Trial Outcomes & Findings for 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) (NCT NCT05256134)

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

25 participants

Primary outcome timeframe

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

Results posted on

2025-06-12

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Placebo Participants received placebo subcutaneous (SC) injection for a maximum of 191 days. Participants had the option to choose between every week (Q1W) or every two weeks (Q2W) dosing regimens for the target dose. A gradual up titration was performed. Participants who chose the Q1W dosing regimen received placebo, SC every 4 weeks (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.	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 milligrams (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.
Overall Study STARTED	12	13
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	12	13

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received placebo subcutaneous (SC) injection for a maximum of 191 days. Participants had the option to choose between every week (Q1W) or every two weeks (Q2W) dosing regimens for the target dose. A gradual up titration was performed. Participants who chose the Q1W dosing regimen received placebo, SC every 4 weeks (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.	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 milligrams (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.
Overall Study Study Terminated by Sponsor	11	10
Overall Study Withdrawal by Subject	1	3

Baseline Characteristics

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)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=12 Participants 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.	Gantenerumab n=13 Participants 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.	Total n=25 Participants Total of all reporting groups
Age, Continuous	70.9 years STANDARD_DEVIATION 3.2 • n=5 Participants	72.7 years STANDARD_DEVIATION 4.7 • n=7 Participants	71.8 years STANDARD_DEVIATION 4.1 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	9 Participants n=7 Participants	17 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	4 Participants n=7 Participants	8 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants n=5 Participants	7 Participants n=7 Participants	17 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	10 Participants n=5 Participants	9 Participants n=7 Participants	19 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Baseline of Preclinical Alzheimer's Cognitive Composite-5 (PACC-5)	0.110 score on a scale STANDARD_DEVIATION 0.7339 • n=5 Participants	-0.101 score on a scale STANDARD_DEVIATION 0.5286 • n=7 Participants	0.000 score on a scale STANDARD_DEVIATION 0.6310 • n=5 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants 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.	Gantenerumab n=13 Participants 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.
Change From Baseline in PACC-5 Score	-0.052 score on a scale Standard Deviation 0.5790	-0.119 score on a scale Standard Deviation 0.6038

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants 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.	Gantenerumab n=13 Participants 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.
Time From Randomization to Clinical Progression to Mild Cognitive Impairment (MCI) or Dementia Due to AD	NA weeks Data was not estimable as none of the participants met the diagnosis criteria for clinical progression i.e., No participant progressed to mild cognitive impairment or dementia due to Alzheimer's disease based on the diagnosis of the iCAC.	NA weeks Data was not estimable as none of the participants met the diagnosis criteria for clinical progression i.e., No participant progressed to mild cognitive impairment or dementia due to Alzheimer's disease based on the diagnosis of the iCAC.

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants 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.	Gantenerumab n=13 Participants 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.
Time to Onset of Confirmed Clinical Progression	NA weeks Data was not estimable as none of the participants met the criteria for confirmed clinical progression i.e., no participant had two consecutive visits (approximately 6 months apart) with a CDR-GS greater than 0.	NA weeks Data was not estimable as none of the participants met the criteria for confirmed clinical progression i.e., no participant had two consecutive visits (approximately 6 months apart) with a CDR-GS greater than 0.

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants 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.	Gantenerumab n=11 Participants 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.
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	-0.4 score on a scale Standard Deviation 1.29

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants 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.	Gantenerumab n=11 Participants 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.
Change From Baseline in the Cognitive Function Instrument Acute (CFIa) Participant Version	0.3 score on a scale Standard Deviation 4.52	0.9 score on a scale Standard Deviation 4.70

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants 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.	Gantenerumab n=10 Participants 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.
Change From Baseline in the CFIa Study Partner Version	-0.8 score on a scale Standard Deviation 3.24	0.2 score on a scale Standard Deviation 5.14

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants 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.	Gantenerumab n=10 Participants 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.
Change From Baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB)	0.29 score on a scale Standard Deviation 0.498	-0.05 score on a scale Standard Deviation 0.158

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants 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.	Gantenerumab n=13 Participants 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.
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs) AESIs	0 Participants	0 Participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs) AEs	6 Participants	5 Participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs) SAEs	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=13 Participants 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.	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.
Number of Participants With Anti-Drug Antibodies (ADAs) to Gantenerumab	0 Participants	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants 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.	Gantenerumab n=13 Participants 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.
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	0 Participants
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	1 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants 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.	Gantenerumab n=13 Participants 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.
Number of Participants With Injection-site Reactions (ISRs)	0 Participants	1 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants 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.	Gantenerumab n=11 Participants 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.
Number of Participants With Post-baseline Suicidal Behaviors and Ideations as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score	1 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline to safety follow-up visit (up to 310 days from start of treatment)

Outcome measures

Outcome data not reported

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Gantenerumab

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=12 participants at risk 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.	Gantenerumab n=13 participants at risk 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.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/12 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	7.7% 1/13 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Endocrine disorders Thyroid disorder	8.3% 1/12 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	0.00% 0/13 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Gastrointestinal disorders Diarrhoea	0.00% 0/12 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	7.7% 1/13 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
General disorders Injection site reaction	0.00% 0/12 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	7.7% 1/13 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
General disorders Pain	8.3% 1/12 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	0.00% 0/13 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
General disorders Vaccination site reaction	8.3% 1/12 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	0.00% 0/13 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Infections and infestations COVID-19	8.3% 1/12 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	7.7% 1/13 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Infections and infestations Urinary tract infection	8.3% 1/12 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	0.00% 0/13 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Infections and infestations Viral infection	0.00% 0/12 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	7.7% 1/13 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Injury, poisoning and procedural complications Arthropod bite	0.00% 0/12 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	7.7% 1/13 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Injury, poisoning and procedural complications Fall	0.00% 0/12 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	7.7% 1/13 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Injury, poisoning and procedural complications Muscle strain	0.00% 0/12 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	7.7% 1/13 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Injury, poisoning and procedural complications Skin abrasion	0.00% 0/12 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	7.7% 1/13 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Injury, poisoning and procedural complications Skin laceration	0.00% 0/12 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	7.7% 1/13 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Investigations Cardiac murmur	8.3% 1/12 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	0.00% 0/13 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Nervous system disorders Headache	0.00% 0/12 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	7.7% 1/13 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Skin and subcutaneous tissue disorders Dermatitis	8.3% 1/12 • Number of events 1 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	0.00% 0/13 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.
Vascular disorders Hypertension	0.00% 0/12 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.	15.4% 2/13 • Number of events 2 • Day 1 to safety follow-up visit (up to 310 days from start of treatment) 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.