Clinical trial NCT02051608: A Study of Gantenerumab in Participants With Mild Alzheimer Disease
Official title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Efficacy and Safety Study of Gantenerumab in Patients With Mild Alzheimer's Disease; Part II: Open-Label Extension For Participating Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Alzheimer's Disease
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2014-01-31
Enrollment: 389
Sex: ALL
Minimum age (years): 50
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Part 1 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of gantenerumab in participants with mild Alzheimer disease. Participants will be randomized to receive either gantenerumab subcutaneously every 4 weeks or placebo subcutaneously every 4 weeks. Approved Alzheimer medication is allowed if on stable dose for 3 months prior to screening. Part 2 is an open-label extension (OLE).

A positron emission tomography (PET) imaging substudy will be conducted within the main study. Eligible participants who provide separate informed consent will undergo PET imaging scans using the radioligand florbetapir as a pharmacodynamic measure of changes in brain amyloid load over time.


Eligibility criteria: Inclusion Criteria:

* Clinical diagnosis of probable mild Alzheimer disease (AD) based on National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria or major NCD based whether or not receiving AD approved medication
* Cerebral spinal fluid (CSF) result consistent with the presence of amyloid pathology
* Availability of a person ('caregiver') who in the investigator's judgment has frequent and sufficient contact with the participant, and is able to provide accurate information regarding the participant's cognitive and functional abilities
* Fluency in the language of the tests used at the study site
* Willingness and ability to complete all aspects of the study
* Adequate visual and auditory acuity, in the investigator's judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted)
* If currently receiving approved medications for AD, the dosing regimen must have been stable for 3 months prior to screening
* Agreement not to participate in other research studies for the duration of this trial and its associated substudies

PART 2 - All participants who have been randomized and are actively participating in the study are eligible for Part 2

Exclusion Criteria:

* Dementia or neurocognitive disorder (NCD) due to a condition other than AD, including, but not limited to, frontotemporal dementia, Parkinson disease, dementia with Lewy bodies, Huntington disease, or vascular dementia
* History or presence of clinically evident vascular disease potentially affecting the brain that in the opinion of the investigator has the potential to affect cognitive function
* History or presence of stroke within the past 2 years or documented history of transient ischemic attack within the last 12 months
* History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease with associated cognitive deficits
* History of schizophrenia, schizoaffective disorder, or bipolar disorder
* Alcohol and/or substance use disorder (according to the DSM-5) within the past 2 years (nicotine use is allowed)
* History or presence of atrial fibrillation
* Within the last 2 years, unstable or clinically significant cardiovascular disease (e.g., myocardial infarction, angina pectoris, cardiac failure New York Heart Association Class II or higher)
* Uncontrolled hypertension
* Chronic kidney disease
* Impaired hepatic function

PET imaging substudy, in addition to above:

- Prior participation in other research study or clinical care within the last year such that the total radiation exposure would exceed the local or national annual limits

Part 2 Participants who have been discontinued from the study

Primary outcomes:
measure: Part 2: Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs)
timeFrame: First dose up to 4 weeks after the last dose of study drug (up to 249 weeks)
measure: Part 2: Percentage of Participants With Treatment Emergent Anti-Drug Antibodies (ADAs)
timeFrame: First dose up to last dose (Baseline up to until maximum 5 years)
measure: Part 2: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment
timeFrame: First dose up to 4 weeks after the last dose in OLE (Up to approximately 249 weeks)
Secondary outcomes:
measure: Part 1: Percentage of Participants With AEs, SAEs
timeFrame: First dose up to last dose (Up to approximately 152 weeks)
measure: Part 1: Percentage of Participants With Treatment Emergent ADAs
timeFrame: First dose up to last dose (Up to approximately 152 weeks)
measure: Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints
timeFrame: Pre-dose: Weeks 4, 8, 12, 24, 48, 72 and Post dose: Day 4
measure: Part 1: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment
timeFrame: First dose up to last dose (Up to approximately 152 weeks)
measure: Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104
timeFrame: Baseline (Part 1 screening), Week 104
measure: Part 2: Percent Change From Baseline in Whole Brain Volume at Week 104
timeFrame: Baseline (Part 1 screening), Week 104
measure: Part 2: Percent Change From Baseline in Cortical Thickness at Week 104
timeFrame: Baseline (Part 1 screening), Week 104
measure: Part 2: Ventricular Volume as Measured by MRI at Week 104
timeFrame: Part 2: Week 104
measure: Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints
timeFrame: Pre-dose: Weeks 104, 116, 156, 208; Post-dose: Weeks 53, 101
measure: Part 2: Change From Baseline in Brain Amyloid Load at Week 156 in a Subset of Participants
timeFrame: Baseline, Week 156
Other outcomes:
measure: Part 1: Mean Change From Baseline in Alzheimer's Disease Activity Scale-Cognitive Subscale 13 (ADAS-Cog13) Scores at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scores at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Percentage Change From Baseline in Total Tau (T-tau) in CSF at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Percentage Change From Baseline in Abeta 1-42 Levels in CSF at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Percentage Change From Baseline in Phosphorylated Tau [P-tau] in CSF at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Percent Change From Baseline in Hippocampal Volume at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Percent Change From Baseline in Whole Brain Volume at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Percent Change From Baseline in Cortical Thickness at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Ventricular Volume as Measured by MRI at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Change From Baseline in Clinical Dementia Rating Global Score (CDR-GS) at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Change From Baseline in CDR Sum of Boxes (SB) at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Change From Baseline in NPI Domain Score at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Change From Baseline in Alzheimer's Dementia (QoL-AD) Global Score at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Change From Baseline in Symptom Guide Facilitated (GAS) at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Change From Baseline in Dependence Scale (DS) at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Change From Baseline in Resource Utilization Dementia-Lite (RUD - Lite) Scale at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Change From Baseline in Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Time to Clinical Decline
timeFrame: Baseline up to Week 104
measure: Part 1: Change From Baseline in Clinical Composite Score (Prespecified Items From The ADAS-Cog, MMSE, and CDR) at Week 104
timeFrame: Baseline, Week 104
measure: Part 1: Percentage of Participants With ADAS-Cog Response
timeFrame: Baseline up to Week 152
Locations:
city: Sun City
country: United States
facility: Banner Sun Health Research Insitute
state: Arizona
city: Tucson
country: United States
facility: Territory Neurology and Research Institute
state: Arizona
city: Costa Mesa
country: United States
facility: ATP Clinical Research, Inc
state: California
city: San Diego
country: United States
facility: Pacific Research Network - PRN
state: California
city: Sherman Oaks
country: United States
facility: California Neuroscience Research Medical Group, Inc
state: California
city: Brooksville
country: United States
facility: Meridien Research
state: Florida
city: Delray Beach
country: United States
facility: Brain Matters Research, Inc.
state: Florida
city: Fort Myers
country: United States
facility: Neuropsychiatric Research; Center of Southwest Florida
state: Florida
city: Miami
country: United States
facility: Miami Jewish Health Systems; Clinical Research
state: Florida
city: Orlando
country: United States
facility: Accelerated Enrollment Solutions
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Wellington
country: United States
facility: Alzheimer's Research and Treatment Center
state: Florida
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Baton Rouge
country: United States
facility: Pennington Biomedical Research Center
state: Louisiana
city: New Orleans
country: United States
facility: Louisiana Research Associates
state: Louisiana
city: Kalamazoo
country: United States
facility: Western Michigan University Homer Stryker M.D. School of Medicine Center for Clinical Research
state: Michigan
city: Saint Louis
country: United States
facility: Millennium Psychiatric Associates, LLC
state: Missouri
city: Manchester
country: United States
facility: Alzheimer's Research Corporation
state: New Jersey
city: Toms River
country: United States
facility: Ocean Rheumatology
state: New Jersey
city: Orangeburg
country: United States
facility: Nathan Kline Institute
state: New York
city: Staten Island
country: United States
facility: Richmond Behavioral Associates
state: New York
city: Matthews
country: United States
facility: Alzheimer's Memory Center
state: North Carolina
city: Raleigh
country: United States
facility: Richard H Weisler, MD
state: North Carolina
city: Tulsa
country: United States
facility: Central States Research
state: Oklahoma
city: Abington
country: United States
facility: Abington Neurological Associates
state: Pennsylvania
city: Plains
country: United States
facility: Northeastern Pennsylvania Memory
state: Pennsylvania
city: East Providence
country: United States
facility: Rhode Island Mood & Memory Research Institute
state: Rhode Island
city: Cordova
country: United States
facility: Neurology Clinic PC
state: Tennessee
city: Austin
country: United States
facility: Senior Adults Specialty Research
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Center for Alzheimer's Care Imaging & Research
state: Utah
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Instituto Neurologia Bs As
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital; Memory Trials Centre
state: South Australia
city: Woodville
country: Australia
facility: The Queen Elizabeth Hospital; Neurology
state: South Australia
city: Heidelberg West
country: Australia
facility: Heidelberg Repatriation Hospital; Medical and Cognitive Research Centre
state: Victoria
city: Nedlands
country: Australia
facility: Australian Alzheimer's Research Foundation
state: Western Australia
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Sofia
country: Bulgaria
facility: Shat Np Sveti Naum; 3Rd Clinic of Neurology
city: Varna
country: Bulgaria
facility: MBAL St. Marina; First Neurology Department
city: Calgary
country: Canada
facility: University of Calgary; Heritage Medical Research Clinic
state: Alberta
city: Halifax
country: Canada
facility: True North Clinical Research-Halifax
state: Nova Scotia
city: New Minas
country: Canada
facility: True North Clinical Research
state: Nova Scotia
city: Burlington
country: Canada
facility: Jbn Medical Diagnostic Services Inc.
state: Ontario
city: London
country: Canada
facility: Parkwood Hospital; Geriatric Medicine
state: Ontario
city: Peterborough
country: Canada
facility: Kawartha Centre - Redefining Healthy Aging
state: Ontario
city: Toronto
country: Canada
facility: Toronto Memory Program
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Gatineau
country: Canada
facility: Recherches Neuro-Hippocame
state: Quebec
city: Greenfield Park
country: Canada
facility: NeuroSearch Developpements inc
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital / McGill University
state: Quebec
city: Quebec City
country: Canada
facility: Centre Hospitalier Affilie Universitaire de Quebec - Hopital de L'Enfant Jesus
state: Quebec
city: Verdun
country: Canada
facility: McGill Univeristy; Douglas Mental Health University Institute; Neurological and Psychiatric
state: Quebec
city: Quebec
country: Canada
facility: Alpha Recherche Clinique
city: Aarhus N
country: Denmark
facility: Aarhus Universitetshospital, Neurologisk Afdeling F, Demensklinikken
city: Koebenhavn Oe
country: Denmark
facility: Rigshospitalet, Hukommelsesklinikken
city: Kuopio
country: Finland
facility: University of Eastern Finland
city: Turku
country: Finland
facility: CRST Oy
city: Bordeaux
country: France
facility: Hopital Pellegrin; Cmrr Aquitaine
city: Bron
country: France
facility: Hopital Pierre Wertheimer; Laboratoire De Neuro Psychologie
city: Limoges
country: France
facility: CHU de Limoges Hopital Dupuytren; Service de Medecine Geriatrique
city: Marseille
country: France
facility: CHU de la Timone - Hopital d Adultes; Service de Neurologie
city: Rennes
country: France
facility: CHU Rennes - hopital Hotel Dieu; Consultation Memoire - Gerontologie
city: Strasbourg
country: France
facility: Hopital Hautepierre; Centre dInvestigation Clinique
city: Toulouse
country: France
facility: Hopital la Grave; Gerontopole - Centre de Recherche Clinique
city: Berlin
country: Germany
facility: ECRC Experimental and Clinical Research Center, Charité Campus Berlin Buch, Memory Clinic
city: Leipzig
country: Germany
facility: PANAKEIA - Arzneimittelforschung Leipzig GmbH
city: Mittweida
country: Germany
facility: Pharmakologisches Studienzentrum
city: Muenchen
country: Germany
facility: Klinikum rechts der Isar der TU München; Klinikapotheke
city: München
country: Germany
facility: Neurologische Praxis Dr. Andrej Pauls
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm; Klinik für Neurologie
city: Westerstede
country: Germany
facility: Studienzentrum Nordwest, Dr. med. Joachim Springub / Herr Wolfgang Schwarz
city: Budapest
country: Hungary
facility: Semmelweis University; Department of Neurology
city: Modena
country: Italy
facility: Nuovo Ospedale Civile S. Agostino-Estense; Clinica Neurologica - Dipartimento di Neuroscienze
state: Emilia-Romagna
city: Roma
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Tor Vergata; Neurologia
state: Lazio
city: Roma
