Alzheimer's Disease
Conditions
Brief summary
Part 1 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of gantenerumab in participants with mild Alzheimer disease. Participants will be randomized to receive either gantenerumab subcutaneously every 4 weeks or placebo subcutaneously every 4 weeks. Approved Alzheimer medication is allowed if on stable dose for 3 months prior to screening. Part 2 is an open-label extension (OLE). A positron emission tomography (PET) imaging substudy will be conducted within the main study. Eligible participants who provide separate informed consent will undergo PET imaging scans using the radioligand florbetapir as a pharmacodynamic measure of changes in brain amyloid load over time.
Interventions
DRUGPlacebo
Participants received Placebo SC injection Q4W.
DRUGGantenerumab
Participants received Gantenerumab at 105 mg , 225 mg, or at doses up to 1200 mg SC injection Q4W.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of probable mild Alzheimer disease (AD) based on National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria or major NCD based whether or not receiving AD approved medication * Cerebral spinal fluid (CSF) result consistent with the presence of amyloid pathology * Availability of a person ('caregiver') who in the investigator's judgment has frequent and sufficient contact with the participant, and is able to provide accurate information regarding the participant's cognitive and functional abilities * Fluency in the language of the tests used at the study site * Willingness and ability to complete all aspects of the study * Adequate visual and auditory acuity, in the investigator's judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted) * If currently receiving approved medications for AD, the dosing regimen must have been stable for 3 months prior to screening * Agreement not to participate in other research studies for the duration of this trial and its associated substudies PART 2 - All participants who have been randomized and are actively participating in the study are eligible for Part 2
Exclusion criteria
* Dementia or neurocognitive disorder (NCD) due to a condition other than AD, including, but not limited to, frontotemporal dementia, Parkinson disease, dementia with Lewy bodies, Huntington disease, or vascular dementia * History or presence of clinically evident vascular disease potentially affecting the brain that in the opinion of the investigator has the potential to affect cognitive function * History or presence of stroke within the past 2 years or documented history of transient ischemic attack within the last 12 months * History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease with associated cognitive deficits * History of schizophrenia, schizoaffective disorder, or bipolar disorder * Alcohol and/or substance use disorder (according to the DSM-5) within the past 2 years (nicotine use is allowed) * History or presence of atrial fibrillation * Within the last 2 years, unstable or clinically significant cardiovascular disease (e.g., myocardial infarction, angina pectoris, cardiac failure New York Heart Association Class II or higher) * Uncontrolled hypertension * Chronic kidney disease * Impaired hepatic function PET imaging substudy, in addition to above: \- Prior participation in other research study or clinical care within the last year such that the total radiation exposure would exceed the local or national annual limits Part 2 Participants who have been discontinued from the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | First dose up to 4 weeks after the last dose of study drug (up to 249 weeks) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. SAE is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment. |
| Part 2: Percentage of Participants With Treatment Emergent Anti-Drug Antibodies (ADAs) | First dose up to last dose (Baseline up to until maximum 5 years) | Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the percentage of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis. |
| Part 2: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment | First dose up to 4 weeks after the last dose in OLE (Up to approximately 249 weeks) | Percentage of participants with adverse events leading to discontinuation from treatment were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints | Pre-dose: Weeks 104, 116, 156, 208; Post-dose: Weeks 53, 101 | — |
| Part 1: Percentage of Participants With Treatment Emergent ADAs | First dose up to last dose (Up to approximately 152 weeks) | Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the percentage of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis. |
| Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints | Pre-dose: Weeks 4, 8, 12, 24, 48, 72 and Post dose: Day 4 | — |
| Part 1: Percentage of Participants With AEs, SAEs | First dose up to last dose (Up to approximately 152 weeks) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. A serious adverse event is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment. |
| Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104 | Baseline (Part 1 screening), Week 104 | Change from baseline in hippocampal right volume (HRV) and hippocampal left volume (HLV) were analyzed at Week 104 using magnetic resonance imaging. |
| Part 2: Percent Change From Baseline in Whole Brain Volume at Week 104 | Baseline (Part 1 screening), Week 104 | Change from baseline brain volume were analyzed at Week 104 using magnetic resonance imaging. |
| Part 2: Change From Baseline in Brain Amyloid Load at Week 156 in a Subset of Participants | Baseline, Week 156 | Brain amyloid load over time was assessed using a Florbetapir \[F18\] injection, a positron emission tomography (PET) radioligand selective to amyloid. Analysis was conducted in a subset of participants who signed consent to participate in the PET substudy. Amyloid PET burden was measured in a composite region of interest (ROI) by using standardized uptake value ratio (SUVR) mapped to the centiloid scale. The composite region was composed of the following six bilateral regions: frontal lobe, parietal lobe, temporal lobe, posterior cingulate cortex, anterior cingulate cortex. The reference region used to normalize the composite region was the cerebellar cortex. SUVR is ratio of tracer uptake in each of cingulate, frontal, parietal and temporal cortexes relative to cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scans. |
| Part 1: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment | First dose up to last dose (Up to approximately 152 weeks) | Percentage of participants with adverse events leading to discontinuation from treatment were reported. |
| Part 2: Percent Change From Baseline in Cortical Thickness at Week 104 | Baseline (Part 1 screening), Week 104 | Change from baseline in cortical thickness were analyzed at Week 104 using magnetic resonance imaging. |
| Part 2: Ventricular Volume as Measured by MRI at Week 104 | Part 2: Week 104 | Ventricular volume were analyzed at Week 104 using magnetic resonance imaging. |
Other
| Measure | Time frame |
|---|---|
| Part 1: Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 104 | Baseline, Week 104 |
| Part 1: Change From Baseline in Alzheimer's Dementia (QoL-AD) Global Score at Week 104 | Baseline, Week 104 |
| Part 1: Change From Baseline in Symptom Guide Facilitated (GAS) at Week 104 | Baseline, Week 104 |
| Part 1: Change From Baseline in Dependence Scale (DS) at Week 104 | Baseline, Week 104 |
| Part 1: Percentage Change From Baseline in Total Tau (T-tau) in CSF at Week 104 | Baseline, Week 104 |
| Part 1: Change From Baseline in Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) at Week 104 | Baseline, Week 104 |
| Part 1: Time to Clinical Decline | Baseline up to Week 104 |
| Part 1: Change From Baseline in Clinical Composite Score (Prespecified Items From The ADAS-Cog, MMSE, and CDR) at Week 104 | Baseline, Week 104 |
| Part 1: Percentage of Participants With ADAS-Cog Response | Baseline up to Week 152 |
| Part 1: Change From Baseline in Resource Utilization Dementia-Lite (RUD - Lite) Scale at Week 104 | Baseline, Week 104 |
| Part 1: Mean Change From Baseline in Alzheimer's Disease Activity Scale-Cognitive Subscale 13 (ADAS-Cog13) Scores at Week 104 | Baseline, Week 104 |
| Part 1: Percentage Change From Baseline in Abeta 1-42 Levels in CSF at Week 104 | Baseline, Week 104 |
| Part 1: Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scores at Week 104 | Baseline, Week 104 |
| Part 1: Percentage Change From Baseline in Phosphorylated Tau [P-tau] in CSF at Week 104 | Baseline, Week 104 |
| Part 1: Percent Change From Baseline in Hippocampal Volume at Week 104 | Baseline, Week 104 |
| Part 1: Percent Change From Baseline in Whole Brain Volume at Week 104 | Baseline, Week 104 |
| Part 1: Percent Change From Baseline in Cortical Thickness at Week 104 | Baseline, Week 104 |
| Part 1: Ventricular Volume as Measured by MRI at Week 104 | Baseline, Week 104 |
| Part 1: Change From Baseline in Clinical Dementia Rating Global Score (CDR-GS) at Week 104 | Baseline, Week 104 |
| Part 1: Change From Baseline in CDR Sum of Boxes (SB) at Week 104 | Baseline, Week 104 |
| Part 1: Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 104 | Baseline, Week 104 |
| Part 1: Change From Baseline in NPI Domain Score at Week 104 | Baseline, Week 104 |
Countries
Argentina, Australia, Belgium, Bulgaria, Canada, Denmark, Finland, France, Germany, Hungary, Italy, Japan, Netherlands, Portugal, Russia, South Korea, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Part 1 of the study was conducted at 116 centers in 21 countries and part 2 was conducted at 75 centers in 17 countries.
