Clinical trial NCT03443973: Safety and Efficacy Study of Gantenerumab in Participants With Early Alzheimer's Disease (AD)
Official title: A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy, and Safety Study of Gantenerumab in Patients With Early (Prodromal to Mild) Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Alzheimer Disease
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2018-02-23
Enrollment: 975
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: This randomized, double-blind, placebo-controlled, parallel group study will evaluate the efficacy and safety of gantenerumab versus placebo in participants with early (prodromal to mild) AD. All participants must show evidence of beta-amyloid pathology. Eligible participants will be randomized 1:1 to receive either subcutaneous (SC) injection of gantenerumab or placebo. The primary efficacy assessment will be performed at the end of the double blind period at week 116. Participants will then be offered to enter into an open-label extension (OLE). Participants not willing to go to the OLE will participate in a long term follow-up period for up to 50 weeks after the last gantenerumab dose.


Eligibility criteria: Key Inclusion criteria:

* 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)
* Evidence of the AD pathological process, as confirmed by CSF tau/A-beta42or amyloid PET scan
* Demonstrated abnormal memory function
* MMSE score greater than or equal to 22 (≥ 22)
* Clinical dementia rating-global score (CDR-GS) of 0.5 or 1.0
* Availability of a reliable study partner who accepts to participate in study procedures throughout the 2 years duration of study
* If receiving symptomatic AD medications, the dosing regimen must have been stable for 3 months prior to screening and until randomization
* For enrollment in the China extension, patients must have residence in mainland China, Hong Kong, or Taiwan and be of Chinese ancestry
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods

Key Exclusion criteria:

* Any evidence of a condition other than AD that may affect cognition
* History of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder
* History or presence of clinically evident systemic vascular disease that in the opinion of the investigator has the potential to affect cognitive function
* History or presence of clinically evident cerebrovascular disease
* History or presence of posterior reversible encephalopathy syndrome
* History or presence of any stroke with clinical symptoms within the past 12 months, or documented history within the last 6 months of an acute event that is consistent with a transient ischemic attack
* History of severe, clinically significant CNS trauma
* History or presence of intracranial mass (e.g., glioma, meningioma) that could potentially impair cognition
* Presence of infections that affect brain function or history of infections that resulted in neurologic sequelae
* History or presence of systemic autoimmune disorders that potentially cause progressive neurologic disease with associated cognitive deficits
* At risk for suicide in the opinion of the investigator
* Alcohol and/or substance abuse or dependants in past 2 years
* Relevant brain hemorrhage, bleeding disorder and cerebrovascular abnormalities
* Any contraindications to brain MRI
* Unstable or clinically significant cardiovascular, kidney or liver disease
* Uncontrolled hypertension
* Unstable or clinically significant cardiovascular disease
* Abnormal thyroid function
* Patients with evidence of folic acid deficiency

Exclusion for Open-Label Extension (OLE):

* Discontinued from study treatment during the double-blind treatment period
* Received any other investigational medication during the double-blind treatment period or after the end of double-blind treatment
* Participation in the OLE deemed inappropriate by the investigator
* Presence of ARIA-E findings at the Week 116 MRI scan

