A Study to Evaluate the Efficacy and Safety of Gantenerumab in Participants at Risk for or at the Earliest Stages of Alzheimer's Disease (AD)
- Registration Number
- NCT05256134
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
A study to evaluate the efficacy and safety of gantenerumab in amyloid-positive, cognitively unimpaired participants at risk for or at the earliest stages of AD. The planned number of participants for this study is approximately 1200 participants randomized in a 1:1 ratio to receive either gantenerumab or placebo (600 participants randomized to gantenerumab ...
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 25
- Willing and able to comply with the study protocol and complete all aspects of the study [including cognitive and functional assessments, physical and neurological examinations, MRI, CSF collection, genotyping, and positron emission tomography (PET) imaging].
- Cognitively unimpaired with a screening clinical dementia rating global score (CDR-GS) of 0, and Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index (RBANS DMI) >=80.
- Evidence of cerebral amyloid accumulation.
- Participants who have an available person (referred to as a "study partner").
- Fluent in the language of the tests used at the study site.
- Adequate visual and auditory acuity, sufficient to perform neuropsychological testing (eye glasses and hearing aids are permitted).
- Agreed not to participate in other interventional research studies for the duration of this trial.
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 17 weeks after the final dose of study treatment.
Key
- Any evidence of an underlying neurological or neurodegenerative condition that may lead to cognitive impairment other than AD.
- Clinical diagnosis of mild cognitive impairment (MCI), prodromal AD, or any form of dementia.
- History or presence of intracranial or intracerebral vascular malformations, aneurysm, subarachnoid hemorrhage, or intracerebral macrohemorrhage.
- History or presence of posterior reversible encephalopathy syndrome.
- History of ischemic stroke with clinical symptoms or an acute event that is consistent with a transient ischemic attack within 12 months of screening.
- History of severe, clinically significant (i.e., resulting in persistent neurologic deficit or structural brain damage) central nervous system (CNS) trauma (e.g., cerebral contusion).
- History or presence of intracranial mass lesion (e.g., glioma, meningioma) that could potentially impair cognition or lead to progressive neurological deficits.
- Infections that may affect brain function or a history of infections that resulted in neurologic sequelae [e.g., human immunodeficiency virus (HIV), syphilis, neuroborreliosis, and viral or bacterial meningitis and encephalitis].
- History of major depression, schizophrenia, schizoaffective disorder, or bipolar disorder.
- At risk for suicide.
- History of alcohol and/or substance abuse or dependence.
- History or presence of clinically significant systemic vascular disease, atrial fibrillation or heart failure.
- Within the last year, experienced unstable or clinically significant cardiovascular disease (e.g., myocardial infarction).
- Uncontrolled hypertension.
- Chronic kidney disease, indicated by creatinine clearance <30 mL/min.
- Confirmed and unexplained impaired hepatic function.
- History of, or are known to currently have an HIV infection, or hepatitis B or hepatitis C virus infection that has not been adequately treated.
- History or presence of systemic autoimmune disorders that may lead to progressive neurological impairment with associated cognitive deficits.
- Systemic immunosuppression or immunomodulation due to the continuing effects of immunosuppressant or immunomodulating medications.
- Current COVID-19 infection.
- Evidence of folic acid or vitamin B-12 deficiency.
- Any passive immunotherapy (Ig) or other long-acting biologic agent to prevent or postpone cognitive decline within 1 year of screening.
- Any other investigational treatment within 5 half-lives or 6 months (whichever is longer) prior to screening.
- Typical/Atypical anti-psychotic medications or neuroleptic medications.
- Anticoagulation medications within 3 months of screening with no plans to initiate any prior to randomization.
- Any previous treatment with cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists are exclusionary at screening.
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 17 weeks after the final dose of gantenerumab.
- Impaired coagulation.
- Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins, including gantenerumab and gantenerumab excipients.
- Participants who reside in a skilled nursing facility such as a convalescent home or long-term care facility.
- Participants who require residence in such facilities during the study may continue in the study and be followed for efficacy and safety, provided that they have a study partner who meets the study partner requirements.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Placebo will be administered as SC injection with gradual uptitration. Gantenerumab Gantenerumab Gantenerumab will be administered as subcutaneous (SC) injection with gradual uptitration.
