A Study of Gantenerumab in Participants With Mild Alzheimer Disease

Alzheimer's Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02051608
• Other study ID #: WN28745
• Secondary ID: 2013-003390-95
• Status: Completed
• Phase: Phase 3
• Start date: March 27, 2014
• Est. completion date: April 16, 2021

Study information

• Verified date: February 2023
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 389
• Est. completion date: April 16, 2021
• Est. primary completion date: April 16, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 90 Years

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease

Intervention

Drug:
• Placebo
Participants received Placebo SC injection Q4W.
• Gantenerumab
Participants received Gantenerumab at 105 mg , 225 mg, or at doses up to 1200 mg SC injection Q4W.

Locations

Country	Name	City	State
Argentina	Instituto Neurologia Bs As	Ciudad Autonoma Buenos Aires
Australia	Royal Adelaide Hospital; Memory Trials Centre	Adelaide	South Australia
Australia	Heidelberg Repatriation Hospital; Medical and Cognitive Research Centre	Heidelberg West	Victoria
Australia	Australian Alzheimer's Research Foundation	Nedlands	Western Australia
Australia	The Queen Elizabeth Hospital; Neurology	Woodville	South Australia
Belgium	Cliniques Universitaires St-Luc	Bruxelles
Belgium	UZ Leuven Gasthuisberg	Leuven
Bulgaria	Shat Np Sveti Naum; 3Rd Clinic of Neurology	Sofia
Bulgaria	MBAL St. Marina; First Neurology Department	Varna
Canada	Jbn Medical Diagnostic Services Inc.	Burlington	Ontario
Canada	University of Calgary; Heritage Medical Research Clinic	Calgary	Alberta
Canada	Recherches Neuro-Hippocame	Gatineau	Quebec
Canada	NeuroSearch Developpements inc	Greenfield Park	Quebec
Canada	True North Clinical Research-Halifax	Halifax	Nova Scotia
Canada	Parkwood Hospital; Geriatric Medicine	London	Ontario
Canada	Jewish General Hospital / McGill University	Montreal	Quebec
Canada	True North Clinical Research	New Minas	Nova Scotia
Canada	Kawartha Centre - Redefining Healthy Aging	Peterborough	Ontario
Canada	Alpha Recherche Clinique	Quebec
Canada	Centre Hospitalier Affilie Universitaire de Quebec - Hopital de L'Enfant Jesus	Quebec City	Quebec
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	Toronto Memory Program	Toronto	Ontario
Canada	McGill Univeristy; Douglas Mental Health University Institute; Neurological and Psychiatric	Verdun	Quebec
Denmark	Aarhus Universitetshospital, Neurologisk Afdeling F, Demensklinikken	Aarhus N
Denmark	Rigshospitalet, Hukommelsesklinikken	Koebenhavn Oe
Finland	University of Eastern Finland	Kuopio
Finland	CRST Oy	Turku
France	Hopital Pellegrin; Cmrr Aquitaine	Bordeaux
France	Hopital Pierre Wertheimer; Laboratoire De Neuro Psychologie	Bron
France	CHU de Limoges Hopital Dupuytren; Service de Medecine Geriatrique	Limoges
France	CHU de la Timone - Hopital d Adultes; Service de Neurologie	Marseille
France	CHU Rennes - hopital Hotel Dieu; Consultation Memoire - Gerontologie	Rennes
France	Hopital Hautepierre; Centre dInvestigation Clinique	Strasbourg
France	Hopital la Grave; Gerontopole - Centre de Recherche Clinique	Toulouse
Germany	ECRC Experimental and Clinical Research Center, Charité Campus Berlin Buch, Memory Clinic	Berlin
Germany	PANAKEIA - Arzneimittelforschung Leipzig GmbH	Leipzig
Germany	Pharmakologisches Studienzentrum	Mittweida
Germany	Klinikum rechts der Isar der TU München; Klinikapotheke	Muenchen
Germany	Neurologische Praxis Dr. Andrej Pauls	München
Germany	Universitätsklinikum Ulm; Klinik für Neurologie	Ulm
Germany	Studienzentrum Nordwest, Dr. med. Joachim Springub / Herr Wolfgang Schwarz	Westerstede
Hungary	Semmelweis University; Department of Neurology	Budapest
Italy	IRCCS "Centro S. Giovanni di Dio" Fatebenefratelli -UO Alzheimer	Brescia	Lombardia
Italy	Irccs Multimedica Santa Maria; Unita' Di Neurologia	Castellanza	Lombardia
Italy	Nuovo Ospedale Civile S. Agostino-Estense; Clinica Neurologica - Dipartimento di Neuroscienze	Modena	Emilia-Romagna
Italy	ASST DI MONZA; Neurologia	Monza	Lombardia
Italy	A.O. Universitaria Pisana; Neurologia	Pisa	Toscana
Italy	Azienda Ospedaliera Universitaria Policlinico Tor Vergata; Neurologia	Roma	Lazio
Italy	Umberto I Policlinico di Roma-Università di Roma La Sapienza	Roma	Lazio
Japan	Juntendo University Urayasu Hospital; Neurology	Chiba
Japan	Medical Corporation Hakuyokai Kashiwado Hospital	Chiba
Japan	National Hospital Organization Chiba-east Hospital; Neurology	Chiba
Japan	Fukuoka University Hospital; Neurology and Health Care	Fukuoka
Japan	Maebashi Red Cross Hospital; Neurology	Gunma
Japan	National Hospital Organization Hiroshima-Nishi Medical Center	Hiroshima
Japan	Hyogo Brain and Heart Center at Himeji; Department of Aging Brain and Cognitive Disorders	Hyogo
Japan	Shonan Kamakura General Hospital; Neurology	Kanagawa
Japan	Oita University Hospital; Neurology	Oita
Japan	Kurashiki Heisei Hospital; Neurology	Okayama
Japan	Shizuoka City Shimizu Hospital; Neurology	Shizuoka
Korea, Republic of	Dong-A University Medical Center	Busan
Korea, Republic of	Seoul National University Bundang Hospital; Neurology Department	Gyeonggi-do
Korea, Republic of	Inha University Hospital; Neurology Department	Incheon
Korea, Republic of	Asan Medical Center.	Seoul
Korea, Republic of	Ewha Womans University Hospital (Seoul)	Seoul
Korea, Republic of	Ewha Womans University Mokdong Hospital; Dept of Neurology	Seoul
Korea, Republic of	Konkuk University Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Netherlands	Brain Research Center B.V	Amsterdam
Netherlands	Erasmus Mc - Locatie Centrum; Dept of Neurology	Rotterdam
Portugal	Hospital Prof. Dr. Fernando Fonseca; Servico de Neurologia	Amadora
Portugal	Hospital de Santa Maria; Servico de Neurologia	Lisboa
Russian Federation	State Autonomous Healthcare Institution "Republican Clinical Neurological Center	Kazan
Russian Federation	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	SBEI of HPI The 1st Moscow State Medical University n.a. I.M. Sechenov of MOH of RF	Moscow
Russian Federation	Saint Petersburg State Institution of Healthcare City Geriatric Medico-Social Center	Saint Petersburg
Russian Federation	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
Spain	Hospital de Cruces; Servicio de Neurologia	Barakaldo	Vizcaya
Spain	Fundació ACE	BArcelon	Barcelona
Spain	Hospital del Mar; Servicio de Neurologia	Barcelona
Spain	Policlínica Guipuzkoa; Servicio de Neurología	Donosti-San Sebastián	Guipuzcoa
Spain	Hospital General Universitario de Elche; Servicio de Neurología	Elche	Alicante
Spain	Hospital Universitario 12 de Octubre; Servicio de Neurologia	Madrid
Spain	Hospital Universitario Virgen Macarena; Servicio de Neurologia	Sevilla
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Sweden	Skånes Universitetssjukhus Malmö, Minneskliniken	Malmö
Sweden	KAROLINSKA UNI HOSPITAL, HUDDINGE; Mottagning Kognitiv Forskning, M54	Stockholm
Switzerland	Felix Platter-Spital Medizin Geriatrie	Basel
Switzerland	CHUV Lausanne Memory clinique	Lausanne
Turkey	Istanbul University Istanbul School of Medicine; Neurology	Istanbul
Turkey	Dokuz Eylul University Medicine Faculty; Noroloji Departmani	Izmir
Turkey	Ondokuz Mayis University School of Medicine; Neurology	Samsun
United Kingdom	Sussex Partnership NHS Foundation Trust; Cognitive Treatment and Research unit	Crowborough
United Kingdom	Glasgow Memory Clinic	Glasgow
United Kingdom	Charing Cross Hospital; Dept of Neurosciences	London
United Kingdom	Manchester Royal Infirmary	Manchester
United Kingdom	Royal Preston Hosptial	Preston
United Kingdom	Memory Service North	Sheffield
United States	Abington Neurological Associates	Abington	Pennsylvania
United States	Senior Adults Specialty Research	Austin	Texas
United States	Pennington Biomedical Research Center	Baton Rouge	Louisiana
United States	Meridien Research	Brooksville	Florida
United States	Neurology Clinic PC	Cordova	Tennessee
United States	ATP Clinical Research, Inc	Costa Mesa	California
United States	Brain Matters Research, Inc.	Delray Beach	Florida
United States	Rhode Island Mood & Memory Research Institute	East Providence	Rhode Island
United States	Neuropsychiatric Research; Center of Southwest Florida	Fort Myers	Florida
United States	Indiana University	Indianapolis	Indiana
United States	Western Michigan University Homer Stryker M.D. School of Medicine Center for Clinical Research	Kalamazoo	Michigan
United States	Alzheimer's Research Corporation	Manchester	New Jersey
United States	Alzheimer's Memory Center	Matthews	North Carolina
United States	Miami Jewish Health Systems; Clinical Research	Miami	Florida
United States	Louisiana Research Associates	New Orleans	Louisiana
United States	Nathan Kline Institute	Orangeburg	New York
United States	Accelerated Enrollment Solutions	Orlando	Florida
United States	Northeastern Pennsylvania Memory	Plains	Pennsylvania
United States	Richard H Weisler, MD	Raleigh	North Carolina
United States	Millennium Psychiatric Associates, LLC	Saint Louis	Missouri
United States	University of Utah, Center for Alzheimer's Care Imaging & Research	Salt Lake City	Utah
United States	Pacific Research Network - PRN	San Diego	California
United States	California Neuroscience Research Medical Group, Inc	Sherman Oaks	California
United States	Richmond Behavioral Associates	Staten Island	New York
United States	Banner Sun Health Research Insitute	Sun City	Arizona
United States	University of South Florida	Tampa	Florida
United States	Ocean Rheumatology	Toms River	New Jersey
United States	Territory Neurology and Research Institute	Tucson	Arizona
United States	Central States Research	Tulsa	Oklahoma
United States	Alzheimer's Research and Treatment Center	Wellington	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Bulgaria,  Canada,  Denmark,  Finland,  France,  Germany,  Hungary,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Portugal,  Russian Federation,  Spain,  Sweden,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Part 1: Mean Change From Baseline in Alzheimer's Disease Activity Scale-Cognitive Subscale 13 (ADAS-Cog13) Scores at Week 104		Baseline, Week 104
Other	Part 1: Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scores at Week 104		Baseline, Week 104
Other	Part 1: Percentage Change From Baseline in Total Tau (T-tau) in CSF at Week 104		Baseline, Week 104
Other	Part 1: Percentage Change From Baseline in Abeta 1-42 Levels in CSF at Week 104		Baseline, Week 104
Other	Part 1: Percentage Change From Baseline in Phosphorylated Tau [P-tau] in CSF at Week 104		Baseline, Week 104
Other	Part 1: Percent Change From Baseline in Hippocampal Volume at Week 104		Baseline, Week 104
Other	Part 1: Percent Change From Baseline in Whole Brain Volume at Week 104		Baseline, Week 104
Other	Part 1: Percent Change From Baseline in Cortical Thickness at Week 104		Baseline, Week 104
Other	Part 1: Ventricular Volume as Measured by MRI at Week 104		Baseline, Week 104
Other	Part 1: Change From Baseline in Clinical Dementia Rating Global Score (CDR-GS) at Week 104		Baseline, Week 104
Other	Part 1: Change From Baseline in CDR Sum of Boxes (SB) at Week 104		Baseline, Week 104
Other	Part 1: Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 104		Baseline, Week 104
Other	Part 1: Change From Baseline in NPI Domain Score at Week 104		Baseline, Week 104
Other	Part 1: Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 104		Baseline, Week 104
Other	Part 1: Change From Baseline in Alzheimer's Dementia (QoL-AD) Global Score at Week 104		Baseline, Week 104
Other	Part 1: Change From Baseline in Symptom Guide Facilitated (GAS) at Week 104		Baseline, Week 104
Other	Part 1: Change From Baseline in Dependence Scale (DS) at Week 104		Baseline, Week 104
Other	Part 1: Change From Baseline in Resource Utilization Dementia-Lite (RUD - Lite) Scale at Week 104		Baseline, Week 104
Other	Part 1: Change From Baseline in Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) at Week 104		Baseline, Week 104
Other	Part 1: Time to Clinical Decline		Baseline up to Week 104
Other	Part 1: Change From Baseline in Clinical Composite Score (Prespecified Items From The ADAS-Cog, MMSE, and CDR) at Week 104		Baseline, Week 104