Primary outcomes:
measure: DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB
timeFrame: Baseline, Week 116
measure: OLE Period: Number of Participants With Adverse Events (AEs)
timeFrame: From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 weeks)
measure: OLE Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 weeks)
measure: OLE Period : Number of Participants With Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) Confirmed by MRI
timeFrame: From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 weeks)
measure: OLE Period: Number of Participants With Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by Magnetic Resonance Imaging (MRI)
timeFrame: From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 weeks)
measure: OLE Period: Number of Participants With Injection-Site Reactions
timeFrame: From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 weeks)
Secondary outcomes:
measure: DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score
timeFrame: Baseline, Week 116
measure: DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) Total Score
timeFrame: Baseline, Week 116
measure: DBT Period: Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score
timeFrame: Baseline, Week 116
measure: DBT Period: Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score
timeFrame: Baseline, Week 116
measure: DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Score
timeFrame: Baseline, Week 116
measure: DBT Period: Change From Baseline to Week 116 in Verbal Fluency Task (VFT) Score
timeFrame: Baseline, Week 116
measure: DBT Period: Change From Baseline to Week 116 in the Coding (Digit Symbol Substitution Test [DSST]) Subtest
timeFrame: Baseline, Week 116
measure: DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Instrumental Score
timeFrame: Baseline, Week 116
measure: DBT Period: Number of Participants With AEs
timeFrame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
measure: DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS
timeFrame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
measure: DBT Period: Number of Participants With ARIA-E Confirmed by MRI
timeFrame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
measure: DBT Period: Number of Participants With ARIA-H Confirmed by MRI
timeFrame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
measure: DBT Period: Number of Participants With Injection-Site Reactions
timeFrame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
measure: DBT Period: Number of Participants With Anti-Drug Antibodies (ADA) to Gantenerumab
timeFrame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
measure: Change From Baseline to Week 116 in Brain Amyloid Load as Measured by Amyloid Positron Emission Tomography (PET) Scan in a Subset of Participants
timeFrame: Baseline, Week 116
measure: Change From Baseline to Week 116 in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants
timeFrame: Baseline, Week 116
measure: DBT Period: Percent Change From Baseline to Week 116 in Cerebrospinal Fluid (CSF) Marker of Disease in a Subset of Participants - Neurofilament Light Chain (NFL)
timeFrame: Baseline, Week 116
measure: DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Neurogranin
timeFrame: Baseline, Week 116
measure: DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Total Tau (tTau)
timeFrame: Baseline, Week 116
measure: DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Phosphorylated Tau (pTau-181)
timeFrame: Baseline, Week 116
Other outcomes:
measure: Plasma Concentration of Gantenerumab
timeFrame: Pre-dose on Days 1, Weeks 24, 52 and 76; Post-dose on Day 4, Weeks 41, 103, and 115
Locations:
city: Phoenix
country: United States
facility: Banner Alzheimer?s Institute
state: Arizona
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Sun City
country: United States
facility: Banner Sun Health Research Insitute
state: Arizona
city: Fayetteville
country: United States
facility: Health Initiatives Research, PLLC
state: Arkansas
city: Fullerton
country: United States
facility: Fullerton Neurology and Headache Center
state: California
city: Fullerton
country: United States
facility: Neurology Center of North Orange County
state: California
city: Irvine
country: United States
facility: Irvine Center for Clinical Research
state: California
city: Redlands
country: United States
facility: Desert Valley Research
state: California
city: Simi Valley
country: United States
facility: Southern California Research LLC
state: California
city: New Haven
country: United States
facility: Yale University School Of Medicine
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Bradenton
country: United States
facility: Accel Research Sites - CRU Tampa
state: Florida
city: Maitland
country: United States
facility: ClinCloud, LLC
state: Florida
city: Miami
country: United States
facility: Optimus U Corp
state: Florida
city: Miami
country: United States
facility: Allied Biomedical Research Institute, Inc
state: Florida
city: Ocala
country: United States
facility: Renstar Medical Research
state: Florida
city: Port Orange
country: United States
facility: Progressive Medical Research
state: Florida
city: Sarasota
country: United States
facility: Intercoastal Medical Group
state: Florida
city: Sunrise
country: United States
facility: Infinity Clinical Research, LLC
state: Florida
city: Tampa
country: United States