- Primary Outcome Measures
Name Time Method Change From Baseline in PACC-5 Score Baseline to early termination visit (up to 225 days from start of treatment) The PACC-5 is computed as the average of z-scores of the following cognitive measures: 1. Wechsler Memory Scale (WMS LM I-II) - Total Score LM II Delayed Recall; 2. Free \& Cued Selective Reminding Test (FCSRT) -Immediate and Delayed Recall - Trials 1-3: Total Recall; 3. Wechsler Adult Intelligence Scale (WAIS) - IV Coding - Total Raw Score; 4. Mini Mental S...
- Secondary Outcome Measures
Name Time Method Time to Onset of Confirmed Clinical Progression Randomization to early termination Visit (up to 225 days from start of treatment) Time to onset of confirmed clinical progression was defined as the time from randomization to the first occurrence of two consecutive visits (approximately 6 months apart) with a Clinical Dementia Rating Global Score (CDR-GS) of \> 0. CDR is a clinician reported (ClinRO) measure used to stage severity of AD dementia based on a semi-structured interview with ...
Change From Baseline in the Cognitive Function Instrument Acute (CFIa) Participant Version Baseline to early termination visit (up to 225 days from start of treatment) The CFIa is an outcome measure developed to assess memory-related cognitive and functional decline in non-demented elderly individuals. The CFIa is a modified version of the original CFI and differs in terms of recall period and item response options. The CFIa is computed as the sum of 14 items, rated on a 5-point Likert scale ranging from Never=0 to Always=...
Number of Participants With Post-baseline Suicidal Behaviors and Ideations as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score Day 1 to safety follow-up visit (up to 310 days from start of treatment) The C-SSRS is an assessment tool used to assess the lifetime suicidality of a participant (baseline) as well as any new instances of suicidality (since last visit). The structured interview prompts recollection of suicidal ideation (SI), including the intensity of the ideation, behavior, \& attempts with actual or potential lethality. Categories have binary ...
Change From Baseline in the Amsterdam Instrumental Activities of Daily Living Questionnaire Short Version (A-IADL-Q-SV) Baseline to early termination visit (up to 225 days from start of treatment) A-IADL-Q-SV=observer reported (ObsRO) measure assessing participant's ability to perform instrumental activities of daily living (including household/leisure activities, use of household appliances, management of finances, etc.). A-IADL-Q-SV includes 30 items rated by study partner. Each item is divided into 2 questions=1st question asks if activity was perf...
Number of Participants With Injection-site Reactions (ISRs) Day 1 to safety follow-up visit (up to 310 days from start of treatment) An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Local injection reactions (or injection-site reactions) are defined as AEs related to the injection site that occur during or within 24 hours after study drug adm...
Time From Randomization to Clinical Progression to Mild Cognitive Impairment (MCI) or Dementia Due to AD Randomization to early termination Visit (up to 225 days from start of treatment) Time from randomization to clinical progression to mild cognitive impairment or dementia due to Alzheimer's disease was based on the diagnosis of the independent Clinical Adjudication Committee (iCAC).
Change From Baseline in the CFIa Study Partner Version Baseline to early termination visit (up to 225 days from start of treatment) The CFIa is an outcome measure developed to assess memory-related cognitive and functional decline in non-demented elderly individuals. The CFIa is a modified version of the original CFI and differs in terms of recall period and item response options. The CFIa is computed as the sum of 14 items, rated on a 5-point Likert scale ranging from Never=0 to Always=...
Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB) Baseline to early termination visit (up to 225 days from start of treatment) The CDR is a ClinRO measure used to stage the severity of AD dementia based on a semi-structured interview with the participant and a reliable informant. The CDR characterizes the participant's level of cognitive and functional impairment across six domains (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal ...
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs) Day 1 to safety follow-up visit (up to 310 days from start of treatment) An AE is any untoward medical occurrence in a patient or clinical study participant temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation o...
Number of Participants With Anti-Drug Antibodies (ADAs) to Gantenerumab Day 1 to early termination visit (up to 216 days from start of treatment) The number of ADA-positive participants after drug administration were determined for participants exposed to gantenerumab. For determining post-baseline incidence, participants were considered to be ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure, or if they were ADA-positive...
Number of Participants With Magnetic Resonance Imaging (MRI) Findings: Amyloid-related Imaging Abnormalities - Edema/Effusion (ARIA-E) and ARIA-Hemosiderin Deposition (ARIA-H) Day 1 to early termination visit (up to 248 days from start of treatment) ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. In ARIA-E, (E for edema or effusion), edema can be seen in different areas of the brain on MRI, representing fluid leakage into the brain parenchyma or sulcal spaces. ARIA-H (H for hemosiderosis) are small foci of signal loss observ...
Change in Brain Amyloid Load Over Time as Measured by Amyloid Positron Emission Tomography (PET) in a Subset of Participants Baseline Brain amyloid load over time was planned to be assessed using \[18F\] florbetaben or \[18F\] flutemetamol tracers. These are PET radioligand selective to amyloid. Amyloid PET burden is measured in a composite region of interest (ROI) by using standardized uptake value ratio (SUVR) mapped to the centiloid scale. The weighted composite target region are compos...
Change in Brain Tau Load Over Time as Measured by Tau PET in a Subset of Participants Baseline Change in tau load represents how much neurofibrillary tau pathology is present in brain assessed using PET scan. For the longitudinal tau PET assessment, \[18F\]-MK-6240 was used. Tau load is measured using SUVR in four composite target ROIs: Temporal composite target region included (both left \& right) anterior \& posterior superior temporal gyrus, poster...
Change in Cerebrospinal Fluid (CSF) Amyloid (A) Peptide Beta (β): Aβ 1-42 Over Time in a Subset of Participants Baseline Amyloid beta is a peptide fragment of the amyloid precursor protein.
Change in CSF Amyloid Peptide: Aβ 1-40 Over Time in a Subset of Participants Baseline Amyloid beta is a peptide fragment of the amyloid precursor protein.
Change in CSF Phosphorylated Tau (pTau) Over Time in a Subset of Participants Baseline CSF pTau is an indicator of neuronal injury and neurodegeneration. An elevation in levels specific pTau species, is thought to be a marker for progressive cellular degeneration in AD.
Change in CSF Neurofilament Light (NFL) Over Time in a Subset of Participants Baseline NFL is a neuronal cytoplasmic protein highly expressed in large, myelinated axons. Its levels increase in CSF proportionally to the degree of axonal damage in a variety of neurological disorders, including AD.
Change in CSF Total Tau (tTau) Over Time in a Subset of Participants Baseline CSF biomarker tTau has been considered as a general marker of neurodegeneration. An elevation in levels of tau, is thought to be a marker for progressive cellular degeneration in AD.
Change in Whole Brain Volume Over Time as Determined by MRI in a Subset of Participants Baseline Whole brain volume is measured by volumetric MRI (vMRI). Volumetric imaging is a three dimensional (3D) technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Whole brain volume represents a summary measure of total brain parenchyma which includes the cer...
Change in Total Ventricular Volume Over Time as Determined by MRI in a Subset of Participants Baseline Total Ventricular Volume is measured by vMRI. Volumetric imaging is a 3D technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Total ventricular volume represents a summary measure of total including right and left lateral ventricles, third ventricle and...
Change in Hippocampal Volume Over Time as Determined by MRI in a Subset of Participants Baseline Total hippocampal volume is measured by vMRI. Volumetric imaging is a 3D technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Total hippocampal volume is calculated by summing up right and left hippocampal volumes.
Trial Locations
- Locations (63)
Visionary Investigators Network - Neurology Aventura
🇺🇸Aventura, Florida, United States
Neuropsychiatric Research; Center of Southwest Florida
🇺🇸Fort Myers, Florida, United States
Premiere Research Institute
🇺🇸West Palm Beach, Florida, United States
Velocity Clinical Research
🇺🇸East Syracuse, New York, United States
Kerwin Medical Center
🇺🇸Dallas, Texas, United States
Re:Cognition Health
🇺🇸Fairfax, Virginia, United States
Toronto Memory Program
🇨🇦Toronto, Ontario, Canada
KLIMED
🇵🇱Bia?ystok, Poland
Optimus U Corp
🇺🇸Miami, Florida, United States
Renstar Medical Research
🇺🇸Ocala, Florida, United States
Bradenton Research Center
🇺🇸Bradenton, Florida, United States
Brain Matters Research, Inc.
