Alzheimer's Disease
Conditions
Brief summary
This Phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group study will evaluate the clinical efficacy, safety, pharmacokinetics, and pharmacodynamics of semorinemab in patients with moderate AD. The study consists of a screening period, a double-blind treatment period, an optional open-label extension (OLE) period, and a safety follow-up period. There may be up to two study cohorts.
Interventions
DRUGSemorinemab
Participants will receive semorinemab every 2 weeks (Q2W) for the first three doses of the double-blind treatment period and every 4 weeks (Q4W) thereafter during the double-blind treatment period. Semorinemab will be administered Q4W in the OLE period.
DRUGPlacebo
Participants will receive placebo every 2 weeks (Q2W) for the first three doses of the double-blind treatment period and every 4 weeks (Q4W) thereafter during the double-blind treatment period.
DRUG[18F]GTP1
\[18F\]GTP1 will be administered as a solution for intravenous (IV) use, as part of positron emission tomography (PET) imaging.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* National Institute on Aging/Alzheimer's Association core clinical criteria for probable AD dementia * Evidence of the AD pathological process, by a positive amyloid assessment either on CSF Aβ1-42 as measured on Elecsys β-Amyloid(1-42) Test System OR amyloid PET scan * AD dementia of moderate severity, as defined by a screening MMSE score of 16-21 points, inclusive, and a CDR-GS of 1 or 2 * Availability of a person with sufficient contact with the participant to be able to provide accurate information on the participant's cognitive, behavioral and functional ability
Exclusion criteria
* Pregnant or breastfeeding * Inability to tolerate MRI procedures or contraindication to MRI * Contraindication to PET imaging * Residence in a skilled nursing facility * Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study, or bias the assessment of the clinical or mental status of the participant to a significant degree * Any evidence of a condition other than AD that may affect cognition * Substance abuse within the past 2 years * Use of any experimental therapy within 90 days or 5 half-lives prior to screening, whichever is greater, or any passive immunotherapy against tau * Use of any passive immunotherapy (immunoglobulin) against Aβ, unless the last dose was at least 1 year prior to screening or any active immunotherapy (vaccine) that is under evaluation to prevent or postpone cognitive decline * Any other biologic therapy or previous treatment with medications specifically intended to treat Parkinsonian symptoms or any other non-AD neurodegenerative disorder within 1 year of screening * Systemic immunosuppressive therapy within 12 months of screening through the entire study period * Typical antipsychotic or neuroleptic medication within 6 months of screening * Daily treatment with any of the following classes of medication (except for intermittent short-term use): opiates or opioids, benzodiazepines, barbiturates, hypnotics, or any medication with clinically significant centrally-acting antihistamine or anticholinergic activity * Stimulant medications, unless the dose has been stable within the 6 months prior to screening and is expected to be stable throughout the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Last Visit of Double-Blind Treatment Period in Cognitive Function as Measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11) | Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2 | The Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11) is an 11 item cognitive subscale used to quantify the areas of cognitive function most often affected in Alzheimer's disease. The total score ranges from 0-70 with lower scores indicating better cognitive function. |
| Change From Baseline to Last Visit of Double-Blind Treatment Period in Functional Capacities as Measured by the Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL) | Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2 | The Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL) is a scale used to quantify performance of activities of daily living (ADL). Scores on the ADCS-ADL range from 0-78, with higher scores indicating better ADL function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events | Baseline up to end of study (approximately 4 years and 7 months) | An Adverse Event is any untoward medical occurrence in a subject 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. Preexisting conditions which worsen during a study are also considered as adverse events. |
| Serum Concentration of RO7105705 at Specified Timepoints | Weeks 1,3,5,9,13,25,37,49, and at treatment discontinuation (up to Week 48) for Cohort 1. Weeks 1,3,5,9,13,25,37,49,61, and at treatment discontinuation (up to Week 60) for Cohort 2. | — |
| Incidence of Anti-drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline | Weeks 1,13,25,37,49, and at treatment discontinuation (up to Week 48) for Cohort 1. Weeks 1,13,25,37,49,61, and at treatment discontinuation (up to Week 60) for Cohort 2. | — |
| Relationship Between ADA Status and Percentage of Participants With Adverse Events | Up to 57 weeks for Cohort 1, and up to 69 weeks for Cohort 2. | Descriptive statistics will be used for assessment. |
| Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period in Cognitive Function as Measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11) | Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2 | Descriptive statistics will be used for assessment. A 70-point scale used to quantify the areas of cognitive function most often affected in Alzheimer's disease. Lower scores indicate better cognitive function. |
| Change From Baseline to Last Visit of Double-Blind Treatment Period on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2 | The Clinical Dementia Rating-Sum of Boxes (CDR-SB) is a scale used to quantify the severity of symptoms of dementia. The CDR-SB is obtained through interviews of patients and informants, and disease severity is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The CDR-SB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18, with the higher values representing more severe impairment. |
| Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2 | Descriptive statistics will be used for assessment. A scale used to quantify the severity of symptoms of dementia. The CDR-SB is obtained through interviews of patients and informants, and disease severity is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The CDR-SOB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18, with the higher values representing more severe impairment. |
| Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period on the Mini-Mental State Examination (MMSE) | Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2 | Descriptive statistics will be used for assessment. The Mini Mental State Examination (MMSE) is a brief clinical cognitive examination commonly used to screen for dementia and other cognitive deficits that has a total score of 0-30. Higher scores indicate better cognitive function. |
| Relationship Between ADA Status and Serum Concentration of RO7105705 at Specified Timepoints | Weeks 1,13,25,37,49, and at treatment discontinuation (up to Week 48) for Cohort 1. Weeks 1,13,25,37,49,61, and at treatment discontinuation (up to Week 60) for Cohort 2. | Descriptive statistics will be used for assessment. |
| Relationship Between ADA Status and Incidence of Anti-Drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline | Weeks 1,13,25,37,49, and at treatment discontinuation (up to Week 48) for Cohort 1. Weeks 1,13,25,37,49,61, and at treatment discontinuation (up to Week 60) for Cohort 2. | Descriptive statistics will be used for assessment. |
| Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period in Functional Capacities as Measured by the Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL) | Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2 | Descriptive statistics will be used for assessment. A scale used to quantify performance of activities of daily living. Scores on the ADCS-ADL range from 0-78, with higher scores indicating better ADL function. |
| Change From Baseline to Last Visit of Double-Blind Treatment Period on the Mini-Mental State Examination (MMSE) | Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2 | The Mini Mental State Examination (MMSE) is a brief clinical cognitive examination commonly used to screen for dementia and other cognitive deficits that has a total score of 0-30. Higher scores indicate better cognitive function. |
Countries
France, Poland, Spain, United States
Participant flow
Recruitment details
The study was conducted at 49 centers in 4 countries.
Pre-assignment details
A total of 272 participants were enrolled at 49 centers.
Participants by arm
| Arm | Count |
|---|---|
| Semorinemab Semorinemab was administered intravenously in the double-blind treatment period and was administered intravenously in the optional open-label extension period. | 136 |
| Placebo Placebo was administered intravenously in the double-blind treatment period and semorinemab was administered intravenously in the optional open-label extension. | 136 |
| Total | 272 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-Blind Treatment Period | Adverse Event | 6 | 6 |
| Double-Blind Treatment Period | Death | 1 | 1 |
| Double-Blind Treatment Period | Lost to Follow-up | 0 | 1 |
| Double-Blind Treatment Period | Physician Decision | 1 | 4 |
| Double-Blind Treatment Period | Various reasons | 5 | 3 |
| Double-Blind Treatment Period | Withdrawal by Subject | 17 | 19 |
| Open-Label Extension | Adverse Event | 9 | 7 |
| Open-Label Extension | Death | 0 | 2 |
| Open-Label Extension | Lost to Follow-up | 4 | 0 |
| Open-Label Extension | Physician Decision | 6 | 2 |
| Open-Label Extension | Various reasons | 4 | 4 |
| Open-Label Extension | Withdrawal by Subject | 31 | 30 |
Baseline characteristics
| Characteristic | Placebo | Total | Semorinemab |
|---|---|---|---|
| Age, Continuous | 73.0 Years STANDARD_DEVIATION 8 | 72.3 Years STANDARD_DEVIATION 8.1 | 71.6 Years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 7 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 115 Participants | 232 Participants | 117 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 33 Participants | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 21 Participants | 9 Participants |
| Race (NIH/OMB) White | 119 Participants | 241 Participants | 122 Participants |
| Sex: Female, Male Female | 84 Participants | 176 Participants | 92 Participants |
| Sex: Female, Male Male | 52 Participants | 96 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 135 | 3 / 132 | 2 / 199 |
| other Total, other adverse events | 78 / 135 | 74 / 132 | 122 / 199 |
| serious Total, serious adverse events | 23 / 135 | 22 / 132 | 37 / 199 |
Outcome results
Primary
Change From Baseline to Last Visit of Double-Blind Treatment Period in Cognitive Function as Measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11)
The Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11) is an 11 item cognitive subscale used to quantify the areas of cognitive function most often affected in Alzheimer's disease. The total score ranges from 0-70 with lower scores indicating better cognitive function.
