-11) Baseline, Week 105 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.
Change From Baseline to Week 105 on Function as Assessed by the ADCS-ADL Total Score Baseline, Week 105 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.
Change From Baseline to Week 105 on Cognition, as Assessed by Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) (Subscale) 13 (ADAS-Cog-13) Baseline, Week 105 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.
Change From Baseline to Week 105 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS) Baseline, Week 105 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.
Change From Baseline to Week 105 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE) Baseline, Week 105 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.
Change From Baseline to Week 105 on Function as Assessed by the ADCS-instrumental (ADCS-iADL) Subscore Baseline, Week 105 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.
Change From Baseline to Week 105 on a Measure of Dependence Derived From the ADCS-ADL Score Baseline, Week 105 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.
Percentage of Participants With Anti-Crenezumab Antibodies Baseline up to Week 105 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.
Change From Baseline to Week 105 Assessed Using the Neuropsychiatric Inventory Questionnaire (NPI-Q) Baseline, Week 105 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.
Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) Scale Score Baseline up to Week 105 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.
Plasma Amyloid Beta (Abeta) 40 Concentrations Week 1 Day 1; Weeks 13, 25, 53, 77 and 105 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.
Percentage Change From Baseline to Week 105 in Ventricle Volume as Determined by Magnetic Resonance Imaging (MRI) Baseline, Week 105 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.
Plasma Amyloid Beta (Abeta) 42 Concentrations Week 1 Day 1; Weeks 13, 25, 53, 77 and 105 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.
Quality of Life-Alzheimer's Disease (QoL-AD) Scale Score Baseline up to Week 105 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.
EQ-5D Questionnaire Domain Score for Caregivers Baseline up to Week 105 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.
Serum Concentration of Crenezumab 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) 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.
EQ-5D Questionnaire Domain Score for Participants Baseline up to Week 105 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.
Percentage of Participants With Adverse Event (AEs) and Serious Adverse Event (SAEs) Baseline up until 16 weeks after the last dose of study drug (up to 117 weeks). 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.
Percentage Change From Baseline to Week 105 in Whole Brain Volume as Determined by Magnetic Resonance Imaging (MRI) Baseline, Week 105 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.
Percentage Change From Baseline to Week 105 in Hippocampal Volume as Determined by Magnetic Resonance Imaging (MRI) Baseline, Week 105 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.
Trial Locations
- Locations (195)
Brain Matters Research, Inc.
🇺🇸Delray Beach, Florida, United States
Quantum Laboratories
🇺🇸Deerfield Beach, Florida, United States
Emory University
🇺🇸Atlanta, Georgia, United States
Drexel Univ College of Med; Clinical Research Group
🇺🇸Philadelphia, Pennsylvania, United States
Kerwin Research Center, LLC
🇺🇸Dallas, Texas, United States
Advanced Memory Research Institute of NJ
🇺🇸Toms River, New Jersey, United States
Terveystalo Tampere
🇫🇮Tampere, Finland
University of Szeged; Department of Psychiatry
🇭🇺Szeged, Hungary
Mie University Hospital
🇯🇵Mie, Japan
ICIMED Instituto de Investigación en Ciencias Médicas
🇨🇷San Jose, Costa Rica
Clinical Hospital Centre Zagreb;Clinic for Neurology