facility: Axiom Clinical Research of Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Rush Alzheimer's Disease Cntr.
state: Illinois
city: Avon
country: United States
facility: American Health Network Institute, LLC
state: Indiana
city: Boston
country: United States
facility: Brigham and Womens Hospital; Center for Alzheimer Research & Treatment
state: Massachusetts
city: Haverhill
country: United States
facility: ActivMed Practices and Research
state: Massachusetts
city: Newton
country: United States
facility: Boston Center for Memory
state: Massachusetts
city: Farmington Hills
country: United States
facility: Quest Research Institute
state: Michigan
city: Bolivar
country: United States
facility: Missouri Memory Center
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center; Dept of Neurological Sciences
state: Nebraska
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo; Center for Brain Research
state: Nevada
city: Springfield
country: United States
facility: The Cognitive and Research Center of New Jersey
state: New Jersey
city: Rochester
country: United States
facility: AD-CARE, University of Rochester Medical Center
state: New York
city: Staten Island
country: United States
facility: Richmond Behavioral Associates
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Charlotte
country: United States
facility: Behavioral Health Research
state: North Carolina
city: Matthews
country: United States
facility: Alzheimer's Memory Center
state: North Carolina
city: Raleigh
country: United States
facility: Raleigh Neurology Associates
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Canton
country: United States
facility: Neuro-Behavioral Clinical Research, Inc.
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic; Cleveland Lou Ruvo Center for Brain Health ? Neurological Institute
state: Ohio
city: Oklahoma City
country: United States
facility: Lynn Health Science Institute
state: Oklahoma
city: Portland
country: United States
facility: Summit Research Network Inc.
state: Oregon
city: Dallas
country: United States
facility: Texas Neurology PA
state: Texas
city: Dallas
country: United States
facility: Kerwin Medical Center
state: Texas
city: Houston
country: United States
facility: Alzheimers Disease & Memory Disorders Center; Department of Neurology Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston
state: Texas
city: Buenos Aires
country: Argentina
facility: Hospital Italiano
city: Caba
country: Argentina
facility: Universidad Maimonides
city: Capital Federal
country: Argentina
facility: Instituto Geriatrico Nuestra Señora de las Nieves
city: Cordoba
country: Argentina
facility: CEN Centro Especializado en Neurociencias
city: Córdoba
country: Argentina
facility: Instituto Kremer
city: La Plata
country: Argentina
facility: Instituto de Neurociencias San Agustín S.A.
city: Mendoza
country: Argentina
facility: Fundacion Scherbovsky
city: Dendermonde
country: Belgium
facility: AZ Sint Blasius (Dendermonde)
city: Gent
country: Belgium
facility: UZ Gent
city: Hasselt
country: Belgium
facility: Jessa Zkh (Campus Virga Jesse)
city: Antofagasta
country: Chile
facility: Psicomed Estudios Médicos
city: Santiago
country: Chile
facility: Biomedica Research Group
city: Santiago
country: Chile
facility: Especialidades Medicas LYS
city: Zagreb
country: Croatia
facility: Clinical Hospital Centre Zagreb;Clinic for Neurology
city: Aarhus N
country: Denmark
facility: Aarhus Universitetshospital; Neurologisk Afd. F, Demensklinikken
city: København Ø
country: Denmark
facility: Rigshospitalet, Hukommelsesklinikken
city: Svendborg
country: Denmark
facility: Svendborg Sygehus; Neurologisk afdeling N, Demensklinik Fyn
city: Helsinki
country: Finland
facility: Terveystalo Ruoholahti
city: Kuopio
country: Finland
facility: University of Eastern Finland
city: Aichi
country: Japan
facility: Yachiyo Hospital
city: Aichi
country: Japan
facility: Nagoya Ekisaikai Hospital
city: Aichi
country: Japan
facility: National Center for Geriatrics and Gerontology
city: Fukuoka
country: Japan
facility: Fukuoka University Hospital
city: Hiroshima
country: Japan
facility: National Hospital Organization Hiroshima-Nishi Medical Center
city: Hyogo
country: Japan
facility: Hyogo Prefectural HarimaHimeji General Medical Center
city: Hyogo
country: Japan
facility: Tsukazaki Hospital
city: Hyogo
country: Japan
facility: Matsui Dietary and Dementia Clinic
city: Kagawa
country: Japan
facility: Kagawa Prefectural Central Hospital
city: Kyoto
country: Japan
facility: Rakuwakai Otowa Hospital
city: Kyoto
country: Japan
facility: Uji Takeda Hospital
city: Okayama
country: Japan
facility: Rijikai Medical Corporation Katayama Medical Clinic
city: Osaka
country: Japan
facility: Kishiwada Tokushukai Hospital
city: Saga
country: Japan
facility: National Hospital Organization Hizen Psychiatric Medical Center
city: Tokushima
country: Japan
facility: Medical corporation Ichiekai Itsuki Hospital
city: Tokushima
country: Japan
facility: Tokushima Hospital
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Gyeonggi-do
country: Korea, Republic of
facility: Myongji Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Hanyang University Seoul Hospital
city: Seoul
country: Korea, Republic of
facility: Konkuk University Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul St Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University Hospital (Seoul)
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University Mokdong Hospital