country: Italy
facility: Umberto I Policlinico di Roma-Università di Roma La Sapienza
state: Lazio
city: Brescia
country: Italy
facility: IRCCS "Centro S. Giovanni di Dio" Fatebenefratelli -UO Alzheimer
state: Lombardia
city: Castellanza
country: Italy
facility: Irccs Multimedica Santa Maria; Unita' Di Neurologia
state: Lombardia
city: Monza
country: Italy
facility: ASST DI MONZA; Neurologia
state: Lombardia
city: Pisa
country: Italy
facility: A.O. Universitaria Pisana; Neurologia
state: Toscana
city: Chiba
country: Japan
facility: Medical Corporation Hakuyokai Kashiwado Hospital
city: Chiba
country: Japan
facility: National Hospital Organization Chiba-east Hospital; Neurology
city: Chiba
country: Japan
facility: Juntendo University Urayasu Hospital; Neurology
city: Fukuoka
country: Japan
facility: Fukuoka University Hospital; Neurology and Health Care
city: Gunma
country: Japan
facility: Maebashi Red Cross Hospital; Neurology
city: Hiroshima
country: Japan
facility: National Hospital Organization Hiroshima-Nishi Medical Center
city: Hyogo
country: Japan
facility: Hyogo Brain and Heart Center at Himeji; Department of Aging Brain and Cognitive Disorders
city: Kanagawa
country: Japan
facility: Shonan Kamakura General Hospital; Neurology
city: Oita
country: Japan
facility: Oita University Hospital; Neurology
city: Okayama
country: Japan
facility: Kurashiki Heisei Hospital; Neurology
city: Shizuoka
country: Japan
facility: Shizuoka City Shimizu Hospital; Neurology
city: Busan
country: Korea, Republic of
facility: Dong-A University Medical Center
city: Gyeonggi-do
country: Korea, Republic of
facility: Seoul National University Bundang Hospital; Neurology Department
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital; Neurology Department
city: Seoul
country: Korea, Republic of
facility: Konkuk University Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University Hospital (Seoul)
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center.
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University Mokdong Hospital; Dept of Neurology
city: Amsterdam
country: Netherlands
facility: Brain Research Center B.V
city: Rotterdam
country: Netherlands
facility: Erasmus Mc - Locatie Centrum; Dept of Neurology
city: Amadora
country: Portugal
facility: Hospital Prof. Dr. Fernando Fonseca; Servico de Neurologia
city: Lisboa
country: Portugal
facility: Hospital de Santa Maria; Servico de Neurologia
city: Kazan
country: Russian Federation
facility: State Autonomous Healthcare Institution "Republican Clinical Neurological Center
city: Kazan
country: Russian Federation
facility: State autonomous institution of healthcare Inter-regional clinical and diagnostic center
city: Moscow
country: Russian Federation
facility: Institution of RAMS (Mental Health Research Center of RAMS)
city: Moscow
country: Russian Federation
facility: SBEI of HPI The 1st Moscow State Medical University n.a. I.M. Sechenov of MOH of RF
city: Saint Petersburg
country: Russian Federation
facility: Saint Petersburg State Institution of Healthcare City Geriatric Medico-Social Center
city: Saratov
country: Russian Federation
facility: City Clinical Hospital # 2 n.a. V.I. Razumovsky
city: St. Petersburg
country: Russian Federation
facility: Russian Medical Military Academy n.a. S.M.Kirov; Neurology Department
city: Elche
country: Spain
facility: Hospital General Universitario de Elche; Servicio de Neurología
state: Alicante
city: BArcelon
country: Spain
facility: Fundació ACE
state: Barcelona
city: Donosti-San Sebastián
country: Spain
facility: Policlínica Guipuzkoa; Servicio de Neurología
state: Guipuzcoa
city: Barakaldo
country: Spain
facility: Hospital de Cruces; Servicio de Neurologia
state: Vizcaya
city: Barcelona
country: Spain
facility: Hospital del Mar; Servicio de Neurologia
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre; Servicio de Neurologia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena; Servicio de Neurologia
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Malmö
country: Sweden
facility: Skånes Universitetssjukhus Malmö, Minneskliniken
city: Stockholm
country: Sweden
facility: KAROLINSKA UNI HOSPITAL, HUDDINGE; Mottagning Kognitiv Forskning, M54
city: Basel
country: Switzerland
facility: Felix Platter-Spital Medizin Geriatrie
city: Lausanne
country: Switzerland
facility: CHUV Lausanne Memory clinique
city: Istanbul
country: Turkey
facility: Istanbul University Istanbul School of Medicine; Neurology
city: Izmir
country: Turkey
facility: Dokuz Eylul University Medicine Faculty; Noroloji Departmani
city: Samsun
country: Turkey
facility: Ondokuz Mayis University School of Medicine; Neurology
city: Crowborough
country: United Kingdom
facility: Sussex Partnership NHS Foundation Trust; Cognitive Treatment and Research unit
city: Glasgow
country: United Kingdom
facility: Glasgow Memory Clinic
city: London
country: United Kingdom
facility: Charing Cross Hospital; Dept of Neurosciences
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Preston
country: United Kingdom
facility: Royal Preston Hosptial
city: Sheffield
country: United Kingdom
facility: Memory Service North
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Klein G, Delmar P, Voyle N, Rehal S, Hofmann C, Abi-Saab D, Andjelkovic M, Ristic S, Wang G, Bateman R, Kerchner GA, Baudler M, Fontoura P, Doody R. Gantenerumab reduces amyloid-beta plaques in patients with prodromal to moderate Alzheimer's disease: a PET substudy interim analysis. Alzheimers Res Ther. 2019 Dec 12;11(1):101. doi: 10.1186/s13195-019-0559-z.