🇺🇸Delray Beach, Florida, United States
Banner Sun Health Research Insitute
🇺🇸Sun City, Arizona, United States
Center for Advanced Research & Education
🇺🇸Gainesville, Georgia, United States
Via Christi Research
🇺🇸Wichita, Kansas, United States
Quest Research Institute
🇺🇸Farmington Hills, Michigan, United States
Ohio State University; College of Medicine
🇺🇸Columbus, Ohio, United States
Senior Adults Specialty Research
🇺🇸Austin, Texas, United States
Alzheimer's Memory Center
🇺🇸Matthews, North Carolina, United States
KaRa Institute of Neurological Diseases
🇦🇺Macquarie Park, New South Wales, Australia
Fundación ACE; Servicio de Neurología
🇪🇸Barcelona, Spain
IRCCS Ospedale San Raffaele; U.O. di Neurologia
🇮🇹Milano, Lombardia, Italy
NZOZ Vitamed
🇵🇱Bydgoszcz, Poland
NZOZ NEURO-KARD Ilkowski i Partnerzy Sp. Partn. Lek
🇵🇱Pozna?, Poland
Senior Sp. Z O.O. Poradnia Psychogeriatryczna
🇵🇱Sopot, Poland
IRCCS Neuromed; Neurologia I-Centro studio e cura delle demenze e UVA
🇮🇹Pozzilli, Molise, Italy
Centrum Medyczne Euromedis Sp. z o.o.
🇵🇱Szczecin, Poland
Heidelberg Repatriation Hospital; Medical and Cognitive Research Centre
🇦🇺Heidelberg West, Victoria, Australia
Okanagan Clinical Trials
🇨🇦Kelowna, British Columbia, Canada
Australian Alzheimer's Research Foundation
🇦🇺Nedlands, Western Australia, Australia
Kawartha Centre - Redefining Healthy Aging
🇨🇦Peterborough, Ontario, Canada
NZOZ WCA
🇵🇱Wroc?aw, Poland
BARCELONABETA BRAIN RESEARCH CENTER (BBRC); FUNDACIÓN PASQUAL MARAGALL, Servicio de Neurologia
🇪🇸Barcelona, Spain
Hospital Quiron de Madrid; Servicio de Neurologia
🇪🇸Pozuelo de Alarcon, Madrid, Spain
KAROLINSKA UNI HOSPITAL, HUDDINGE; Mottagning Kognitiv Forskning, M54
🇸🇪Stockholm, Sweden
Panthera Biopartners Sheffield
🇬🇧Sheffield, United Kingdom
Southampton General Hospital
🇬🇧Southampton, United Kingdom
Hospital Virgen del Rocío; Servicio de Neurología
🇪🇸Sevilla, Spain
Banner Alzheimer's Institute
🇺🇸Tucson, Arizona, United States
ClinCloud, LLC
🇺🇸Maitland, Florida, United States
Banner Alzheimer?s Institute
🇺🇸Phoenix, Arizona, United States
JEM Research LLC
🇺🇸Atlantis, Florida, United States
California Neuroscience Research Medical Group, Inc
🇺🇸Sherman Oaks, California, United States
K2 Medical Research, LLC
🇺🇸Maitland, Florida, United States
Alzheimer?s Research and Treatment Center
🇺🇸Wellington, Florida, United States
Charter Research - Lady Lake/The Villages
🇺🇸The Villages, Florida, United States
Progressive Medical Research
🇺🇸Port Orange, Florida, United States
University of Nebraska Medical Center; Dept of Neurological Sciences
🇺🇸Omaha, Nebraska, United States
Great Lakes Clinical Trials
🇺🇸Chicago, Illinois, United States
Instituto Kremer
🇦🇷Córdoba, Argentina
Dong-A University Hospital
🇰🇷Busan, Korea, Republic of
Konkuk University Medical Center
🇰🇷Seoul, Korea, Republic of
Gachon University Gil Medical Center
🇰🇷Incheon, Korea, Republic of
Sahlgrenska Academy University,Neuroscience and Physiology;Departmt of Psychiatry and Neurochemistry
🇸🇪Mölndal, Sweden
Re-Cognition
🇬🇧Birmingham, United Kingdom
University of Exeter; College of Medicine and Health
🇬🇧Exeter, United Kingdom
Charter Research - Winter Park/Orlando
🇺🇸Orlando, Florida, United States
The Cognitive and Research Center of New Jersey
🇺🇸Springfield, New Jersey, United States
True North Clinical Research-Halifax
🇨🇦Halifax, Nova Scotia, Canada
Fondazione Santa Lucia IRCCS; Neurologia e Riabilitazione Neurologica
🇮🇹Roma, Lazio, Italy
Tandem Clinical Research, LLC
🇺🇸Marrero, Louisiana, United States
AO di Perugia - Ospedale S. Maria della Misericordia; Clinica Neurologica
🇮🇹Perugia, Umbria, Italy
Alzheimer's Research and Treatment Center
🇺🇸Stuart, Florida, United States