city: Ciudad de México
country: Mexico
facility: Mexico Centre for Clinical Research
state: Mexico CITY (federal District)
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr Jose Eleuterio Gonzalez UANL; Depto.de NeurologíaPta.BajaConsulta
state: Nuevo LEON
city: Monterrey
country: Mexico
facility: AVIX Investigación Clínica S.C
state: Nuevo LEON
city: Culiacán Rosales
country: Mexico
facility: Hospital Angeles Culiacan; Neurociencias
state: Sinaloa
city: Amsterdam
country: Netherlands
facility: Brain Research Center B.V
city: ?cinawa
country: Poland
facility: O?rodek Badawczo-Naukowo-Dydaktyczny Chorób Ot?piennych w ?cinawie
city: Bia?ystok
country: Poland
facility: Podlaskie Centrum Psychogeriatrii
city: Bydgoszcz
country: Poland
facility: NZOZ Vitamed
city: Lublin
country: Poland
facility: KO-MED Centra Kliniczne Lublin II
city: Plewiska
country: Poland
facility: Neurologiczny NZOZ Centrum Leczenia SM; Osrodek Badan Klinicznych
city: Siemianowice ?l?skie
country: Poland
facility: NEURO-CARE Sp. z o.o. Sp. Komandytowa
city: Sopot
country: Poland
facility: Senior Sp. Z O.O. Poradnia Psychogeriatryczna
city: Warszawa
country: Poland
facility: mMED Maciej Czarnecki
city: Warszawa
country: Poland
facility: Pratia S.A.
city: Wroc?aw
country: Poland
facility: NZOZ WCA
city: Amadora
country: Portugal
facility: Hospital Prof. Dr. Fernando Fonseca; Servico de Neurologia
city: Braga
country: Portugal
facility: Hospital de Braga; Servico de Neurologia
city: Coimbra
country: Portugal
facility: HUC; Servico de Neurologia
city: Guimarães
country: Portugal
facility: Hospital da Senhora da Oliveira-Guimarães; Serviço de Neurologia
city: Porto
country: Portugal
facility: Hospital Geral de Santo Antonio; Servico de Neurologia
city: Bayamon
country: Puerto Rico
facility: Santa Cruz Behavioral PSC
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico - Medical Science Campus; Internal Medicine
city: Singapore
country: Singapore
facility: National University Hospital (NUH); Neuroscience
city: Singapore
country: Singapore
facility: National Neuroscience Institute; Neurology
city: Elche
country: Spain
facility: Hospital General Universitario de Elche; Servicio de Neurología
state: Alicante
city: Terrassa
country: Spain
facility: Hospital Mutua De Terrasa; Servicio de Neurologia
state: Barcelona
city: Plasencia
country: Spain
facility: Hospital Virgen del Puerto. Servicio de Neurología
state: Caceres
city: Donostia-san Sebastian
country: Spain
facility: Policlínica Guipuzcoa; Servicio de Neurología
state: Guipuzcoa
city: Lleida
country: Spain
facility: Hospital Universitario de Santa Maria; Servicio de Neurología
state: Lerida
city: Pozuelo de Alarcon
country: Spain
facility: Hospital Quiron de Madrid; Servicio de Neurologia
state: Madrid
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra; Servicio de Neurología
state: Navarra
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
state: Navarra
city: Getxo
country: Spain
facility: CAE OROITU; Servicio de Neurología
state: Vizcaya
city: Barcelona
country: Spain
facility: Hospital del Mar; Servicio de Neurologia
city: Barcelona
country: Spain
facility: Fundación ACE; Servicio de Neurología
city: Madrid
country: Spain
facility: Universitario de La Princesa; Servicio de Neurología
city: Sevilla
country: Spain
facility: Hospital Victoria Eugenia; Servico Neurología
city: Valencia
country: Spain
facility: Hospital Universitario la Fe; Servicio de Neurologia
city: Zamora
country: Spain
facility: Complejo Asistencial de Zamora; Servicio Psiquiatria
city: Malmö
country: Sweden
facility: Skånes Universitetssjukhus Malmö, Minneskliniken
city: Mölndal
country: Sweden
facility: Sahlgrenska Academy University,Neuroscience and Physiology;Departmt of Psychiatry and Neurochemistry
city: Stockholm
country: Sweden
facility: KAROLINSKA UNI HOSPITAL, HUDDINGE; Mottagning Kognitiv Forskning, M54
city: Istanbul
country: Turkey
facility: Istanbul University Istanbul School of Medicine; Neurology
city: Istanbul
country: Turkey
facility: Bezmialem Vakif Univ Medical
city: Samsun
country: Turkey
facility: Ondokuz Mayis Univ. Med. Fac.; Neurology
city: Aberdeen
country: United Kingdom
facility: Royal Cornhill Hospital; OAP Directorate
city: Bath
country: United Kingdom
facility: The Rice Centre; Royal United Hospital
city: Birmingham
country: United Kingdom
facility: Re-Cognition
city: Cheltenham
country: United Kingdom
facility: The Fritchie Centre, Charlton Lane Centre, Charlon Lane, Leckhampton; The Fritchie Centre
city: Chertsey
country: United Kingdom
facility: Surrey and Borders NHS Foundation Trust; Brain Science Research Unit
city: Crowborough
country: United Kingdom
facility: Sussex Partnership NHS Foundation Trust; Cognitive Treatment and Research unit
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital; Clinical Research Facility
city: London
country: United Kingdom
facility: St George's Hospital
city: London
country: United Kingdom
facility: RE:Cognition Health
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: Newcastle
country: United Kingdom
facility: Campus for Ageing and Vitality
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital Sheffield Teaching Hospitals NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: University Southampton NHS Foundation Trust; Wessex Neurologica Centre
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: