Alzheimers Disease
Conditions
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 and 600 participants randomized to placebo).
Interventions
DRUGGantenerumab
Gantenerumab will be administered as per the dosing schedule described in the Arm description.
DRUGPlacebo
Placebo will be administered as per the dosing schedule described in the Arm description.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
60 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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 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. |
| 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=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. |
| 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=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. |
| 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 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. |
| 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 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. |
| 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 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. |
| 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 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. |
| 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 administration that are judged to be related to the study drug injection. |
| 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 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 cerebrum, basal ganglia, diencephalon, and cerebellum. |
| 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 fourth ventricle of brain. |
| 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. |
| 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 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. |
| 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 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. |
| 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, 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. |
| 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 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 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Blood Aβ 1-40 Over Time in All Participants | Baseline to safety follow-up visit (up to 310 days from start of treatment) | Amyloid beta is a peptide fragment of the amyloid precursor protein. |
| Change in Blood NFL Over Time in All Participants | Baseline to safety follow-up visit (up to 310 days from start of treatment) | NFL is a neuronal cytoplasmic protein highly expressed in large, myelinated axons. Its levels increase in blood proportionally to the degree of axonal damage in AD. |
| Change in Blood pTau Over Time in All Participants | Baseline to safety follow-up visit (up to 310 days from start of treatment) | — |
| Change in Blood Aβ 1-42 Over Time in All Participants | Baseline to safety follow-up visit (up to 310 days from start of treatment) | Amyloid beta is a peptide fragment of the amyloid precursor protein. |
Countries
Argentina, Australia, Canada, Italy, Poland, South Korea, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in this study at 12 investigative centers in Australia, Canada, and the United States from 19 April 2022 to 13 March 2023.
Pre-assignment details
A total of 25 amyloid-positive, cognitively unimpaired participants at risk for or at the earliest stages of Alzheimer's Disease (AD) were randomized in a 1:1 ratio to receive either gantenerumab or placebo in this study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo SC injection for a maximum of 191 days. Participants had the option to choose between Q1W or Q2W dosing regimens for the target dose. A gradual up titration was performed. Participants who chose the Q1W dosing regimen received placebo, SC Q4W six times, and then Q2W six times, prior to reaching the target dose of Q1W. Participants who chose the Q2W dosing regimen received placebo, SC Q4W nine times, prior to reaching the target dose of Q2W. By the time the study was terminated, none of the participants had reached the target dose. | 12 |
| Gantenerumab Participants received gantenerumab SC injection for a maximum of 172 days. Participants had the option to choose between Q1W or Q2W dosing regimens for the target dose. A gradual up titration was performed. Participants who chose the Q1W dosing regimen received a dose of gantenerumab 120 mg SC Q4W three times, 255 mg SC Q4W three times, and 255 mg SC Q2W six times, prior to reaching the target dose of 255 mg Q1W (i.e., 1020 mg per month). Participants who chose the Q2W dosing regimen received a dose of gantenerumab 120 mg SC Q4W three times, 255 mg SC Q4W three times, and 510 mg SC Q4W three times, prior to reaching the target dose of 510 mg Q2W (i.e., 1020 mg per month). By the time the study was terminated, none of the participants had reached the target dose. | 13 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study Terminated by Sponsor | 11 | 10 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Placebo | Gantenerumab | Total |
|---|---|---|---|
| Age, Continuous | 70.9 years STANDARD_DEVIATION 3.2 | 72.7 years STANDARD_DEVIATION 4.7 | 71.8 years STANDARD_DEVIATION 4.1 |