Pre-assignment details
A total of 389 participants were enrolled out of which 387 were randomized and treated (192 received gantenerumab and 195 received placebo) in part 1 of the study. Of these, a total of 230 participants enrolled into Part 2 of the study: 225 participants received at least one dose of study drug. Participants who had discontinued from Part 1 of the study were not allowed to enroll in Part 2.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Placebo Participants received matching placebo by SC injection every 4 weeks Q4W up to 100 weeks during Part 1 of study. | 195 |
| Part 1: Gantenerumab Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study. | 192 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years. | 117 |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years. | 108 |
| Total | 612 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part 1: Double Blind Treatment | Adverse Event | 2 | 8 | 0 | 0 |
| Part 1: Double Blind Treatment | Death | 3 | 3 | 0 | 0 |
| Part 1: Double Blind Treatment | Lost to Follow-up | 1 | 2 | 0 | 0 |
| Part 1: Double Blind Treatment | Non-Compliance | 2 | 4 | 0 | 0 |
| Part 1: Double Blind Treatment | Other | 6 | 3 | 0 | 0 |
| Part 1: Double Blind Treatment | Part 1 Terminated by Sponsor | 3 | 2 | 0 | 0 |
| Part 1: Double Blind Treatment | Physician Decision | 2 | 4 | 0 | 0 |
| Part 1: Double Blind Treatment | Protocol Violation | 0 | 1 | 0 | 0 |
| Part 1: Double Blind Treatment | Withdrawal by Subject | 42 | 29 | 0 | 0 |
| Part 2: Open-label Extension | Adverse Event | 0 | 0 | 6 | 8 |
| Part 2: Open-label Extension | Death | 0 | 0 | 7 | 4 |
| Part 2: Open-label Extension | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Part 2: Open-label Extension | Non-Compliance | 0 | 0 | 1 | 1 |
| Part 2: Open-label Extension | Other | 0 | 0 | 9 | 9 |
| Part 2: Open-label Extension | Physician Decision | 0 | 0 | 8 | 5 |
| Part 2: Open-label Extension | Study Terminated By Sponsor | 0 | 0 | 0 | 1 |
| Part 2: Open-label Extension | Withdrawal by Subject | 0 | 0 | 39 | 32 |
Baseline characteristics
| Characteristic | Part 1: Gantenerumab | Total | Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 1: Placebo | Part 2 (OLE Treatment): Gantenerumab up to 1200 mg |
|---|---|---|---|---|---|
| Age, Continuous | 69.7 years STANDARD_DEVIATION 8.9 | 71.43 years STANDARD_DEVIATION 8.69 | 71.82 years STANDARD_DEVIATION 8.09 | 70.1 years STANDARD_DEVIATION 8.6 | 71.01 years STANDARD_DEVIATION 9.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 23 Participants | 9 Participants | 11 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 176 Participants | 354 Participants | 108 Participants | 178 Participants | 96 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 0 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 21 Participants | 38 Participants | 19 Participants | 23 Participants | 19 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 7 Participants | 2 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) White | 166 Participants | 179 Participants | 94 Participants | 164 Participants | 85 Participants |
| Sex: Female, Male Female | 98 Participants | 130 Participants | 69 Participants | 113 Participants | 61 Participants |
| Sex: Female, Male Male | 94 Participants | 95 Participants | 48 Participants | 82 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 195 | 8 / 192 | 5 / 117 | 5 / 108 |
| other Total, other adverse events | 147 / 195 | 159 / 192 | 94 / 117 | 91 / 108 |
| serious Total, serious adverse events | 53 / 195 | 61 / 192 | 29 / 117 | 41 / 108 |
Outcome results
Primary
Part 2: Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. SAE is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment.
Time frame: First dose up to 4 weeks after the last dose of study drug (up to 249 weeks)
Population: The safety-evaluable population consisted of all participants who had received at least one dose of study drug, regardless of whether the participant withdrew prematurely or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 91.5 Percentage of Participants |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 24.8 Percentage of Participants |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 2: Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 95.4 Percentage of Participants |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 2: Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 38.0 Percentage of Participants |
Primary
Part 2: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment
Percentage of participants with adverse events leading to discontinuation from treatment were reported.
Time frame: First dose up to 4 weeks after the last dose in OLE (Up to approximately 249 weeks)
Population: The safety population consisted of all participants who had received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment | 12.0 Percentage of Participants |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 2: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment | 15.7 Percentage of Participants |
Primary
Part 2: Percentage of Participants With Treatment Emergent Anti-Drug Antibodies (ADAs)
Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the percentage of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis.