Other	Part 1: Percentage of Participants With ADAS-Cog Response		Baseline up to Week 152
Primary	Part 2: Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs)	An AE 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. SAE is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment.	First dose up to 4 weeks after the last dose of study drug (up to 249 weeks)
Primary	Part 2: Percentage of Participants With Treatment Emergent Anti-Drug Antibodies (ADAs)	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 participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage 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 percentage 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.	First dose up to last dose (Baseline up to until maximum 5 years)
Primary	Part 2: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment	Percentage of participants with adverse events leading to discontinuation from treatment were reported.	First dose up to 4 weeks after the last dose in OLE (Up to approximately 249 weeks)
Secondary	Part 1: Percentage of Participants With AEs, SAEs	An AE 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. A serious adverse event is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment.	First dose up to last dose (Up to approximately 152 weeks)
Secondary	Part 1: Percentage of Participants With Treatment Emergent ADAs	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 participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage 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 percentage 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.	First dose up to last dose (Up to approximately 152 weeks)
Secondary	Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints		Pre-dose: Weeks 4, 8, 12, 24, 48, 72 and Post dose: Day 4
Secondary	Part 1: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment	Percentage of participants with adverse events leading to discontinuation from treatment were reported.	First dose up to last dose (Up to approximately 152 weeks)
Secondary	Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104	Change from baseline in hippocampal right volume (HRV) and hippocampal left volume (HLV) were analyzed at Week 104 using magnetic resonance imaging.	Baseline (Part 1 screening), Week 104
Secondary	Part 2: Percent Change From Baseline in Whole Brain Volume at Week 104	Change from baseline brain volume were analyzed at Week 104 using magnetic resonance imaging.	Baseline (Part 1 screening), Week 104
Secondary	Part 2: Percent Change From Baseline in Cortical Thickness at Week 104	Change from baseline in cortical thickness were analyzed at Week 104 using magnetic resonance imaging.	Baseline (Part 1 screening), Week 104
Secondary	Part 2: Ventricular Volume as Measured by MRI at Week 104	Ventricular volume were analyzed at Week 104 using magnetic resonance imaging.	Part 2: Week 104
Secondary	Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints		Pre-dose: Weeks 104, 116, 156, 208; Post-dose: Weeks 53, 101
Secondary	Part 2: Change From Baseline in Brain Amyloid Load at Week 156 in a Subset of Participants	Brain amyloid load over time was assessed using a Florbetapir [F18] injection, a positron emission tomography (PET) radioligand selective to amyloid. Analysis was conducted in a subset of participants who signed consent to participate in the PET substudy. Amyloid PET burden was measured in a composite region of interest (ROI) by using standardized uptake value ratio (SUVR) mapped to the centiloid scale. The composite region was composed of the following six bilateral regions: frontal lobe, parietal lobe, temporal lobe, posterior cingulate cortex, anterior cingulate cortex. The reference region used to normalize the composite region was the cerebellar cortex. SUVR is ratio of tracer uptake in each of cingulate, frontal, parietal and temporal cortexes relative to cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scans.	Baseline, Week 156