🇭🇷Zagreb, Croatia
Ente Ospedaliero Ospedali Galliera; Ambulatorio di Neurologia
🇮🇹Genova, Liguria, Italy
Precise Research Centers
🇺🇸Flowood, Mississippi, United States
The Cognitive and Research Center of New Jersey
🇺🇸Springfield, New Jersey, United States
CRST Oy
🇫🇮Turku, Finland
Tokyo Medical University Hospital
🇯🇵Tokyo, Japan
Hospital Angeles de Culiacán, Neurociencias Estudios Clínicos SC
🇲🇽Culiacan, Mexico
Przychodnia Specjalistyczna PROSEN
🇵🇱Warszawa, Poland
Regional mental hospital; Department of psychiatry, psychology and sexology
🇺🇦Lviv, KIEV Governorate, Ukraine
National Medical Academy of Postgraduate Education named after P.L.Shupik; Neurology Department #1
🇺🇦Kiev, Ukraine
Vancouver Island Health Authority
🇨🇦Victoria, British Columbia, Canada
Caulfield Hospital; Aged Psychiatry Research Unit
🇦🇺Caulfield, Victoria, Australia
Hospital Universitario de Saltillo
🇲🇽Saltillo, Mexico
Vancouver Hospital - UBC Hospital Site
🇨🇦Vancouver, British Columbia, Canada
Tokyo Metropolitan Geriatric Hospital
🇯🇵Tokyo, Japan
SHI City Psychoneurological Dispensary #7
🇷🇺St Petersburg, Russian Federation
Fundació ACE
🇪🇸BArcelon, Barcelona, Spain
National Center of Neurology and Psychiatry
🇯🇵Tokyo, Japan
AVIX Investigación Clínica S.C
🇲🇽Monterrey, Mexico
Centrum Medyczne NeuroProtect
🇵🇱Warszawa, Poland
Hospital Universitari de Bellvitge; Servicio de Neurologia
🇪🇸L'Hospitalet de Llobregat, Barcelona, Spain
Istanbul University Istanbul School of Medicine; Neurology
🇹🇷Istanbul, Turkey
Ondokuz Mayis University School of Medicine; Neurology
🇹🇷Samsun, Turkey
Complejo Asistencial Universitario de Salamanca; Servicio de Psiquiatría
🇪🇸Salamaca, Salamanca, Spain
Aarhus Universitetshospital, Neurologisk Afdeling F, Demensklinikken
🇩🇰Aarhus N, Denmark
Collaborative Neuroscience Network Inc.
🇺🇸Long Beach, California, United States
Alliance for Wellness, dba Alliance for Research
🇺🇸Long Beach, California, United States
Pharmacology Research Institute
🇺🇸Los Alamitos, California, United States
Shankle Clinic
🇺🇸Newport Beach, California, United States
UCLA Medical Center, Department of Neurology
🇺🇸Los Angeles, California, United States
Associated Neurologists PC - Danbury
🇺🇸Danbury, Connecticut, United States
Galiz Research, LLC
🇺🇸Hialeah, Florida, United States
Research Center for Clinical Studies, Inc.
🇺🇸Norwalk, Connecticut, United States
Bradenton Research Center
🇺🇸Bradenton, Florida, United States
Maine Research Associates
🇺🇸Auburn, Maine, United States
MMP Neurology
🇺🇸Scarborough, Maine, United States
MidAmerica Neuroscience Institute
🇺🇸Prairie Village, Kansas, United States
Guilford Neurologic Associates
🇺🇸Greensboro, North Carolina, United States
Jacksonville Center For Clinical Research
🇺🇸Jacksonville, Florida, United States
Alzheimer's Research and Treatment Center
🇺🇸Lake Worth, Florida, United States
Renstar Medical Research
🇺🇸Ocala, Florida, United States
Progressive Medical Research
🇺🇸Port Orange, Florida, United States
Alexian Brothers Neurosci Inst
🇺🇸Elk Grove Village, Illinois, United States
NeuroStudies.net, LLC
🇺🇸Decatur, Georgia, United States
Springfield Neurology Associates
🇺🇸Springfield, Massachusetts, United States
South Shore Neurologic Associates P.C.
🇺🇸Patchogue, New York, United States
Parkwood Hospital; Geriatric Medicine
🇨🇦London, Ontario, Canada
The Queen Elizabeth Hospital; Neurology
🇦🇺Woodville, South Australia, Australia
ACIBADEM CITY CLINIC TOKUDA HOSPITAL EAD; Clinic of Neurology and Sleep Medicine
🇧🇬Sofia, Bulgaria
Neurological Associates of Albany, PC
🇺🇸Albany, New York, United States
Heidelberg Repatriation Hospital; Medical and Cognitive Research Centre
🇦🇺Heidelberg West, Victoria, Australia
Neurodegenerative Disorders Research; Neurology
🇦🇺West Perth, Western Australia, Australia
Behavioral Health Research
🇺🇸Charlotte, North Carolina, United States
Dent Neurological Institute
🇺🇸Amherst, New York, United States
Devonshire Clinical Research Inc.