Time frame: First dose up to last dose (Baseline up to until maximum 5 years)
Population: The safety population consisted of all participants who had received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not. The number of participants analyzed indicates the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Percentage of Participants With Treatment Emergent Anti-Drug Antibodies (ADAs) | 2.6 Percentage of Participants |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 2: Percentage of Participants With Treatment Emergent Anti-Drug Antibodies (ADAs) | 2.8 Percentage of Participants |
Secondary
Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints
Time frame: Pre-dose: Weeks 4, 8, 12, 24, 48, 72 and Post dose: Day 4
Population: The pharmacokinetic (PK) evaluable population consisted of all participants that were treated with gantenerumab and provided at least 1 post-baseline PK sample. Number analyzed is the number of participants with data available for analyses at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints | Week 48 | 7.61 μg/mL | Standard Deviation 3.88 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints | Day 4 | 4.11 μg/mL | Standard Deviation 2.59 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints | Week 4 | 2.06 μg/mL | Standard Deviation 0.89 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints | Week 8 | 3.11 μg/mL | Standard Deviation 1.41 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints | Week 12 | 3.35 μg/mL | Standard Deviation 1.63 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints | Week 24 | 3.71 μg/mL | Standard Deviation 2.13 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints | Week 72 | 7.66 μg/mL | Standard Deviation 4.44 |
Secondary
Part 1: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment
Percentage of participants with adverse events leading to discontinuation from treatment were reported.
Time frame: First dose up to last dose (Up to approximately 152 weeks)
Population: The safety population consisted of all participants who received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 1: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment | 2.6 Percentage of Participants |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 1: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment | 6.8 Percentage of Participants |
Secondary
Part 1: Percentage of Participants With AEs, SAEs
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. A serious adverse event is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment.
Time frame: First dose up to last dose (Up to approximately 152 weeks)
Population: The safety population consisted of all participants who received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 1: Percentage of Participants With AEs, SAEs | AEs | 80.5 Percentage of Participants |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 1: Percentage of Participants With AEs, SAEs | SAEs | 12.3 Percentage of Participants |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 1: Percentage of Participants With AEs, SAEs | AEs | 82.8 Percentage of Participants |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 1: Percentage of Participants With AEs, SAEs | SAEs | 12.0 Percentage of Participants |
Secondary
Part 1: Percentage of Participants With Treatment Emergent ADAs
Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the percentage of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis.
Time frame: First dose up to last dose (Up to approximately 152 weeks)
Population: The safety population consisted of all participants who received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not. The number of participants analyzed indicates the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 1: Percentage of Participants With Treatment Emergent ADAs | 3.6 Percentage of Participants |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 1: Percentage of Participants With Treatment Emergent ADAs | 11.5 Percentage of Participants |
Secondary
Part 2: Change From Baseline in Brain Amyloid Load at Week 156 in a Subset of Participants
Brain amyloid load over time was assessed using a Florbetapir \[F18\] injection, a positron emission tomography (PET) radioligand selective to amyloid. Analysis was conducted in a subset of participants who signed consent to participate in the PET substudy. Amyloid PET burden was measured in a composite region of interest (ROI) by using standardized uptake value ratio (SUVR) mapped to the centiloid scale. The composite region was composed of the following six bilateral regions: frontal lobe, parietal lobe, temporal lobe, posterior cingulate cortex, anterior cingulate cortex. The reference region used to normalize the composite region was the cerebellar cortex. SUVR is ratio of tracer uptake in each of cingulate, frontal, parietal and temporal cortexes relative to cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scans.
Time frame: Baseline, Week 156
Population: The safety population consisted of all participants who had received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not. The number of participants analysed indicates the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Change From Baseline in Brain Amyloid Load at Week 156 in a Subset of Participants | -81.01 Score on a scale | Standard Deviation 47.08 |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 2: Change From Baseline in Brain Amyloid Load at Week 156 in a Subset of Participants | -84.93 Score on a scale | Standard Deviation 28.38 |
Secondary
Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints
Time frame: Pre-dose: Weeks 104, 116, 156, 208; Post-dose: Weeks 53, 101
Population: Of the 225 participants in the OLE safety evaluable population, evaluable PK information was available from 223 participants. The PK evaluable population consisted of all participants that were treated with gantenerumab and provided at least 1 post-baseline PK sample. Number analysed is the number of participants with data available for analyses at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints | Week 101 | 89.1 μg/mL | Standard Deviation 33.6 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints | Week 104 | 43.5 μg/mL | Standard Deviation 22.4 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints | Week 53 | 80.6 μg/mL | Standard Deviation 38.4 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints | Week 116 | 3.66 μg/mL | Standard Deviation 2.29 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints | Week 156 | 45.2 μg/mL | Standard Deviation 22.5 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints | Week 208 | 55.8 μg/mL | Standard Deviation 37.9 |
Secondary
Part 2: Percent Change From Baseline in Cortical Thickness at Week 104
Change from baseline in cortical thickness were analyzed at Week 104 using magnetic resonance imaging.
