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)

Phase 3TerminatedNCT05256134

Hoffmann-La Roche25 enrolled

Overview

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 and 600 participants randomized to placebo).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Alzheimers Disease

Interventions

GantenerumabDRUG

Gantenerumab will be administered as per the dosing schedule described in the Arm description.

PlaceboDRUG

Placebo will be administered as per the dosing schedule described in the Arm description.

Eligibility

Sex: ALLMin age: 60 YearsMax age: 80 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: * 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 Exclusion Criteria: * 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.

Locations (63)

Outcomes

Primary Outcomes

Change From Baseline in PACC-5 Score

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 State Examination (MMSE) - Total Score; 5. Category Fluency Test (CFT) - 3 categories - Vegetables, Fruits and Animals - Total Admissible Words. The z-score was defined as the difference between the assessment and the mean of baseline assessments, divided by the standard deviation of baseline assessments. Z-scores range from -3 to +3 with higher scores indicating better cognitive performance.

Time frame: Baseline to early termination visit (up to 225 days from start of treatment)

Secondary Outcomes

Time From Randomization to Clinical Progression to Mild Cognitive Impairment (MCI) or Dementia Due to AD

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).

Time frame: Randomization to early termination Visit (up to 225 days from start of treatment)

Time to Onset of Confirmed Clinical Progression

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 participant \& a reliable informant. CDR characterizes participant's level of cognitive \& functional impairment across six domains (memory, orientation, judgment \& problem solving, community affairs, home \& hobbies, \& personal care) on a 5-point rating. CDR-GS is calculated based on the Washington University CDR-assignment algorithm \& characterizes a participant's level of global impairment/stage of dementia according to following categories: 0 (normal), 0.5 (very mild dementia), 1 (mild dementia), 2 (moderate dementia), \& 3 (severe dementia). Score ranges from 0 to 3 \& a high score on CDR-GS would indicate a high disease severity.

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Banner Alzheimer?s Institute

Phoenix, Arizona, United States

Banner Sun Health Research Insitute

Sun City, Arizona, United States

Banner Alzheimer's Institute

Tucson, Arizona, United States

California Neuroscience Research Medical Group, Inc

Sherman Oaks, California, United States

JEM Research LLC

Atlantis, Florida, United States

Visionary Investigators Network - Neurology Aventura

Aventura, Florida, United States

Bradenton Research Center

Bradenton, Florida, United States

Brain Matters Research, Inc.

Delray Beach, Florida, United States

Neuropsychiatric Research; Center of Southwest Florida

Fort Myers, Florida, United States

ClinCloud, LLC

Maitland, Florida, United States

...and 53 more locations

Time frame: Randomization to early termination Visit (up to 225 days from start of treatment)

Change From Baseline in the Amsterdam Instrumental Activities of Daily Living Questionnaire Short Version (A-IADL-Q-SV)

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 performed by participant during past 4 weeks (Yes/No/Don't know). If performed, 2nd question captures level of difficulty while performing activity on 5-point Likert scale (no difficulty to no longer able to perform the activity). If not performed, 2nd question captures why activity was not performed (never done before, no longer able to do so due to physical problems, no longer able to do so due to difficulties with memory/planning/thinking/other, including free text response). A-IADL-Q-SV=average of all scored responses multiplied by 25. Score range=0-100. Higher scores=better functioning. Negative change from baseline=worsening.

Time frame: Baseline to early termination visit (up to 225 days from start of treatment)

Change From Baseline in the Cognitive Function Instrument Acute (CFIa) Participant Version

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=4 and referring to the participant's current ability (most recent experience). Total scores range from 0 to 56. Higher scores indicate greater cognitive impairment. Negative change from baseline indicates improvement. The participant (PRO) and study partner (ObsRO) versions of the CFIa were used in this study.

Time frame: Baseline to early termination visit (up to 225 days from start of treatment)

Change From Baseline in the CFIa Study Partner Version

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=4 and referring to the participant's current ability (most recent experience). Total scores range from 0 to 56. Higher scores indicate greater cognitive impairment. Negative change from baseline indicates improvement. The PRO and ObsRO versions of the CFIa were used in this study.

Time frame: Baseline to early termination visit (up to 225 days from start of treatment)

Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB)

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 care) on a 5-point rating scale in which 0 = None, 0.5 = questionable, 1 = mild, 2 = moderate, 3 = severe (with the exception of personal care, which is rated on a 4-point rating scale and excludes the questionable impairment level). The CDR-SB is calculated by summing the ratings across each of the six domains (total score: 0 to 18), with higher scores indicating greater impairment. A negative change from baseline indicates improvement.

Time frame: Baseline to early termination visit (up to 225 days from start of treatment)

Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs)

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 of existing hospitalization, results in persistent disability or incapacity, and leads to congenital anomaly or birth defect. An AESI included drug induced liver injury and suspected transmission of infectious agent via medicinal products.

Time frame: Day 1 to safety follow-up visit (up to 310 days from start of treatment)

Number of Participants With Anti-Drug Antibodies (ADAs) to Gantenerumab

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 at baseline and the titer of 1 or more post-baseline samples was at least 4-fold higher in comparison to the titer at the baseline. As prespecified in the protocol, this outcome measure was applicable only to participants exposed to gantenerumab.

Time frame: Day 1 to early termination visit (up to 216 days from start of treatment)

Number of Participants With Magnetic Resonance Imaging (MRI) Findings: Amyloid-related Imaging Abnormalities - Edema/Effusion (ARIA-E) and ARIA-Hemosiderin Deposition (ARIA-H)

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 observed on MRI sequences sensitive for paramagnetic tissue properties and comprise cerebral microbleeds (small foci of bleeding in the brain parenchyma) and leptomeningeal hemosiderosis (small foci of bleeding on the surface of the brain). These changes also occur sporadically in AD.

Time frame: Day 1 to early termination visit (up to 248 days from start of treatment)

Number of Participants With Injection-site Reactions (ISRs)

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 administration that are judged to be related to the study drug injection.

Time frame: Day 1 to safety follow-up visit (up to 310 days from start of treatment)

Number of Participants With Post-baseline Suicidal Behaviors and Ideations as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score

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 responses (yes/no) \& include: Wish to be Dead; Non-specific Active Suicidal Thoughts; Active SI with Any Methods (Not Plan) without Intent to Act; Active SI with Some Intent to Act, without Specific Plan; Active SI with Specific Plan \& Intent, Preparatory Acts \& Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. SI or behavior is indicated by a "yes" answer to any of the listed categories. A score of 0 is assigned if no suicide risk is present. A score of 1 or higher indicates SI or behavior. Only categories with at least one participant with event are reported.

Time frame: Day 1 to safety follow-up visit (up to 310 days from start of treatment)

Change in Brain Amyloid Load Over Time as Measured by Amyloid Positron Emission Tomography (PET) in a Subset of Participants

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 composed of (both left and right side): frontal lobe, parietal lobe, temporal lobe lateral, cingulum posterior and anterior cingulate gyrus. The reference region used to normalize the composite region is the whole 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 scan.

Time frame: Baseline

Change in Brain Tau Load Over Time as Measured by Tau PET in a Subset of Participants

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, posterior temporal lobe, fusiform gyrus, \& middle and inferior temporal gyrus; Medial temporal composite region not including hippocampus included (both left \& right): amygdala, parahippocampus \& anterior medial \& lateral temporal lobe; Frontal lobe (both left \& right) \& Parietal lobe (both left \& right). Inferior cerebellar grey matter = reference region for calculating median SUVRs for all four target regions.

Time frame: Baseline

Change in Cerebrospinal Fluid (CSF) Amyloid (A) Peptide Beta (β): Aβ 1-42 Over Time in a Subset of Participants

Amyloid beta is a peptide fragment of the amyloid precursor protein.

Time frame: Baseline

Change in CSF Amyloid Peptide: Aβ 1-40 Over Time in a Subset of Participants

Amyloid beta is a peptide fragment of the amyloid precursor protein.

Time frame: Baseline

Change in CSF Neurofilament Light (NFL) Over Time in a Subset of Participants

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.

Time frame: Baseline

Change in CSF Phosphorylated Tau (pTau) Over Time in a Subset of Participants

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.

Time frame: Baseline

Change in CSF Total Tau (tTau) Over Time in a Subset of Participants

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.

Time frame: Baseline

Change in Whole Brain Volume Over Time as Determined by MRI in a Subset of Participants

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 cerebrum, basal ganglia, diencephalon, and cerebellum.

Time frame: Baseline

Change in Total Ventricular Volume Over Time as Determined by MRI in a Subset of Participants

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 fourth ventricle of brain.

Time frame: Baseline

Change in Hippocampal Volume Over Time as Determined by MRI in a Subset of Participants

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.

Time frame: Baseline