🇨🇦Woodstock, Ontario, Canada
Albany Medical Faculty Physicians COmmunity Division. The Neurology Group
🇺🇸Albany, New York, United States
Valley Medical Primary Care
🇺🇸Centerville, Ohio, United States
Sentara Medical Group
🇺🇸Norfolk, Virginia, United States
Abington Neurological Associates
🇺🇸Willow Grove, Pennsylvania, United States
Hopital Avicenne; Neurologie
🇫🇷Bobigny, France
Konventhospital Barmherzige Brüder; Neurologie I
🇦🇹Linz, Austria
UZ Gent
🇧🇪Gent, Belgium
Rigshospitalet, Hukommelsesklinikken
🇩🇰København Ø, Denmark
The Centre for Memory and Aging
🇨🇦Toronto, Ontario, Canada
Alexandrovska hospital; Neurology Department
🇧🇬Sofia, Bulgaria
CHA Hopital de I enfant-Jesus
🇨🇦Quebec City, Quebec, Canada
Kawartha Centre - Redefining Healthy Aging
🇨🇦Peterborough, Ontario, Canada
Klinikum rechts der Isar der TU München; Klinik für Psychiatrie und Psychotherapie
🇩🇪München, Germany
Universitätsklinikum Münster; Klinik und Poliklinik für Neurologie
🇩🇪Münster, Germany
Hospital Clínica Biblica
🇨🇷San José, Costa Rica
Charles University, Medical faculty, Hradec Kralove ;Department of Neurology
🇨🇿Hradec Králové, Czechia
General Teaching Hospital, Departmetn of Neurology
🇨🇿Praha, Czechia
Hopital neurologique Pierre Wertheimer - CHU Lyon; Neurologie
🇫🇷Bron, France
Hopital Lariboisiere
🇫🇷Paris, France
CHU Poitiers - Hopital La Miletrie
🇫🇷Poitiers, France
CHU Toulouse - La Grave
🇫🇷Toulouse, France
Forschungszentrum Ruhr
🇩🇪Witten, Germany
Neurologische Praxis Dr. Andrej Pauls
🇩🇪München, Germany
Szent Borbala Korhaz; Neurologiai es Stroke Osztaly
🇭🇺Tatabánya, Hungary
Universitätsklinikum Ulm; Klinik für Neurologie
🇩🇪Ulm, Germany
Prince of Wales Hospital; Dept. of Medicine & Therapeutics
🇭🇰Hong Kong, Hong Kong
Casa di Cura Policlinico; Dipartimento di Scienze Neuroriabilitative
🇮🇹Milano, Lombardia, Italy
Jávorszky Ödön Kórház, Neurológia és stroke osztály
🇭🇺VAC, Hungary
Fondazione Santa Lucia IRCCS; Neurologia e Riabilitazione Neurologica
🇮🇹Roma, Lazio, Italy
Ospedale S. Maria Nascente; Fondazione Don Gnocchi; Dip. Neurologia Riabilitativa
🇮🇹Milano, Lombardia, Italy
Konkuk University Medical Center
🇰🇷Seoul, Korea, Republic of
Miyoshi Clinic of Neurology, Hananosato
🇯🇵Hiroshima, Japan
Ospedale San Giovanni Calibita Fatebenefratell;Neurologia
🇮🇹Roma, Lazio, Italy
National Hospital Organization Hiroshima-Nishi Medical Center
🇯🇵Hiroshima, Japan
Rakuwakai Otowarehabilitation Hospital
🇯🇵Kyoto, Japan
Katayama Medical Clinic
🇯🇵Okayama, Japan
Vilnius University Hospital Santariskiu Clinic
🇱🇹Vilnius, Lithuania
Ospedale Casati Passirana di Rho; Centro Regionale Alzheimer