Time frame: Baseline (Part 1 screening), Week 104
Population: The safety population consisted of all participants who received at least one dose of gantenerumab during the OLE and also had at least one post baseline MRI. The number of participants analyzed indicates the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Percent Change From Baseline in Cortical Thickness at Week 104 | -5.84 Percent Change | Standard Deviation 2.33 |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 2: Percent Change From Baseline in Cortical Thickness at Week 104 | -5.58 Percent Change | Standard Deviation 1.87 |
Secondary
Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104
Change from baseline in hippocampal right volume (HRV) and hippocampal left volume (HLV) were analyzed at Week 104 using magnetic resonance imaging.
Time frame: Baseline (Part 1 screening), Week 104
Population: The safety population consisted of all participants who received at least one dose of gantenerumab during the OLE and also had at least one post baseline MRI. The number of participants analyzed indicates the number of participants evaluated for the outcome measure. Number analyzed is the number of participants with data available for analyses at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104 | Hippocampal Left Volume- Percent Change at Week 104 | -11.24 Percent Change | Standard Deviation 4.04 |
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104 | Hippocampal Right Volume- Percent Change at Week 104 | -12.49 Percent Change | Standard Deviation 4.03 |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104 | Hippocampal Left Volume- Percent Change at Week 104 | -12.10 Percent Change | Standard Deviation 4.45 |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104 | Hippocampal Right Volume- Percent Change at Week 104 | -11.34 Percent Change | Standard Deviation 4.41 |
Secondary
Part 2: Percent Change From Baseline in Whole Brain Volume at Week 104
Change from baseline brain volume were analyzed at Week 104 using magnetic resonance imaging.
Time frame: Baseline (Part 1 screening), Week 104
Population: The safety population consisted of all participants who received at least one dose of gantenerumab during the OLE and also had at least one post baseline MRI. The number of participants analyzed indicates the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Percent Change From Baseline in Whole Brain Volume at Week 104 | -4.89 Percent Change | Standard Deviation 1.9 |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 2: Percent Change From Baseline in Whole Brain Volume at Week 104 | -4.91 Percent Change | Standard Deviation 1.58 |
Secondary
Part 2: Ventricular Volume as Measured by MRI at Week 104
Ventricular volume were analyzed at Week 104 using magnetic resonance imaging.
Time frame: Part 2: Week 104
Population: The safety population consisted of all participants who received at least one dose of gantenerumab during the OLE and also had at least one post baseline MRI. The number of participants analyzed indicates the number of participants evaluated for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg | Part 2: Ventricular Volume as Measured by MRI at Week 104 | 86.70 mL | Standard Deviation 38.37 |
| Part 2 (OLE Treatment): Gantenerumab up to 1200 mg | Part 2: Ventricular Volume as Measured by MRI at Week 104 | 86.21 mL | Standard Deviation 30.49 |
Other Pre-specified
Part 1: Change From Baseline in Alzheimer's Dementia (QoL-AD) Global Score at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Change From Baseline in CDR Sum of Boxes (SB) at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Change From Baseline in Clinical Composite Score (Prespecified Items From The ADAS-Cog, MMSE, and CDR) at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Change From Baseline in Clinical Dementia Rating Global Score (CDR-GS) at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Change From Baseline in Dependence Scale (DS) at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Change From Baseline in NPI Domain Score at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Change From Baseline in Resource Utilization Dementia-Lite (RUD - Lite) Scale at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Change From Baseline in Symptom Guide Facilitated (GAS) at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Change From Baseline in Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Mean Change From Baseline in Alzheimer's Disease Activity Scale-Cognitive Subscale 13 (ADAS-Cog13) Scores at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scores at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Percentage Change From Baseline in Abeta 1-42 Levels in CSF at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Percentage Change From Baseline in Phosphorylated Tau [P-tau] in CSF at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Percentage Change From Baseline in Total Tau (T-tau) in CSF at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Percentage of Participants With ADAS-Cog Response
Time frame: Baseline up to Week 152
Other Pre-specified
Part 1: Percent Change From Baseline in Cortical Thickness at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Percent Change From Baseline in Hippocampal Volume at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Percent Change From Baseline in Whole Brain Volume at Week 104
Time frame: Baseline, Week 104
Other Pre-specified
Part 1: Time to Clinical Decline
Time frame: Baseline up to Week 104
Other Pre-specified
Part 1: Ventricular Volume as Measured by MRI at Week 104
Time frame: Baseline, Week 104