| Baseline of Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) | 0.110 score on a scale STANDARD_DEVIATION 0.7339 | -0.101 score on a scale STANDARD_DEVIATION 0.5286 | 0.000 score on a scale STANDARD_DEVIATION 0.631 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 7 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) White | 10 Participants | 9 Participants | 19 Participants |
| Sex: Female, Male Female | 8 Participants | 9 Participants | 17 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 13 |
| other Total, other adverse events | 6 / 12 | 5 / 13 |
| serious Total, serious adverse events | 0 / 12 | 0 / 13 |
Outcome results
Primary
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)
Population: ITT Population included all participants randomly assigned to study treatment. Participants were grouped into the two arms (placebo or gantenerumab) according to the treatment assigned at randomization. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in PACC-5 Score | -0.052 score on a scale | Standard Deviation 0.579 |
| Gantenerumab | Change From Baseline in PACC-5 Score | -0.119 score on a scale | Standard Deviation 0.6038 |
Secondary
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)
Population: ITT Population included all participants randomly assigned to study treatment. Participants were grouped into the two arms (placebo or gantenerumab) according to the treatment assigned at randomization. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Amsterdam Instrumental Activities of Daily Living Questionnaire Short Version (A-IADL-Q-SV) | -1.3 score on a scale | Standard Deviation 3.93 |
| Gantenerumab | Change From Baseline in the Amsterdam Instrumental Activities of Daily Living Questionnaire Short Version (A-IADL-Q-SV) | -0.4 score on a scale | Standard Deviation 1.29 |
Secondary
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)
Population: ITT Population included all participants randomly assigned to study treatment. Participants were grouped into the two arms (placebo or gantenerumab) according to the treatment assigned at randomization. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the CFIa Study Partner Version | -0.8 score on a scale | Standard Deviation 3.24 |
| Gantenerumab | Change From Baseline in the CFIa Study Partner Version | 0.2 score on a scale | Standard Deviation 5.14 |
Secondary
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)
Population: ITT Population included all participants randomly assigned to study treatment. Participants were grouped into the two arms (placebo or gantenerumab) according to the treatment assigned at randomization. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB) | 0.29 score on a scale | Standard Deviation 0.498 |
| Gantenerumab | Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB) | -0.05 score on a scale | Standard Deviation 0.158 |
Secondary
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)
Population: ITT Population included all participants randomly assigned to study treatment. Participants were grouped into the two arms (placebo or gantenerumab) according to the treatment assigned at randomization. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Cognitive Function Instrument Acute (CFIa) Participant Version | 0.3 score on a scale | Standard Deviation 4.52 |
| Gantenerumab | Change From Baseline in the Cognitive Function Instrument Acute (CFIa) Participant Version | 0.9 score on a scale | Standard Deviation 4.7 |
Secondary
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
Population: Data is not reported as no postbaseline samples were collected due to early termination of study by the sponsor.
Secondary
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
Population: Data is not reported as no postbaseline samples were collected due to early termination of study by the sponsor.
Secondary
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
Population: Data is not reported as no postbaseline samples were collected due to early termination of study by the sponsor.
Secondary
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
Population: Data is not reported as no postbaseline samples were collected due to early termination of study by the sponsor.
Secondary
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
Population: Data is not reported as no postbaseline samples were collected due to early termination of study by the sponsor.
Secondary
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
Population: Data is not reported as no postbaseline samples were collected due to early termination of study by the sponsor.
Secondary
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
Population: Data is not reported as no postbaseline samples were collected due to early termination of study by the sponsor.
Secondary
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
Population: Data is not reported as no postbaseline samples were collected due to early termination of study by the sponsor.
Secondary
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
Population: Data is not reported as no postbaseline samples were collected due to early termination of study by the sponsor.
Secondary
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
Population: Data is not reported as no postbaseline samples were collected due to early termination of study by the sponsor.