🇮🇹Passirana, Lombardia, Italy
Ewha Womans University Mokdong Hospital; Dept of Neurology
🇰🇷Seoul, Korea, Republic of
National Hospital Organization Matsumoto Medical Center
🇯🇵Nagano, Japan
Saigata Medical Center
🇯🇵Niigata, Japan
Inha University Hospital
🇰🇷Incheon, Korea, Republic of
NZOZ NEURO-KARD Ilkowski i Partnerzy Sp. Partn. Lek
🇵🇱Poznań, Poland
NEURO-CARE Sp. z o.o. Sp. Komandytowa
🇵🇱Siemianowice Śląskie, Poland
State autonomous institution of healthcare Inter-regional clinical and diagnostic center
🇷🇺Kazan, Russian Federation
Institution of RAMS (Mental Health Research Center of RAMS)
🇷🇺Moscow, Russian Federation
Chonnam National University Hospital
🇰🇷Gwangju, Korea, Republic of
Hospital Uni; Dr. Jose E. Gonzalez
🇲🇽Monterrey, Mexico
Podlaskie Centrum Psychogeriatrii
🇵🇱Białystok, Poland
Optimum
🇵🇱Warszawa, Poland
Hospital Prof. Dr. Fernando Fonseca; Servico de Neurologia
🇵🇹Amadora, Portugal
Hospital Beatriz Angelo; Servico de Neurologia
🇵🇹Loures, Portugal
State Autonomous Healthcare Institution "Republican Clinical Neurological Center
🇷🇺Kazan, Russian Federation
University Medical Centre Maribor
🇸🇮Maribor, Slovenia
Clinica Ruber, 4 planta; Servicio de Neurologia
🇪🇸Madrid, Spain
Hospital Vall d'Hebron; Servicio de Neurología
🇪🇸Barcelona, Spain
St George's Hospital
🇬🇧London, United Kingdom
Skånes Universitetssjukhus Malmö, Minneskliniken
🇸🇪Malmö, Sweden
D.F.Chebotarev Institute of Gerontology NAMS;Depart of Age Physiology&Pathology of Nervous System
🇺🇦Kiev, Ukraine
Hopital Gui de Chauliac; Neurologie
🇫🇷Montpellier, France
Hopital Hautepierre; Centre dInvestigation Clinique
🇫🇷Strasbourg, France
Banner Alzheimer's Institute
🇺🇸Phoenix, Arizona, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
Summit Research Network Inc.
🇺🇸Portland, Oregon, United States
UCSF - Memory and Aging Center
🇺🇸San Francisco, California, United States
Cutting Edge Research Group
🇺🇸Oklahoma City, Oklahoma, United States
Miami Jewish Health Systems
🇺🇸Miami, Florida, United States
Oklahoma Clinical Research
🇺🇸Oklahoma City, Oklahoma, United States
Manchester Royal Infirmary
🇬🇧Manchester, United Kingdom
Campus for Ageing and Vitality
🇬🇧Newcastle Upon Tyne, United Kingdom
John Radcliffe Hospital
🇬🇧Oxford, United Kingdom
Bruyere Continuing Care
🇨🇦Ottawa, Ontario, Canada
Toronto Western Hospital
🇨🇦Toronto, Ontario, Canada
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Universitätsklinikum Rostock Zentrum für Nervenheilkunde
🇩🇪Rostock, Germany
Studienzentrum Nordwest, Dr. med. Joachim Springub / Herr Wolfgang Schwarz
🇩🇪Westerstede, Germany
Anderson Clinical Research, Inc.
🇺🇸Redlands, California, United States
Stanford Univ Medical Center
🇺🇸Palo Alto, California, United States
North Bay Neuro Science Institute
🇺🇸Sebastopol, California, United States
Southern Illinois University, School of Medicine
🇺🇸Springfield, Illinois, United States
Insight Clinical Trials LLC
🇺🇸Shaker Heights, Ohio, United States
Central States Research
🇺🇸Tulsa, Oklahoma, United States
Pharmacology Research Inst
🇺🇸Newport Beach, California, United States
Neurological Research Inst
🇺🇸Santa Monica, California, United States
Compass Research
🇺🇸The Villages, Florida, United States
Merritt - Island Medical Research
🇺🇸Merritt Island, Florida, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
University of North Texas Health Science Center; Fort Worth Patient Care Center
🇺🇸Fort Worth, Texas, United States
Steinwachs Klaus; Arztpraxis fur Neurologie u. Psychiatrie
🇩🇪Nürnberg, Germany
Szabolcs-Szatmár-Bereg Megyei Kórházak - Jósa András Oktatókórház; Pszichiátria
🇭🇺Nyíregyháza, Hungary
Semmelweis University; Department of Neurology
🇭🇺Budapest, Hungary
KyungHee Medical Center
🇰🇷Seoul, Korea, Republic of
City Clinical Hospital # 2 n.a. V.I. Razumovsky
🇷🇺Saratov, Russian Federation
Russian Medical Military Academy n.a. S.M.Kirov; Neurology Department
🇷🇺St. Petersburg, Russian Federation
Hospital General Universitario de Albacete; Servicio de Neurología
🇪🇸Albacete, Spain
Hospital Virgen del Puerto. Servicio de Neurología
🇪🇸Plasencia, Caceres, Spain
Clinica Universitaria de Navarra; Servicio de Neurología
🇪🇸Pamplona, Navarra, Spain
Universitario de La Princesa; Servicio de Neurología
🇪🇸Madrid, Spain
Hospital Universitario de Burgos. Servicio de Neurología
🇪🇸Burgos, Spain
Hospital Universitario Marques de Valdecilla; Servicio de Neurología
🇪🇸Santander, Cantabria, Spain
Hospital General De Catalunya; Servicio de Neurologia
🇪🇸Sant Cugat del Valles, Barcelona, Spain
Hospital Regional Universitario Carlos Haya; Servicio de Neurologia
🇪🇸Malaga, Spain
Hospital Universitario la Fe; Servicio de Neurologia
🇪🇸Valencia, Spain
Hospital Universitario Virgen de Arrixaca; Servicio de Neurología
🇪🇸Murcia, Spain
Servicio de Neurología Hospital Viamed Montecanal.
🇪🇸Zaragoza, Spain
Karolinska Uni Hospital, Huddinge; Dept. of Geriatric Med
🇸🇪Stockholm, Sweden
Universitäres Zentrum für Altersmedizin und Rehabilitation
🇨🇭Basel, Switzerland
Hacettepe University School of Medicine; Neurology
🇹🇷Ankara, Turkey
Sahlgrenska Academy University,Neuroscience and Physiology;Departmt of Psychiatry and Neurochemistry
🇸🇪Mölndal, Sweden
Osmangazi University School of Medicine,Neurology Department
🇹🇷Eskişehir, Turkey
Coventry and Warwickshire Partnership NHS Trust
🇬🇧Coventry, United Kingdom
Royal Preston Hospital
🇬🇧Blackburn, United Kingdom
Surrey and Borders NHS Foundation Trust; Brain Science Research Unit
🇬🇧Chertsey, United Kingdom
USC Keck School Of Medicine
🇺🇸Los Angeles, California, United States
Hospital Universitario 12 de Octubre; Servicio de Neurologia
🇪🇸Madrid, Spain
National Clinical Research Inc.-Richmond
🇺🇸Richmond, Virginia, United States
Senior Adults Specialty Research
🇺🇸Austin, Texas, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
University of California, Davis; Alzheimers Disease Center, Department of Neurology
🇺🇸Sacramento, California, United States
Institute for Neurodegenerative Disorders
🇺🇸New Haven, Connecticut, United States
Yale University School Of Medicine
🇺🇸New Haven, Connecticut, United States
Bioclinica Research
🇺🇸Orlando, Florida, United States
Johnnie B. Byrd Sr. Alzheimer's Center & Research Institute
🇺🇸Tampa, Florida, United States
Stedman Clinical Trials, LLC
🇺🇸Tampa, Florida, United States
Hospital Mutua De Terrasa; Servicio de Neurologia
🇪🇸Terrassa, Barcelona, Spain
Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia; S.C. Geriatria
🇮🇹Perugia, Umbria, Italy
SBEI of HPI The 1st Moscow State Medical University n.a. I.M. Sechenov of MOH of RF
🇷🇺Moscow, Russian Federation
Hospital Sant Joan de Deu; Servicio de Neurología
🇪🇸Manresa, Barcelona, Spain
Charing Cross Hospital
🇬🇧London, United Kingdom
Queen Mary Hospital, Division of Geriatric Medicine
🇭🇰Hong Kong, Hong Kong