Time frame: Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2
Population: The modified intent-to-treat population included all randomized participants who received at least one dose of study drug and had at least one baseline and one postbaseline ADAS-Cog11 score.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Semorinemab | Change From Baseline to Last Visit of Double-Blind Treatment Period in Cognitive Function as Measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11) | Baseline | 23.93 Units on a scale | Standard Error 0.533 |
| Semorinemab | Change From Baseline to Last Visit of Double-Blind Treatment Period in Cognitive Function as Measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11) | Change from Baseline at Week 49 (includes Cohort 1 and 2) | 3.96 Units on a scale | Standard Error 0.658 |
| Semorinemab | Change From Baseline to Last Visit of Double-Blind Treatment Period in Cognitive Function as Measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11) | Change from Baseline at Week 61 (only Cohort 2) | 5.71 Units on a scale | Standard Error 0.907 |
| Placebo | Change From Baseline to Last Visit of Double-Blind Treatment Period in Cognitive Function as Measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11) | Baseline | 24.09 Units on a scale | Standard Error 0.589 |
| Placebo | Change From Baseline to Last Visit of Double-Blind Treatment Period in Cognitive Function as Measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11) | Change from Baseline at Week 49 (includes Cohort 1 and 2) | 6.85 Units on a scale | Standard Error 0.643 |
| Placebo | Change From Baseline to Last Visit of Double-Blind Treatment Period in Cognitive Function as Measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11) | Change from Baseline at Week 61 (only Cohort 2) | 8.47 Units on a scale | Standard Error 0.965 |
Comparison: Change from Baseline at Week 49p-value: 0.000895% CI: [-4.56, -1.21]Mixed Models Analysis
Comparison: Change from Baseline at Week 61p-value: 0.035195% CI: [-5.31, -0.2]Mixed Models Analysis
Primary
Change From Baseline to Last Visit of Double-Blind Treatment Period in Functional Capacities as Measured by the Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL)
The Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL) is a scale used to quantify performance of activities of daily living (ADL). Scores on the ADCS-ADL range from 0-78, with higher scores indicating better ADL function.
Time frame: Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2
Population: The modified intent-to-treat population included all randomized participants who received at least one dose of study drug and had at least one baseline and one postbaseline ADAS-Cog11 and the ADCS-ADL score at the given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Semorinemab | Change From Baseline to Last Visit of Double-Blind Treatment Period in Functional Capacities as Measured by the Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL) | Baseline | 62.03 Units on a scale | Standard Error 0.764 |
| Semorinemab | Change From Baseline to Last Visit of Double-Blind Treatment Period in Functional Capacities as Measured by the Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL) | Change from Baseline at Week 49 (includes Cohort 1 and 2) | -7.63 Units on a scale | Standard Error 1.002 |
| Semorinemab | Change From Baseline to Last Visit of Double-Blind Treatment Period in Functional Capacities as Measured by the Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL) | Change from Baseline at Week 61 (only Cohort 2) | -9.29 Units on a scale | Standard Error 1.343 |
| Placebo | Change From Baseline to Last Visit of Double-Blind Treatment Period in Functional Capacities as Measured by the Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL) | Baseline | 59.74 Units on a scale | Standard Error 0.842 |
| Placebo | Change From Baseline to Last Visit of Double-Blind Treatment Period in Functional Capacities as Measured by the Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL) | Change from Baseline at Week 49 (includes Cohort 1 and 2) | -6.80 Units on a scale | Standard Error 0.974 |
| Placebo | Change From Baseline to Last Visit of Double-Blind Treatment Period in Functional Capacities as Measured by the Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL) | Change from Baseline at Week 61 (only Cohort 2) | -7.57 Units on a scale | Standard Error 1.462 |
Comparison: Change from Baseline at Week 49p-value: 0.520795% CI: [-3.39, 1.72]Mixed Models Analysis
Comparison: Change from Baseline at Week 61p-value: 0.370495% CI: [-5.5, 2.07]Mixed Models Analysis
Secondary
Change From Baseline to Last Visit of Double-Blind Treatment Period on the Clinical Dementia Rating-Sum of Boxes (CDR-SB)
The Clinical Dementia Rating-Sum of Boxes (CDR-SB) is a scale used to quantify the severity of symptoms of dementia. The CDR-SB is obtained through interviews of patients and informants, and disease severity is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The CDR-SB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18, with the higher values representing more severe impairment.
Time frame: Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2
Population: The modified intent-to-treat population included all randomized participants who received at least one dose of study drug and had at least one baseline and one postbaseline ADAS-Cog11 and the CDR-SB score at the given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Semorinemab | Change From Baseline to Last Visit of Double-Blind Treatment Period on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Baseline | 6.23 Units on a scale | Standard Error 0.156 |
| Semorinemab | Change From Baseline to Last Visit of Double-Blind Treatment Period on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Change from Baseline at Week 49 (includes Cohort 1 and 2) | 1.80 Units on a scale | Standard Error 0.217 |
| Semorinemab | Change From Baseline to Last Visit of Double-Blind Treatment Period on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Change from Baseline at Week 61 (only Cohort 2) | 2.45 Units on a scale | Standard Error 0.367 |
| Placebo | Change From Baseline to Last Visit of Double-Blind Treatment Period on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Baseline | 6.51 Units on a scale | Standard Error 0.182 |
| Placebo | Change From Baseline to Last Visit of Double-Blind Treatment Period on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Change from Baseline at Week 49 (includes Cohort 1 and 2) | 1.54 Units on a scale | Standard Error 0.214 |
| Placebo | Change From Baseline to Last Visit of Double-Blind Treatment Period on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Change from Baseline at Week 61 (only Cohort 2) | 2.28 Units on a scale | Standard Error 0.393 |
Comparison: Change from Baseline at Week 49p-value: 0.350195% CI: [-0.29, 0.82]Mixed Models Analysis
Comparison: Change from Baseline at Week 61p-value: 0.743195% CI: [-0.87, 1.22]Mixed Models Analysis
Secondary
Change From Baseline to Last Visit of Double-Blind Treatment Period on the Mini-Mental State Examination (MMSE)
The Mini Mental State Examination (MMSE) is a brief clinical cognitive examination commonly used to screen for dementia and other cognitive deficits that has a total score of 0-30. Higher scores indicate better cognitive function.
Time frame: Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2
Population: The modified intent-to-treat population included all randomized participants who received at least one dose of study drug and had at least one baseline and one postbaseline ADAS-Cog11 and the MMSE score at the given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Semorinemab | Change From Baseline to Last Visit of Double-Blind Treatment Period on the Mini-Mental State Examination (MMSE) | Baseline | 18.38 Units on a scale | Standard Error 0.182 |
| Semorinemab | Change From Baseline to Last Visit of Double-Blind Treatment Period on the Mini-Mental State Examination (MMSE) | Change from Baseline at Week 49 (includes Cohort 1 and 2) | -2.86 Units on a scale | Standard Error 0.33 |
| Semorinemab | Change From Baseline to Last Visit of Double-Blind Treatment Period on the Mini-Mental State Examination (MMSE) | Change from Baseline at Week 61 (only Cohort 2) | -3.14 Units on a scale | Standard Error 0.429 |
| Placebo | Change From Baseline to Last Visit of Double-Blind Treatment Period on the Mini-Mental State Examination (MMSE) | Baseline | 18.15 Units on a scale | Standard Error 0.197 |
| Placebo | Change From Baseline to Last Visit of Double-Blind Treatment Period on the Mini-Mental State Examination (MMSE) | Change from Baseline at Week 49 (includes Cohort 1 and 2) | -3.12 Units on a scale | Standard Error 0.325 |
| Placebo | Change From Baseline to Last Visit of Double-Blind Treatment Period on the Mini-Mental State Examination (MMSE) | Change from Baseline at Week 61 (only Cohort 2) | -4.22 Units on a scale | Standard Error 0.466 |
Comparison: Change from Baseline at Week 49p-value: 0.536695% CI: [-0.58, 1.11]Mixed Models Analysis
Comparison: Change from Baseline at Week 61p-value: 0.085195% CI: [-0.15, 2.3]Mixed Models Analysis
Secondary
Incidence of Anti-drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline
Time frame: Weeks 1,13,25,37,49, and at treatment discontinuation (up to Week 48) for Cohort 1. Weeks 1,13,25,37,49,61, and at treatment discontinuation (up to Week 60) for Cohort 2.
Population: Participants with at least one predose and one postdose ADA assessment were included in this analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Semorinemab | Incidence of Anti-drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline | Baseline (BL) - positive sample | 0 Participants |
| Semorinemab | Incidence of Anti-drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline | BL - negative sample | 133 Participants |
| Semorinemab | Incidence of Anti-drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline | Post-BL - positive treatment emergent ADA | 0 Participants |
| Semorinemab | Incidence of Anti-drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline | Post-BL - negative treatment emergent ADA | 128 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline | Baseline (BL) - positive sample | 1 Participants |
| Placebo | Incidence of Anti-drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline | BL - negative sample | 128 Participants |
Secondary
Percentage of Participants With Adverse Events
An Adverse Event is any untoward medical occurrence in a subject 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. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Baseline up to end of study (approximately 4 years and 7 months)
Population: The safety population included all randomized participants who received at least one dose of either semorinemab or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Semorinemab | Percentage of Participants With Adverse Events | 112 Participants |
| Placebo | Percentage of Participants With Adverse Events | 107 Participants |
| Semorinemab (Open-label Extension) | Percentage of Participants With Adverse Events | 170 Participants |
Secondary
Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period in Cognitive Function as Measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11)
Descriptive statistics will be used for assessment. A 70-point scale used to quantify the areas of cognitive function most often affected in Alzheimer's disease. Lower scores indicate better cognitive function.
Time frame: Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2
Population: Participants with at least one predose and one postdose ADA assessment were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Semorinemab | Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period in Cognitive Function as Measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11) | NA Participants |
| Placebo | Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period in Cognitive Function as Measured by the Alzheimer's Disease Assessment Scale, Cognitive Subscale, 11-Item Version (ADAS-Cog11) | NA Participants |
Secondary
Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period in Functional Capacities as Measured by the Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL)
Descriptive statistics will be used for assessment. A scale used to quantify performance of activities of daily living. Scores on the ADCS-ADL range from 0-78, with higher scores indicating better ADL function.
Time frame: Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2
Population: Participants with at least one predose and one postdose ADA assessment were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Semorinemab | Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period in Functional Capacities as Measured by the Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL) | NA Participants |
| Placebo | Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period in Functional Capacities as Measured by the Alzheimer's Disease Cooperative Study-Daily Living Inventory (ADCS-ADL) | NA Participants |
Secondary
Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period on the Clinical Dementia Rating-Sum of Boxes (CDR-SB)
Descriptive statistics will be used for assessment. A scale used to quantify the severity of symptoms of dementia. The CDR-SB is obtained through interviews of patients and informants, and disease severity is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The CDR-SOB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18, with the higher values representing more severe impairment.
Time frame: Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2
Population: Participants with at least one predose and one postdose ADA assessment were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Semorinemab | Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) | NA Participants |
| Placebo | Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) | NA Participants |
Secondary
Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period on the Mini-Mental State Examination (MMSE)
Descriptive statistics will be used for assessment. The Mini Mental State Examination (MMSE) is a brief clinical cognitive examination commonly used to screen for dementia and other cognitive deficits that has a total score of 0-30. Higher scores indicate better cognitive function.
Time frame: Baseline to Week 49 for Cohorts 1 and 2, and Baseline to Week 61 for Cohort 2
Population: Participants with at least one predose and one postdose ADA assessment were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Semorinemab | Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period on the Mini-Mental State Examination (MMSE) | NA Participants |
| Placebo | Relationship Between ADA Status and Change From Baseline to Last Visit of Double-Blind Treatment Period on the Mini-Mental State Examination (MMSE) | NA Participants |
Secondary
Relationship Between ADA Status and Incidence of Anti-Drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline
Descriptive statistics will be used for assessment.
Time frame: Weeks 1,13,25,37,49, and at treatment discontinuation (up to Week 48) for Cohort 1. Weeks 1,13,25,37,49,61, and at treatment discontinuation (up to Week 60) for Cohort 2.
Population: Participants with at least one predose and one postdose ADA assessment were included in this analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Semorinemab | Relationship Between ADA Status and Incidence of Anti-Drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline | Positive Sample at BL | 0 Participants |
| Semorinemab | Relationship Between ADA Status and Incidence of Anti-Drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline | Positive Sample post BL | NA Participants |
| Placebo | Relationship Between ADA Status and Incidence of Anti-Drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline | Positive Sample at BL | 1 Participants |
| Placebo | Relationship Between ADA Status and Incidence of Anti-Drug Antibodies (ADAs) During the Study Relative to the Prevalence of ADAs at Baseline | Positive Sample post BL | NA Participants |
Secondary
Relationship Between ADA Status and Percentage of Participants With Adverse Events
Descriptive statistics will be used for assessment.
Time frame: Up to 57 weeks for Cohort 1, and up to 69 weeks for Cohort 2.
Population: Participants with at least one predose and one postdose ADA assessment were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Semorinemab | Relationship Between ADA Status and Percentage of Participants With Adverse Events | NA Participants |
| Placebo | Relationship Between ADA Status and Percentage of Participants With Adverse Events | NA Participants |
Secondary
Relationship Between ADA Status and Serum Concentration of RO7105705 at Specified Timepoints
Descriptive statistics will be used for assessment.
Time frame: Weeks 1,13,25,37,49, and at treatment discontinuation (up to Week 48) for Cohort 1. Weeks 1,13,25,37,49,61, and at treatment discontinuation (up to Week 60) for Cohort 2.
Population: Participants with at least one predose and one postdose ADA assessment were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Semorinemab | Relationship Between ADA Status and Serum Concentration of RO7105705 at Specified Timepoints | NA Participants |
| Placebo | Relationship Between ADA Status and Serum Concentration of RO7105705 at Specified Timepoints | NA Participants |
Secondary
Serum Concentration of RO7105705 at Specified Timepoints
Time frame: Weeks 1,3,5,9,13,25,37,49, and at treatment discontinuation (up to Week 48) for Cohort 1. Weeks 1,3,5,9,13,25,37,49,61, and at treatment discontinuation (up to Week 60) for Cohort 2.
Population: The pharmacokinetic(PK)-evaluable population included all safety-evaluable participants with at least 1 post-dose serum PK sample
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 37 postdose | 2430 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 31.1 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 49 predose | 1020 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 35.2 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 1 predose | NA Microgram per milliliter (µg/ml) | — |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 1 postdose | 1610 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 27.9 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 3 predose | 546 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 32.1 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 3 postdose | 1980 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 32.6 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 5 predose | 951 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 30.4 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 5 postdose | 2260 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 47 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 9 predose | 935 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 32.2 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 9 postdose | 2520 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 27.2 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 13 predose | 943 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 32.9 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 13 postdose | 2480 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 31.2 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 25 predose | 996 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 37.1 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 25 postdose | 2420 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 37.9 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 37 predose | 981 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 45.4 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 49 postdose | 2650 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 34.2 |
| Semorinemab | Serum Concentration of RO7105705 at Specified Timepoints | Week 61 | 1100 Microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 26.8 |