Secondary
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)
Population: Safety Evaluable Population included all participants randomly assigned to study treatment and who received at least 1 dose of study drug. Participants were grouped according to the treatment they received at first exposure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs) | AEs | 6 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs) | SAEs | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs) | AESIs | 0 Participants |
| Gantenerumab | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs) | AEs | 5 Participants |
| Gantenerumab | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs) | SAEs | 0 Participants |
| Gantenerumab | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs) | AESIs | 0 Participants |
Secondary
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)
Population: Safety Evaluable Population included all participants randomly assigned to study treatment and who received at least 1 dose of study drug. Participants were grouped according to the treatment they received at first exposure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Anti-Drug Antibodies (ADAs) to Gantenerumab | 0 Participants |
Secondary
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)
Population: Safety Evaluable Population included all participants randomly assigned to study treatment and who received at least 1 dose of study drug. Participants were grouped according to the treatment they received at first exposure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Injection-site Reactions (ISRs) | 0 Participants |
| Gantenerumab | Number of Participants With Injection-site Reactions (ISRs) | 1 Participants |
Secondary
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)
Population: Safety Evaluable Population included all participants randomly assigned to study treatment and who received at least 1 dose of study drug. Participants were grouped according to the treatment they received at first exposure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Magnetic Resonance Imaging (MRI) Findings: Amyloid-related Imaging Abnormalities - Edema/Effusion (ARIA-E) and ARIA-Hemosiderin Deposition (ARIA-H) | ARIA-E | 0 Participants |
| Placebo | Number of Participants With Magnetic Resonance Imaging (MRI) Findings: Amyloid-related Imaging Abnormalities - Edema/Effusion (ARIA-E) and ARIA-Hemosiderin Deposition (ARIA-H) | ARIA-H | 0 Participants |
| Gantenerumab | Number of Participants With Magnetic Resonance Imaging (MRI) Findings: Amyloid-related Imaging Abnormalities - Edema/Effusion (ARIA-E) and ARIA-Hemosiderin Deposition (ARIA-H) | ARIA-E | 0 Participants |
| Gantenerumab | Number of Participants With Magnetic Resonance Imaging (MRI) Findings: Amyloid-related Imaging Abnormalities - Edema/Effusion (ARIA-E) and ARIA-Hemosiderin Deposition (ARIA-H) | ARIA-H | 1 Participants |
Secondary
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)
Population: Safety Evaluable Population included all participants randomly assigned to study treatment and who received at least 1 dose of study drug. Participants were grouped according to the treatment they received at first exposure. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Post-baseline Suicidal Behaviors and Ideations as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score | 1 Participants |
| Gantenerumab | Number of Participants With Post-baseline Suicidal Behaviors and Ideations as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score | 0 Participants |
Secondary
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)
Population: ITT Population included all participants randomly assigned to study treatment. Participants were grouped into the two arms (placebo or gantenerumab) according to the treatment assigned at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Randomization to Clinical Progression to Mild Cognitive Impairment (MCI) or Dementia Due to AD | NA weeks |
| Gantenerumab | Time From Randomization to Clinical Progression to Mild Cognitive Impairment (MCI) or Dementia Due to AD | NA weeks |
Secondary
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.
Time frame: Randomization to early termination Visit (up to 225 days from start of treatment)
Population: ITT Population included all participants randomly assigned to study treatment. Participants were grouped into the two arms (placebo or gantenerumab) according to the treatment assigned at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Onset of Confirmed Clinical Progression | NA weeks |
| Gantenerumab | Time to Onset of Confirmed Clinical Progression | NA weeks |
Other Pre-specified
Change in Blood Aβ 1-40 Over Time in All Participants
Amyloid beta is a peptide fragment of the amyloid precursor protein.
Time frame: Baseline to safety follow-up visit (up to 310 days from start of treatment)
Other Pre-specified
Change in Blood Aβ 1-42 Over Time in All Participants
Amyloid beta is a peptide fragment of the amyloid precursor protein.
Time frame: Baseline to safety follow-up visit (up to 310 days from start of treatment)
Other Pre-specified
Change in Blood NFL Over Time in All Participants
NFL is a neuronal cytoplasmic protein highly expressed in large, myelinated axons. Its levels increase in blood proportionally to the degree of axonal damage in AD.
Time frame: Baseline to safety follow-up visit (up to 310 days from start of treatment)
Other Pre-specified
Change in Blood pTau Over Time in All Participants
Time frame: Baseline to safety follow-up visit (up to 310 days from start of treatment)