Alzheimer Disease
Conditions
Brief summary
This randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of gantenerumab versus placebo in participants with early (prodromal to mild) AD. All participants must show evidence of beta-amyloid pathology. Eligible participants will be randomized 1:1 to receive either subcutaneous (SC) injection of gantenerumab or placebo. The primary efficacy assessment will be performed at the end of the double blind period at week 116. Participants will then be offered to enter into an open-label extension (OLE). Participants not willing to go to the OLE will participate in a long term follow-up period for up to 50 weeks after the last gantenerumab dose.
Interventions
DRUGGantenerumab
Gantenerumab will be administered as per the schedule specified in the respective arm.
DRUGPlacebo
Placebo will be administered as per the schedule specified in the respective arm.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion criteria: * Meets National Institute on Aging/Alzheimer's Association (NIAAA) core clinical criteria for probable AD dementia or prodromal AD (consistent with the NIAAA diagnostic criteria and guidelines for mild cognitive impairment) * Evidence of the AD pathological process, as confirmed by CSF tau/A-beta42or amyloid PET scan * Demonstrated abnormal memory function * MMSE score greater than or equal to 22 (≥ 22) * Clinical dementia rating-global score (CDR-GS) of 0.5 or 1.0 * Availability of a reliable study partner who accepts to participate in study procedures throughout the 2 years duration of study * If receiving symptomatic AD medications, the dosing regimen must have been stable for 3 months prior to screening and until randomization * For enrollment in the China extension, patients must have residence in mainland China, Hong Kong, or Taiwan and be of Chinese ancestry * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods Key
Exclusion criteria
* Any evidence of a condition other than AD that may affect cognition * History of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder * History or presence of clinically evident systemic vascular disease that in the opinion of the investigator has the potential to affect cognitive function * History or presence of clinically evident cerebrovascular disease * History or presence of posterior reversible encephalopathy syndrome * History or presence of any stroke with clinical symptoms within the past 12 months, or documented history within the last 6 months of an acute event that is consistent with a transient ischemic attack * History of severe, clinically significant CNS trauma * History or presence of intracranial mass (e.g., glioma, meningioma) that could potentially impair cognition * Presence of infections that affect brain function or history of infections that resulted in neurologic sequelae * History or presence of systemic autoimmune disorders that potentially cause progressive neurologic disease with associated cognitive deficits * At risk for suicide in the opinion of the investigator * Alcohol and/or substance abuse or dependants in past 2 years * Relevant brain hemorrhage, bleeding disorder and cerebrovascular abnormalities * Any contraindications to brain MRI * Unstable or clinically significant cardiovascular, kidney or liver disease * Uncontrolled hypertension * Unstable or clinically significant cardiovascular disease * Abnormal thyroid function * Patients with evidence of folic acid deficiency Exclusion for Open-Label Extension (OLE): * Discontinued from study treatment during the double-blind treatment period * Received any other investigational medication during the double-blind treatment period or after the end of double-blind treatment * Participation in the OLE deemed inappropriate by the investigator * Presence of ARIA-E findings at the Week 116 MRI scan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB | Baseline, Week 116 | CDR was derived through semi-structured interview with the participant and an appropriate informant, and it rated impairment across six domains: memory, orientation, judgment, and problem solving, community affairs, home and hobbies, and personal care on a 5-point scale for which 0=no impairment, 0.5=questionable impairment, and 1, 2, and 3=mild, moderate, and severe impairment, respectively. The CDR-SB is based on summing each of the domain box scores with total score ranging from 0-18 with higher scores reflecting greater cognitive and functional impairment. A negative change from baseline indicates improvement. |
| China Extension: DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB | Baseline, Week 116 | CDR was derived through semi-structured interview with the participant and an appropriate informant, and it rated impairment across six domains: memory, orientation, judgment, and problem solving, community affairs, home and hobbies, and personal care on a 5-point scale for which 0=no impairment, 0.5=questionable impairment, and 1, 2, and 3=mild, moderate, and severe impairment, respectively. The CDR-SB is based on summing each of the domain box scores with total score ranging from 0-18 with higher scores reflecting greater cognitive and functional impairment. A negative change from baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DBT Period: Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score | Baseline, Week 116 | FAQ is a rater-administered ObsRO (informant-based measure) that measures a participant's functional ability to perform complex higher-order activities. The observer provides performance ratings of the target person on ten complex higher-order activities. Total score that ranges from 0-30, with higher scores reflecting greater functional impairment. A negative change from baseline indicates improvement. |
| DBT Period: Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score | Baseline, Week 116 | MMSE is a rater-administered performance-based outcome (PerfO) that includes a set of standardized questions used to evaluate possible cognitive impairment and help stage the severity level of this impairment. The questions target six areas: orientation, registration, attention, short-term recall, language, and constructional praxis/visuospatial abilities. Total score ranges from 0-30, with lower scores indicating greater impairment. A positive change from baseline indicates improvement. |
| DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Score | Baseline, Week 116 | The ADAS-Cog11 was designed to measure cognitive symptom change in participants with Alzheimer's Disease (AD) and consisted of 11 tasks. The standard 11 items (and corresponding score range) were: word recall (0-10), commands (0-5), constructional praxis (0-5), naming objects and fingers (0-5), ideational praxis (0-5), orientation (0-8), word recognition (0-12), spoken language ability (0-5), comprehension of spoken language (0-5), word-finding difficulty (0-5), and remembering test instructions (0-5). The test included 7 performance items and 4 clinician-rated items. The ADAS-Cog11 total score was the sum of all 11 individual items, with a total score ranging from 0 (no impairment) to 70 (severe impairment). Higher scores indicated more severe cognitive impairment. A negative change from baseline indicates improvement. |
| DBT Period: Change From Baseline to Week 116 in Verbal Fluency Task (VFT) Score | Baseline, Week 116 | VFT is a rater administered PerfO that measures speed and flexibility of verbal thought with a total score that ranges from 0-99 (lower scores indicating lower performance). A positive change from baseline indicates improvement. |
| DBT Period: Change From Baseline to Week 116 in the Coding (Digit Symbol Substitution Test [DSST]) Subtest | Baseline, Week 116 | Coding, also called DSST is a rater administered PerfO that measures speed of processing and associative memory with a total score that ranges from 0-135 (lower scores indicating lower performance). The DSST was adapted from the Wechsler Adult Intelligence Scale. The 120-second version of the test was used in this study. Positive change from baseline indicates improvement. |
| DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Instrumental Score | Baseline, Week 116 | The ADCS-iADL measures activities such as using the telephone, shopping and preparing a meal. The ADCS-iADL consists of 16 questions with a score range of 0 to 56 where a higher score represents better function. Positive change from baseline indicates improvement. |
| DBT Period: Number of Participants With at Least One Adverse Event (AE) | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 131 weeks) | An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. |
| DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 131 weeks) | C-SSRS=assessment tool used to assess lifetime suicidality of a participant (at baseline) as well as any new instances of suicidality (C-SSRS since last visit). Structured interview prompts recollection of suicidal ideation, including intensity of ideation, behavior, & attempts with actual/potential lethality. Categories have binary responses (yes/no) & include Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation/behavior is indicated by a yes answer to any of the listed categories. Score of 0 is assigned if no suicide risk is present. Score of 1 or higher= suicidal ideation or behavior. Categories with non-zero values are only reported here. |
| DBT Period: Number of Participants With at Least One Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Magnetic Resonance Imaging (MRI) Finding | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 131 weeks) | ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. In ARIA-E, (E for oedema or effusion), oedema can be seen in different areas of the brain on MRI, representing fluid leakage into the brain parenchyma or sulcal spaces. |
| DBT Period: Number of Participants With at Least One Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) MRI Finding | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 131 weeks) | ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. 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. |
| DBT Period: Number of Participants With Injection-Site Reactions | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 131 weeks) | 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. |
| DBT Period: Number of Participants With Anti-Drug Antibodies (ADA) to Gantenerumab | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 131 weeks) | The number of participants with positive results for ADA against gantenerumab at any of the post-baseline assessment time-points were reported. Participant with an ADA assay result from at least one post-baseline sample was defined as a post-baseline evaluable participant. Treatment Emergent ADA = A participant with a negative or missing baseline ADA result(s) and at least one positive post-baseline ADA result. |
| DBT Period: Change From Baseline to Week 116 in Brain Amyloid Load as Measured by Amyloid Positron Emission Tomography (PET) Scan in a Subset of Participants | Baseline, Week 116 | Brain amyloid load over time was assessed using \[18F\] florbetaben or \[18F\] flutemetamol tracers. These are PET radioligand selective to amyloid. Amyloid PET burden was measured in a composite region of interest (ROI) by using standardized uptake value ratio (SUVR) mapped to the centiloid scale. The weighted composite target region are composed of (both left and right side): frontal lobe, parietal lobe, temporal lobe lateral, cingulum posterior and anterior cingulate gyrus. The reference region used to normalize the composite region was the whole cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scan. |
| DBT Period: Change From Baseline to Week 116 in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants | Baseline, Week 116 | Change in tau load= how much neurofibrillary tau pathology is present in brain assessed by PET Scan. \[18F\] GTP1 was the tau PET radioligand. Tau load was measured using SUVR in 4 composite target ROIs: Temporal composite target region (left & right)=anterior & posterior superior temporal gyrus, posterior temporal lobe, fusiform gyrus, & middle & inferior temporal gyrus; Medial temporal composite region excluding hippocampus (left & right): amygdala, parahippocampus & anterior medial & lateral temporal lobe; Frontal lobe (left & right) & Parietal lobe (left & right). Inferior cerebellar grey matter=reference region for calculating SUVRs for all 4 regions. Tau-PET-mITT analysis set=all participants in ITT analysis set who participated in Tau PET sub-study & who had at least one Tau PET scan with a valid quantitative measurement & who did not withdraw from Tau PET substudy before randomization. Overall number analyzed=number of participants with data available for analysis. |
| DBT Period: Percent Change From Baseline to Week 116 in Cerebrospinal Fluid (CSF) Marker of Disease in a Subset of Participants - Total Tau (tTau) | Baseline, Week 116 | CSF biomarker tTau has been considered as a general marker of neurodegeneration. An elevation in levels of tau, as well as specific pTau species, is thought to be a marker for progressive cellular degeneration in AD. |
| DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Phosphorylated Tau (pTau-181) | Baseline, Week 116 | CSF phospho-tau is an indicator of neuronal injury and neurodegeneration. CSF biomarker tTau has been considered as a general marker of neurodegeneration. An elevation in levels of pTau species, is thought to be a marker for progressive cellular degeneration in AD. |
| DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Neurofilament Light Chain (NFL) | Baseline, Week 116 | NFL is a neuronal cytoplasmic protein highly expressed in large, myelinated axons. Its levels increase in CSF and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including AD. |
| DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score | Baseline, Week 116 | The ADAS-Cog13 total score includes all of the items in the ADAS-Cog11 in addition to delayed word recall and the number cancellation. For the ADAS-cog 13 the range is 0-85 (score range for Delayed Word Recall \[DWR\] score is 0-10 and for Number Cancellation \[NC\] is 0-5, thus the score is ADAS-cog 11\[0-70\] plus the scores for DWR and NC). A higher score indicates worse performance. A negative change from baseline indicates improvement in cognitive function. |
| China - DBT Period: Change From Baseline to Week 116 in ADAS-Cog13 Score | Baseline, Week 116 | The ADAS-Cog13 total score includes all of the items in the ADAS-Cog11 in addition to delayed word recall and the number cancellation. For the ADAS-cog 13 the range is 0-85 (score range for Delayed Word Recall \[DWR\] score is 0-10 and for Number Cancellation \[NC\] is 0-5, thus the score is ADAS-cog 11\[0-70\] plus the scores for DWR and NC). A higher score indicates worse performance. A negative change from baseline indicates improvement in cognitive function. |
| China - DBT Period: Change From Baseline to Week 116 in ADCS-ADL Total Score | Baseline, Week 116 | ADCS-ADL is a 23-item rater-administered, ObsRO that captures a participant's ability to perform basic activities of daily living (e.g., eating and toileting) and more complex ADL or instrumental activities of daily living (iADL, e.g., using the telephone, managing finances, preparing a meal). Total score ranges from 0-78, with higher scores reflecting better functioning. A positive change from baseline indicates improvement. |
| China - DBT Period: Change From Baseline to Week 116 in FAQ Score | Baseline, Week 116 | FAQ is a rater-administered ObsRO (informant-based measure) that measures a participant's functional ability to perform complex higher-order activities. The observer provides performance ratings of the target person on ten complex higher-order activities. Total score that ranges from 0-30, with higher scores reflecting greater functional impairment. A negative change from baseline indicates improvement. |
| China - DBT Period: DBT Period: Change From Baseline to Week 116 in MMSE Total Score | Baseline, Week 116 | MMSE is a rater-administered PerfO that includes a set of standardized questions used to evaluate possible cognitive impairment and help stage the severity level of this impairment. The questions target six areas: orientation, registration, attention, short-term recall, language, and constructional praxis/visuospatial abilities. Total score ranges from 0-30, with lower scores indicating greater impairment. A positive change from baseline indicates improvement. |
| China - DBT Period: Change From Baseline to Week 116 in ADAS-Cog11 Score | Baseline, Week 116 | The ADAS-Cog11 was designed to measure cognitive symptom change in participants with AD and consisted of 11 tasks. The standard 11 items (and corresponding score range) were: word recall (0-10), commands (0-5), constructional praxis (0-5), naming objects and fingers (0-5), ideational praxis (0-5), orientation (0-8), word recognition (0-12), spoken language ability (0-5), comprehension of spoken language (0-5), word-finding difficulty (0-5), and remembering test instructions (0-5). The test included 7 performance items and 4 clinician-rated items. The ADAS-Cog11 total score was the sum of all 11 individual items, with a total score ranging from 0 (no impairment) to 70 (severe impairment). Higher scores indicated more severe cognitive impairment. A negative change from baseline indicates improvement. |
| China - DBT Period: Change From Baseline to Week 116 in VFT Score | Baseline, Week 116 | VFT is a rater administered PerfO that measures speed and flexibility of verbal thought with a total score that ranges from 0-99 (lower scores indicating lower performance). A positive change from baseline indicates improvement. |
| China - DBT Period: Change From Baseline to Week 116 in the Coding (DSST) Subtest | Baseline, Week 116 | Coding, also called DSST is a rater administered PerfO that measures speed of processing and associative memory with a total score that ranges from 0-135 (lower scores indicating lower performance). The DSST was adapted from the Wechsler Adult Intelligence Scale. The 120-second version of the test was used in this study. Positive change from baseline indicates improvement. |
| China - DBT Period: Number of Participants With at Least One AE | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 124 weeks) | An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. Total number of participants with at least one event (AEs) have been reported here. |
| China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 124 weeks) | C-SSRS=assessment tool used to assess lifetime suicidality of a participant (at baseline) as well as any new instances of suicidality (C-SSRS since last visit). Structured interview prompts recollection of suicidal ideation, including intensity of ideation, behavior, & attempts with actual/potential lethality. Categories have binary responses (yes/no) & include Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation/behavior is indicated by a yes answer to any of the listed categories. Score of 0 is assigned if no suicide risk is present. Score of 1 or higher= suicidal ideation or behavior. Categories with non-zero values are only reported here. |
| China - DBT Period: Number of Participants With at Least One ARIA-E MRI Finding | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 124 weeks) | ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. In ARIA-E, (E for oedema or effusion), oedema can be seen in different areas of the brain on MRI, representing fluid leakage into the brain parenchyma or sulcal spaces. |
| China - DBT Period: Number of Participants With at Least One ARIA-H MRI Finding | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 124 weeks) | ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. 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. |
| China - DBT Period: Number of Participants With Injection-Site Reactions | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 124 weeks) | 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. |
| OLE Period: Number of Participants With at Least One AEs | From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 68 weeks) | An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. |
| OLE Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 68 weeks) | C-SSRS=assessment tool used to assess lifetime suicidality of a participant (at baseline) as well as any new instances of suicidality (C-SSRS since last visit). Structured interview prompts recollection of suicidal ideation, including intensity of ideation, behavior, & attempts with actual/potential lethality. Categories have binary responses (yes/no) & include Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation/behavior is indicated by a yes answer to any of the listed categories. Score of 0 is assigned if no suicide risk is present. Score of 1 or higher= suicidal ideation or behavior. Categories with non-zero values are only reported here. |
| OLE Period: Number of Participants With at Least One ARIA-H MRI Finding | From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 68 weeks) | ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. 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. |
| OLE Period: Number of Participants With at Least One ARIA-E MRI Finding | From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 68 weeks) | ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. In ARIA-E, (E for oedema or effusion), oedema can be seen in different areas of the brain on MRI, representing fluid leakage into the brain parenchyma or sulcal spaces. |
| DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Neurogranin | Baseline, Week 116 | — |
| DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) Total Score | Baseline, Week 116 | ADCS-ADL is a 23-item rater-administered, observer-reported outcome (ObsRO) that captures a participant's ability to perform basic activities of daily living (e.g., eating and toileting) and more complex ADL or instrumental activities of daily living (iADL, e.g., using the telephone, managing finances, preparing a meal). Total score ranges from 0-78, with higher scores reflecting better functioning. A positive change from baseline indicates improvement. |
Countries
Australia, Brazil, Canada, China, France, Germany, Hungary, Italy, Japan, Lithuania, Peru, Russia, Spain, Taiwan, United States
Participant flow
Recruitment details
Participants were enrolled in this study at 137 sites across 15 countries (Australia, Brazil, Canada, China, France, Germany, Hungary, Italy, Japan, Lithuania, Peru, Russia, Taiwan, Spain, and the United States) during the global phase. Participants were enrolled at 21 sites in China during the China extension phase of the study. The open-label period in China was not started as the study was terminated early by the Sponsor.
Pre-assignment details
A total of 985 participants with early (prodromal to mild) Alzheimer's Disease (AD) were randomized to either the gantenerumab (n=499) or placebo arm (n=486) to enter the double-blind treatment (DBT) period of the global phase. A total of 68 early (prodromal to mild) AD participants were randomized to the gantenerumab (n=35) or placebo arm (n=33) to enter the DBT period of the China extension phase.
Participants by arm
| Arm | Count |
|---|---|
| Global - DBT Period: Placebo Participants received gantenerumab matching placebo, SC injection, Q4W up to Week 36 and then Q2W up to approximately 114 weeks of the DBT period. | 485 |
| Global - DBT Period: Gantenerumab Participants received gantenerumab, SC injection with gradual up-titration starting at a dose of 120 mg, Q4W for 3 doses, followed by 255 mg, Q4W for 3 doses, and 510 mg, Q4W for 3 doses, and 510 mg, Q4W for 3 doses. Following this, from Week 36 onwards, participants received gantenerumab, SC injection at a dose of 510 mg, Q2W up to Week 114 of the DBT period. | 499 |
| China Extension - DBT Period: Placebo Participants received gantenerumab matching placebo, SC injection, Q4W up to Week 36 and then Q2W up to approximately 110 weeks of the DBT period. | 33 |
| China Extension - DBT Period: Gantenerumab Participants received gantenerumab, SC injection with gradual up-titration starting at a dose of 120 mg, Q4W for 3 doses, followed by 255 mg, Q4W for 3 doses, and 510 mg, Q4W for 3 doses. Following this, from Week 36 onwards, participants received gantenerumab, SC injection at a dose of 510 mg, Q2W up to approximately 110 weeks of the DBT period. | 35 |
| Total | 1,052 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Double-Blind Treatment (DBT) Period | Adverse Event | 7 | 29 | 0 | 0 | 0 | 0 |
| Double-Blind Treatment (DBT) Period | Death | 10 | 2 | 0 | 0 | 0 | 0 |
| Double-Blind Treatment (DBT) Period | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 |
| Double-Blind Treatment (DBT) Period | Physician Decision | 3 | 11 | 0 | 0 | 0 | 0 |
| Double-Blind Treatment (DBT) Period | Protocol Deviation | 4 | 3 | 0 | 0 | 0 | 0 |
| Double-Blind Treatment (DBT) Period | Randomized, but not Treated | 1 | 0 | 0 | 0 | 0 | 0 |
| Double-Blind Treatment (DBT) Period | Reason not Specified | 17 | 16 | 1 | 0 | 0 | 0 |
| Double-Blind Treatment (DBT) Period | Study Terminated By Sponsor | 0 | 0 | 30 | 35 | 0 | 0 |
| Double-Blind Treatment (DBT) Period | Withdrawal by Subject | 56 | 63 | 2 | 0 | 0 | 0 |
| Open-Label Extension (OLE) Period | Death | 0 | 0 | 0 | 0 | 1 | 0 |
| Open-Label Extension (OLE) Period | Physician Decision | 0 | 0 | 0 | 0 | 1 | 0 |
| Open-Label Extension (OLE) Period | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Global - DBT Period: Placebo | Global - DBT Period: Gantenerumab | China Extension - DBT Period: Placebo | China Extension - DBT Period: Gantenerumab | Total |
|---|---|---|---|---|---|
| Age, Continuous | 72.1 years STANDARD_DEVIATION 7.8 | 71.1 years STANDARD_DEVIATION 7.9 | 65.9 years STANDARD_DEVIATION 8.5 | 68.5 years STANDARD_DEVIATION 7.3 | 71.4 years STANDARD_DEVIATION 7.9 |
| China Extension: Clinical Dementia Rating-Sum of Boxes (CDR-SB) | — | — | 3.29 score on a scale STANDARD_DEVIATION 1.22 | 3.69 score on a scale STANDARD_DEVIATION 1.5 | 3.49 score on a scale STANDARD_DEVIATION 1.38 |
| DBT Period: CDR-SB | 3.71 score on a scale STANDARD_DEVIATION 1.67 | 3.71 score on a scale STANDARD_DEVIATION 1.57 | — | — | 3.71 score on a scale STANDARD_DEVIATION 1.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 58 Participants | 52 Participants | 0 Participants | 0 Participants | 110 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 422 Participants | 439 Participants | 32 Participants | 34 Participants | 927 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 8 Participants | 1 Participants | 1 Participants | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 18 Participants | 18 Participants | 0 Participants | 0 Participants | 36 Participants |
| Race (NIH/OMB) Asian | 53 Participants | 52 Participants | 33 Participants | 35 Participants | 173 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 1 Participants | 0 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 14 Participants | 0 Participants | 0 Participants | 24 Participants |
| Race (NIH/OMB) White | 398 Participants | 414 Participants | 0 Participants | 0 Participants | 812 Participants |
| Sex: Female, Male Female | 255 Participants | 290 Participants | 16 Participants | 18 Participants | 579 Participants |
| Sex: Female, Male Male | 230 Participants | 209 Participants | 17 Participants | 17 Participants | 473 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 481 | 3 / 503 | 0 / 33 | 0 / 35 | 1 / 9 | 0 / 20 |
| other Total, other adverse events | 329 / 481 | 366 / 503 | 11 / 33 | 20 / 35 | 8 / 9 | 16 / 20 |
| serious Total, serious adverse events | 95 / 481 | 76 / 503 | 0 / 33 | 2 / 35 | 2 / 9 | 2 / 20 |
Outcome results
Primary
China Extension: DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB
CDR was derived through semi-structured interview with the participant and an appropriate informant, and it rated impairment across six domains: memory, orientation, judgment, and problem solving, community affairs, home and hobbies, and personal care on a 5-point scale for which 0=no impairment, 0.5=questionable impairment, and 1, 2, and 3=mild, moderate, and severe impairment, respectively. The CDR-SB is based on summing each of the domain box scores with total score ranging from 0-18 with higher scores reflecting greater cognitive and functional impairment. A negative change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: The study was terminated early by the sponsor before any participant had reached Week 116 visit in the China extension phase.
Primary
DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB
CDR was derived through semi-structured interview with the participant and an appropriate informant, and it rated impairment across six domains: memory, orientation, judgment, and problem solving, community affairs, home and hobbies, and personal care on a 5-point scale for which 0=no impairment, 0.5=questionable impairment, and 1, 2, and 3=mild, moderate, and severe impairment, respectively. The CDR-SB is based on summing each of the domain box scores with total score ranging from 0-18 with higher scores reflecting greater cognitive and functional impairment. A negative change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: ITT analysis set included all participants randomized during the global phase, who received at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB | 3.65 score on a scale | Standard Error 0.16 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB | 3.35 score on a scale | Standard Error 0.14 |
Comparison: Change from Baseline was calculated based on ANCOVA analysis model which included the following covariates and stratification factors =Treatment + Baseline (BL) + Geographic Region + Disease Stage + AD Medication at BL + Apolipoprotein E, Allele e4 (APOE e4) + Baseline Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score + Baseline Alzheimer Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL).p-value: 0.095495% CI: [-0.66, 0.05]ANCOVA
Secondary
China - DBT Period: Change From Baseline to Week 116 in ADAS-Cog11 Score
The ADAS-Cog11 was designed to measure cognitive symptom change in participants with AD and consisted of 11 tasks. The standard 11 items (and corresponding score range) were: word recall (0-10), commands (0-5), constructional praxis (0-5), naming objects and fingers (0-5), ideational praxis (0-5), orientation (0-8), word recognition (0-12), spoken language ability (0-5), comprehension of spoken language (0-5), word-finding difficulty (0-5), and remembering test instructions (0-5). The test included 7 performance items and 4 clinician-rated items. The ADAS-Cog11 total score was the sum of all 11 individual items, with a total score ranging from 0 (no impairment) to 70 (severe impairment). Higher scores indicated more severe cognitive impairment. A negative change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: The study was terminated early by the sponsor before any participant had reached Week 116 visit in the China extension phase.
Secondary
China - DBT Period: Change From Baseline to Week 116 in ADAS-Cog13 Score
The ADAS-Cog13 total score includes all of the items in the ADAS-Cog11 in addition to delayed word recall and the number cancellation. For the ADAS-cog 13 the range is 0-85 (score range for Delayed Word Recall \[DWR\] score is 0-10 and for Number Cancellation \[NC\] is 0-5, thus the score is ADAS-cog 11\[0-70\] plus the scores for DWR and NC). A higher score indicates worse performance. A negative change from baseline indicates improvement in cognitive function.
Time frame: Baseline, Week 116
Population: The study was terminated early by the sponsor before any participant had reached Week 116 visit in the China extension phase.
Secondary
China - DBT Period: Change From Baseline to Week 116 in ADCS-ADL Total Score
ADCS-ADL is a 23-item rater-administered, ObsRO that captures a participant's ability to perform basic activities of daily living (e.g., eating and toileting) and more complex ADL or instrumental activities of daily living (iADL, e.g., using the telephone, managing finances, preparing a meal). Total score ranges from 0-78, with higher scores reflecting better functioning. A positive change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: The study was terminated early by the sponsor before any participant had reached Week 116 visit in the China extension phase.
Secondary
China - DBT Period: Change From Baseline to Week 116 in FAQ Score
FAQ is a rater-administered ObsRO (informant-based measure) that measures a participant's functional ability to perform complex higher-order activities. The observer provides performance ratings of the target person on ten complex higher-order activities. Total score that ranges from 0-30, with higher scores reflecting greater functional impairment. A negative change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: The study was terminated early by the sponsor before any participant had reached Week 116 visit in the China extension phase.
Secondary
China - DBT Period: Change From Baseline to Week 116 in the Coding (DSST) Subtest
Coding, also called DSST is a rater administered PerfO that measures speed of processing and associative memory with a total score that ranges from 0-135 (lower scores indicating lower performance). The DSST was adapted from the Wechsler Adult Intelligence Scale. The 120-second version of the test was used in this study. Positive change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: The study was terminated early by the sponsor before any participant had reached Week 116 visit in the China extension phase.
Secondary
China - DBT Period: Change From Baseline to Week 116 in VFT Score
VFT is a rater administered PerfO that measures speed and flexibility of verbal thought with a total score that ranges from 0-99 (lower scores indicating lower performance). A positive change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: The study was terminated early by the sponsor before any participant had reached Week 116 visit in the China extension phase.
Secondary
China - DBT Period: DBT Period: Change From Baseline to Week 116 in MMSE Total Score
MMSE is a rater-administered PerfO that includes a set of standardized questions used to evaluate possible cognitive impairment and help stage the severity level of this impairment. The questions target six areas: orientation, registration, attention, short-term recall, language, and constructional praxis/visuospatial abilities. Total score ranges from 0-30, with lower scores indicating greater impairment. A positive change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: The study was terminated early by the sponsor before any participant had reached Week 116 visit in the China extension phase.
Secondary
China - DBT Period: Number of Participants With at Least One AE
An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. Total number of participants with at least one event (AEs) have been reported here.
Time frame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 124 weeks)
Population: SE analysis set (China) included all participants enrolled in China in the China extension phase who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global - DBT Period: Placebo | China - DBT Period: Number of Participants With at Least One AE | 17 Participants |
| Global - DBT Period: Gantenerumab | China - DBT Period: Number of Participants With at Least One AE | 24 Participants |
Secondary
China - DBT Period: Number of Participants With at Least One ARIA-E MRI Finding
ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. In ARIA-E, (E for oedema or effusion), oedema can be seen in different areas of the brain on MRI, representing fluid leakage into the brain parenchyma or sulcal spaces.
Time frame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 124 weeks)
Population: SE analysis set (China) included all participants enrolled in China in the China extension phase who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global - DBT Period: Placebo | China - DBT Period: Number of Participants With at Least One ARIA-E MRI Finding | 1 Participants |
| Global - DBT Period: Gantenerumab | China - DBT Period: Number of Participants With at Least One ARIA-E MRI Finding | 4 Participants |
Secondary
China - DBT Period: Number of Participants With at Least One ARIA-H MRI Finding
ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. ARIA-H (H for hemosiderosis) are small foci of signal loss observed on MRI sequences sensitive for paramagnetic tissue properties and comprise cerebral microbleeds (small foci of bleeding in the brain parenchyma) and leptomeningeal hemosiderosis (small foci of bleeding on the surface of the brain). These changes also occur sporadically in AD.
Time frame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 124 weeks)
Population: SE analysis set (China) included all participants enrolled in China in the China extension phase who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global - DBT Period: Placebo | China - DBT Period: Number of Participants With at Least One ARIA-H MRI Finding | 0 Participants |
| Global - DBT Period: Gantenerumab | China - DBT Period: Number of Participants With at Least One ARIA-H MRI Finding | 1 Participants |
Secondary
China - DBT Period: Number of Participants With Injection-Site Reactions
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Local injection reactions (or injection site reactions) are defined as AEs related to the injection site that occur during or within 24 hours after study drug administration that are judged to be related to the study drug injection.
Time frame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 124 weeks)
Population: SE analysis set (China) included all participants enrolled in China in the China extension phase who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global - DBT Period: Placebo | China - DBT Period: Number of Participants With Injection-Site Reactions | 0 Participants |
| Global - DBT Period: Gantenerumab | China - DBT Period: Number of Participants With Injection-Site Reactions | 0 Participants |
Secondary
China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS
C-SSRS=assessment tool used to assess lifetime suicidality of a participant (at baseline) as well as any new instances of suicidality (C-SSRS since last visit). Structured interview prompts recollection of suicidal ideation, including intensity of ideation, behavior, & attempts with actual/potential lethality. Categories have binary responses (yes/no) & include Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation/behavior is indicated by a yes answer to any of the listed categories. Score of 0 is assigned if no suicide risk is present. Score of 1 or higher= suicidal ideation or behavior. Categories with non-zero values are only reported here.
Time frame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 124 weeks)
Population: SE analysis set (China) included all participants enrolled in China in the China extension phase who received at least one dose of study drug. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Global - DBT Period: Placebo | China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Passive | 1 Participants |
| Global - DBT Period: Placebo | China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Active-Nonspecific (no method, intent, or plan) | 0 Participants |
| Global - DBT Period: Placebo | China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Active-Method and intent, but no plan | 1 Participants |
| Global - DBT Period: Placebo | China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: No Event | 23 Participants |
| Global - DBT Period: Placebo | China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Behavior: No Event | 25 Participants |
| Global - DBT Period: Placebo | China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Self-injurious Behavior Without Suicidal Intent: No event | 25 Participants |
| Global - DBT Period: Gantenerumab | China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Behavior: No Event | 30 Participants |
| Global - DBT Period: Gantenerumab | China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Passive | 1 Participants |
| Global - DBT Period: Gantenerumab | China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: No Event | 28 Participants |
| Global - DBT Period: Gantenerumab | China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Active-Nonspecific (no method, intent, or plan) | 1 Participants |
| Global - DBT Period: Gantenerumab | China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Self-injurious Behavior Without Suicidal Intent: No event | 30 Participants |
| Global - DBT Period: Gantenerumab | China - DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Active-Method and intent, but no plan | 0 Participants |
Secondary
DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Score
The ADAS-Cog11 was designed to measure cognitive symptom change in participants with Alzheimer's Disease (AD) and consisted of 11 tasks. The standard 11 items (and corresponding score range) were: word recall (0-10), commands (0-5), constructional praxis (0-5), naming objects and fingers (0-5), ideational praxis (0-5), orientation (0-8), word recognition (0-12), spoken language ability (0-5), comprehension of spoken language (0-5), word-finding difficulty (0-5), and remembering test instructions (0-5). The test included 7 performance items and 4 clinician-rated items. The ADAS-Cog11 total score was the sum of all 11 individual items, with a total score ranging from 0 (no impairment) to 70 (severe impairment). Higher scores indicated more severe cognitive impairment. A negative change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: ITT analysis set included all participants randomized during the global phase, who received at least one dose of study drug. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Score | 8.42 score on a scale | Standard Error 0.52 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Score | 7.44 score on a scale | Standard Error 0.43 |
Comparison: Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Geographical Region + Disease Stage + AD Medication at BL + APOE e4.p-value: 0.103695% CI: [-2.14, 0.2]ANCOVA
Secondary
DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score
The ADAS-Cog13 total score includes all of the items in the ADAS-Cog11 in addition to delayed word recall and the number cancellation. For the ADAS-cog 13 the range is 0-85 (score range for Delayed Word Recall \[DWR\] score is 0-10 and for Number Cancellation \[NC\] is 0-5, thus the score is ADAS-cog 11\[0-70\] plus the scores for DWR and NC). A higher score indicates worse performance. A negative change from baseline indicates improvement in cognitive function.
Time frame: Baseline, Week 116
Population: ITT analysis set included all participants randomized during the global phase, who received at least one dose of study drug. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score | 9.82 score on a scale | Standard Error 0.57 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score | 8.57 score on a scale | Standard Error 0.47 |
Comparison: Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Geographical Region + Disease Stage + AD Medication at BL + APOE e4.p-value: 0.054495% CI: [-2.52, 0.02]ANCOVA
Secondary
DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) Total Score
ADCS-ADL is a 23-item rater-administered, observer-reported outcome (ObsRO) that captures a participant's ability to perform basic activities of daily living (e.g., eating and toileting) and more complex ADL or instrumental activities of daily living (iADL, e.g., using the telephone, managing finances, preparing a meal). Total score ranges from 0-78, with higher scores reflecting better functioning. A positive change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: ITT analysis set included all participants randomized during the global phase, who received at least one dose of study drug. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) Total Score | -12.32 score on a scale | Standard Error 0.68 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) Total Score | -11.21 score on a scale | Standard Error 0.6 |
Comparison: Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Region + Disease Stage + AD Medication at BL + APOE e4.p-value: 0.172995% CI: [-0.48, 2.7]ANCOVA
Secondary
DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Instrumental Score
The ADCS-iADL measures activities such as using the telephone, shopping and preparing a meal. The ADCS-iADL consists of 16 questions with a score range of 0 to 56 where a higher score represents better function. Positive change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: ITT analysis set included all participants randomized during the global phase, who received at least one dose of study drug. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Instrumental Score | -10.80 score on a scale | Standard Error 0.56 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Instrumental Score | -9.80 score on a scale | Standard Error 0.51 |
Comparison: Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Geographical Region + Disease Stage + AD Medication at BL + APOE e4.p-value: 0.143995% CI: [-0.34, 2.34]ANCOVA
Secondary
DBT Period: Change From Baseline to Week 116 in Brain Amyloid Load as Measured by Amyloid Positron Emission Tomography (PET) Scan in a Subset of Participants
Brain amyloid load over time was assessed using \[18F\] florbetaben or \[18F\] flutemetamol tracers. These are PET radioligand selective to amyloid. Amyloid PET burden was measured in a composite region of interest (ROI) by using standardized uptake value ratio (SUVR) mapped to the centiloid scale. The weighted composite target region are composed of (both left and right side): frontal lobe, parietal lobe, temporal lobe lateral, cingulum posterior and anterior cingulate gyrus. The reference region used to normalize the composite region was the whole cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scan.
Time frame: Baseline, Week 116
Population: Amyloid-PET modified ITT (mITT) analysis set included all participants in the ITT analysis set who participated in the Amyloid-PET substudy and who had at least one Amyloid-PET scan with a valid quantitative measurement performed with either florbetaben or flutemetamol and who did not withdraw from the Amyloid-PET substudy before randomization. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Brain Amyloid Load as Measured by Amyloid Positron Emission Tomography (PET) Scan in a Subset of Participants | 9.06 score on a scale | Standard Error 3.046 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Brain Amyloid Load as Measured by Amyloid Positron Emission Tomography (PET) Scan in a Subset of Participants | -57.38 score on a scale | Standard Error 2.841 |
Comparison: Change from BL was calculated based on mixed-effect model of repeated measure which included the following covariates and stratification factors = Baseline + APOE e4 status + Type of Tracer + Analysis Visit + Treatment + Treatment\*Analysis Visit + Analysis Visit\*Baseline.p-value: <0.000195% CI: [-74.71, -58.16]Mixed Model for Repeated Measures
Secondary
DBT Period: Change From Baseline to Week 116 in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants
Change in tau load= how much neurofibrillary tau pathology is present in brain assessed by PET Scan. \[18F\] GTP1 was the tau PET radioligand. Tau load was measured using SUVR in 4 composite target ROIs: Temporal composite target region (left & right)=anterior & posterior superior temporal gyrus, posterior temporal lobe, fusiform gyrus, & middle & inferior temporal gyrus; Medial temporal composite region excluding hippocampus (left & right): amygdala, parahippocampus & anterior medial & lateral temporal lobe; Frontal lobe (left & right) & Parietal lobe (left & right). Inferior cerebellar grey matter=reference region for calculating SUVRs for all 4 regions. Tau-PET-mITT analysis set=all participants in ITT analysis set who participated in Tau PET sub-study & who had at least one Tau PET scan with a valid quantitative measurement & who did not withdraw from Tau PET substudy before randomization. Overall number analyzed=number of participants with data available for analysis.
Time frame: Baseline, Week 116
Population: As pre-specified in protocol/SAP, single tau PET substudy analyzed participants from 2 studies i.e. WN29922 (NCT03444870) \& WN39658 (NCT03443973), hence data for Tau PET was analyzed at pooled level of WN29922 \&WN39658. These studies had identical study design \& enrolled an Early AD population. Tau PET analysis was planned in a subset of participants, to get an optimum sample size for analysis, it was pre-planned to conduct 1 tau PET substudy for participants willing to consent to the procedure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants | ROI: Temporal Composite Region | 0.12 SUVR | Standard Error 0.018 |
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants | ROI: Medial Temporal Composite Region [not including the Hippocampus] | 0.08 SUVR | Standard Error 0.014 |
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants | ROI: Frontal Lobe | 0.08 SUVR | Standard Error 0.012 |
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants | ROI: Parietal Lobe | 0.09 SUVR | Standard Error 0.02 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants | ROI: Parietal Lobe | 0.09 SUVR | Standard Error 0.016 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants | ROI: Temporal Composite Region | 0.13 SUVR | Standard Error 0.014 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants | ROI: Frontal Lobe | 0.08 SUVR | Standard Error 0.009 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Participants | ROI: Medial Temporal Composite Region [not including the Hippocampus] | 0.09 SUVR | Standard Error 0.011 |
Comparison: Temporal Composite Region: Change from BL was calculated based on mixed-effect model of repeated measure which included the following covariates and stratification factors = Baseline + APOE e4 status + Study + Analysis Visit + Treatment + Treatment\*Analysis Visit + Analysis Visit\*Baseline.p-value: 0.781695% CI: [-0.04, 0.05]Mixed Model for Repeated Measures
Comparison: Medial Temporal Composite Region: Change from BL was calculated based on mixed-effect model of repeated measure which included the following covariates and stratification factors = Baseline + APOE e4 status + Study + Analysis Visit + Treatment + Treatment\*Analysis Visit + Analysis Visit\*Baseline.p-value: 0.620395% CI: [-0.03, 0.05]Mixed Model for Repeated Measures
Comparison: Frontal Lobe: Change from BL was calculated based on mixed-effect model of repeated measure which included the following covariates and stratification factors = Baseline + APOE e4 status + Study + Analysis Visit + Treatment + Treatment\*Analysis Visit + Analysis Visit\*Baseline.p-value: 0.775495% CI: [-0.03, 0.03]Mixed Model for Repeated Measures
Comparison: Parietal Lobe: Change from BL was calculated based on mixed-effect model of repeated measure which included the following covariates and stratification factors = Baseline + APOE e4 status + Study + Analysis Visit + Treatment + Treatment\*Analysis Visit + Analysis Visit\*Baseline.p-value: 0.902295% CI: [-0.05, 0.05]Mixed Model for Repeated Measures
Secondary
DBT Period: Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score
FAQ is a rater-administered ObsRO (informant-based measure) that measures a participant's functional ability to perform complex higher-order activities. The observer provides performance ratings of the target person on ten complex higher-order activities. Total score that ranges from 0-30, with higher scores reflecting greater functional impairment. A negative change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: ITT analysis set included all participants randomized during the global phase, who received at least one dose of study drug. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score | 8.13 score on a scale | Standard Error 0.33 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score | 7.28 score on a scale | Standard Error 0.3 |
Comparison: Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Geographical Region + Disease Stage + AD Medication at BL + APOE e4.p-value: 0.042595% CI: [-1.68, -0.03]ANCOVA
Secondary
DBT Period: Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score
MMSE is a rater-administered performance-based outcome (PerfO) that includes a set of standardized questions used to evaluate possible cognitive impairment and help stage the severity level of this impairment. The questions target six areas: orientation, registration, attention, short-term recall, language, and constructional praxis/visuospatial abilities. Total score ranges from 0-30, with lower scores indicating greater impairment. A positive change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: ITT analysis set included all participants randomized during the global phase, who received at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score | -5.18 score on a scale | Standard Error 0.25 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score | -4.86 score on a scale | Standard Error 0.23 |
Comparison: Change from Baseline was calculated based on ANCOVA analysis model which included the following covariates and stratification factors =Treatment + Baseline + Geographic Region + Disease Stage + AD Medication at BL + APOE e4.p-value: 0.290495% CI: [-0.28, 0.93]ANCOVA
Secondary
DBT Period: Change From Baseline to Week 116 in the Coding (Digit Symbol Substitution Test [DSST]) Subtest
Coding, also called DSST is a rater administered PerfO that measures speed of processing and associative memory with a total score that ranges from 0-135 (lower scores indicating lower performance). The DSST was adapted from the Wechsler Adult Intelligence Scale. The 120-second version of the test was used in this study. Positive change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: ITT analysis set included all participants randomized during the global phase, who received at least one dose of study drug. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in the Coding (Digit Symbol Substitution Test [DSST]) Subtest | -6.47 score on a scale | Standard Error 0.64 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in the Coding (Digit Symbol Substitution Test [DSST]) Subtest | -6.27 score on a scale | Standard Error 0.54 |
Comparison: Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Geographical Region + Disease Stage + AD Medication at BL + APOE e4.p-value: 0.80395% CI: [-1.35, 1.74]ANCOVA
Secondary
DBT Period: Change From Baseline to Week 116 in Verbal Fluency Task (VFT) Score
VFT is a rater administered PerfO that measures speed and flexibility of verbal thought with a total score that ranges from 0-99 (lower scores indicating lower performance). A positive change from baseline indicates improvement.
Time frame: Baseline, Week 116
Population: ITT analysis set included all participants randomized during the global phase, who received at least one dose of study drug. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Change From Baseline to Week 116 in Verbal Fluency Task (VFT) Score | -3.46 score on a scale | Standard Error 0.31 |
| Global - DBT Period: Gantenerumab | DBT Period: Change From Baseline to Week 116 in Verbal Fluency Task (VFT) Score | -3.53 score on a scale | Standard Error 0.3 |
Comparison: Change from BL was calculated based on ANCOVA analysis model which included the following covariates and stratification factors = Treatment + Baseline + Geographical Region + Disease Stage + AD Medication at BL + APOE e4.p-value: 0.846895% CI: [-0.79, 0.65]ANCOVA
Secondary
DBT Period: Number of Participants With Anti-Drug Antibodies (ADA) to Gantenerumab
The number of participants with positive results for ADA against gantenerumab at any of the post-baseline assessment time-points were reported. Participant with an ADA assay result from at least one post-baseline sample was defined as a post-baseline evaluable participant. Treatment Emergent ADA = A participant with a negative or missing baseline ADA result(s) and at least one positive post-baseline ADA result.
Time frame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 131 weeks)
Population: SE analysis set included all participants randomized during the global phase who received at least one dose of study drug. In the DBT period, four participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety analysis set. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Number of Participants With Anti-Drug Antibodies (ADA) to Gantenerumab | 10 Participants |
Secondary
DBT Period: Number of Participants With at Least One Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution.
Time frame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 131 weeks)
Population: SE analysis set included all participants randomized during the global phase who received at least one dose of study drug. In the DBT period, four participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Number of Participants With at Least One Adverse Event (AE) | 423 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With at Least One Adverse Event (AE) | 454 Participants |
Secondary
DBT Period: Number of Participants With at Least One Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Magnetic Resonance Imaging (MRI) Finding
ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. In ARIA-E, (E for oedema or effusion), oedema can be seen in different areas of the brain on MRI, representing fluid leakage into the brain parenchyma or sulcal spaces.
Time frame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 131 weeks)
Population: SEMRI analysis set included all participants in the SE analysis set who had at least one post-baseline safety MRI scan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Number of Participants With at Least One Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Magnetic Resonance Imaging (MRI) Finding | 5 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With at Least One Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Magnetic Resonance Imaging (MRI) Finding | 105 Participants |
Secondary
DBT Period: Number of Participants With at Least One Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) MRI Finding
ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. ARIA-H (H for hemosiderosis) are small foci of signal loss observed on MRI sequences sensitive for paramagnetic tissue properties and comprise cerebral microbleeds (small foci of bleeding in the brain parenchyma) and leptomeningeal hemosiderosis (small foci of bleeding on the surface of the brain). These changes also occur sporadically in AD.
Time frame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 131 weeks)
Population: SEMRI analysis set included all participants in the SE analysis set who had at least one post-baseline safety MRI scan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Number of Participants With at Least One Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) MRI Finding | 6 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With at Least One Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) MRI Finding | 40 Participants |
Secondary
DBT Period: Number of Participants With Injection-Site Reactions
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Local injection reactions (or injection site reactions) are defined as AEs related to the injection site that occur during or within 24 hours after study drug administration that are judged to be related to the study drug injection.
Time frame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 131 weeks)
Population: SE analysis set included all participants randomized during the global phase who received at least one dose of study drug. In the DBT period, four participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Number of Participants With Injection-Site Reactions | 43 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With Injection-Site Reactions | 94 Participants |
Secondary
DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS)
C-SSRS=assessment tool used to assess lifetime suicidality of a participant (at baseline) as well as any new instances of suicidality (C-SSRS since last visit). Structured interview prompts recollection of suicidal ideation, including intensity of ideation, behavior, & attempts with actual/potential lethality. Categories have binary responses (yes/no) & include Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation/behavior is indicated by a yes answer to any of the listed categories. Score of 0 is assigned if no suicide risk is present. Score of 1 or higher= suicidal ideation or behavior. Categories with non-zero values are only reported here.
Time frame: From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 131 weeks)
Population: SE analysis set included all participants randomized during the global phase who received at least one dose of study drug. In the DBT period, four participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety analysis set. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Active-Method, Intent, and Plan | 2 Participants |
| Global - DBT Period: Placebo | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Self-injurious Behavior Without Suicidal Intent: No Event | 467 Participants |
| Global - DBT Period: Placebo | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior: Interrupted Attempt | 0 Participants |
| Global - DBT Period: Placebo | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Passive | 13 Participants |
| Global - DBT Period: Placebo | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: No Event | 443 Participants |
| Global - DBT Period: Placebo | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Active-Nonspecific | 1 Participants |
| Global - DBT Period: Placebo | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior: No Event | 467 Participants |
| Global - DBT Period: Placebo | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Active-Method, But No Intent or Plan | 6 Participants |
| Global - DBT Period: Placebo | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Active-Method and Intent, But No Plan | 2 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Active-Method, But No Intent or Plan | 3 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Active-Method and Intent, But No Plan | 0 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Active-Method, Intent, and Plan | 0 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: No Event | 466 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior: Interrupted Attempt | 1 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior: No Event | 488 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Self-injurious Behavior Without Suicidal Intent: No Event | 489 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Passive | 17 Participants |
| Global - DBT Period: Gantenerumab | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation: Active-Nonspecific | 3 Participants |
Secondary
DBT Period: Percent Change From Baseline to Week 116 in Cerebrospinal Fluid (CSF) Marker of Disease in a Subset of Participants - Total Tau (tTau)
CSF biomarker tTau has been considered as a general marker of neurodegeneration. An elevation in levels of tau, as well as specific pTau species, is thought to be a marker for progressive cellular degeneration in AD.
Time frame: Baseline, Week 116
Population: CSF mITT Analysis Set included all participants in the ITT analysis set who had at least one valid quantitative CSF measurement. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Percent Change From Baseline to Week 116 in Cerebrospinal Fluid (CSF) Marker of Disease in a Subset of Participants - Total Tau (tTau) | 3.2 percent change in tTau |
| Global - DBT Period: Gantenerumab | DBT Period: Percent Change From Baseline to Week 116 in Cerebrospinal Fluid (CSF) Marker of Disease in a Subset of Participants - Total Tau (tTau) | -16.6 percent change in tTau |
Comparison: Parietal Lobe: Change from BL was calculated based on mixed-effect model of repeated measure which included the following covariates and stratification factors = Baseline + APOE e4 status + Study + Analysis Visit + Treatment + Treatment\*Analysis Visit + Analysis Visit\*Baseline.p-value: <0.001ANCOVA
Secondary
DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Neurofilament Light Chain (NFL)
NFL is a neuronal cytoplasmic protein highly expressed in large, myelinated axons. Its levels increase in CSF and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including AD.
Time frame: Baseline, Week 116
Population: CSF mITT Analysis Set included all participants in the ITT analysis set who had at least one valid quantitative CSF measurement. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Neurofilament Light Chain (NFL) | 15.8 percent change in NFL |
| Global - DBT Period: Gantenerumab | DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Neurofilament Light Chain (NFL) | 12.1 percent change in NFL |
p-value: 0.396ANCOVA
Secondary
DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Neurogranin
Time frame: Baseline, Week 116
Population: CSF mITT Analysis Set included all participants in the ITT analysis set who had at least one valid quantitative CSF measurement. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Neurogranin | -0.6 percent change in neurogranin |
| Global - DBT Period: Gantenerumab | DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Neurogranin | -22.3 percent change in neurogranin |
p-value: <0.001ANCOVA
Secondary
DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Phosphorylated Tau (pTau-181)
CSF phospho-tau is an indicator of neuronal injury and neurodegeneration. CSF biomarker tTau has been considered as a general marker of neurodegeneration. An elevation in levels of pTau species, is thought to be a marker for progressive cellular degeneration in AD.
Time frame: Baseline, Week 116
Population: CSF modified ITT analysis set included all participants in the ITT analysis set who had at least one valid quantitative CSF measurement. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Global - DBT Period: Placebo | DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Phosphorylated Tau (pTau-181) | 1.1 percent change in pTau-181 |
| Global - DBT Period: Gantenerumab | DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Phosphorylated Tau (pTau-181) | -25.2 percent change in pTau-181 |
p-value: <0.001ANCOVA
Secondary
OLE Period: Number of Participants With at Least One AEs
An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution.
Time frame: From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 68 weeks)
Population: SE analysis set included all participants randomized during the global phase who received at least one dose of study drug. In the DBT period, 4 participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety analysis set, of which one participant entered OLE period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global - DBT Period: Placebo | OLE Period: Number of Participants With at Least One AEs | 8 Participants |
| Global - DBT Period: Gantenerumab | OLE Period: Number of Participants With at Least One AEs | 16 Participants |
Secondary
OLE Period: Number of Participants With at Least One ARIA-E MRI Finding
ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. In ARIA-E, (E for oedema or effusion), oedema can be seen in different areas of the brain on MRI, representing fluid leakage into the brain parenchyma or sulcal spaces.
Time frame: From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 68 weeks)
Population: SEMRI analysis set included all participants in SE analysis set who had at least one post-baseline safety MRI scan. In DBT period, 4 participants randomized to placebo arm received at least one dose of gantenerumab and were considered in gantenerumab arm for SE analysis set, of which 1 participant entered OLE period. Overall number analyzed is the number of participants with data available for analysis. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global - DBT Period: Placebo | OLE Period: Number of Participants With at Least One ARIA-E MRI Finding | 3 Participants |
| Global - DBT Period: Gantenerumab | OLE Period: Number of Participants With at Least One ARIA-E MRI Finding | 2 Participants |
Secondary
OLE Period: Number of Participants With at Least One ARIA-H MRI Finding
ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. ARIA-H (H for hemosiderosis) are small foci of signal loss observed on MRI sequences sensitive for paramagnetic tissue properties and comprise cerebral microbleeds (small foci of bleeding in the brain parenchyma) and leptomeningeal hemosiderosis (small foci of bleeding on the surface of the brain). These changes also occur sporadically in AD.
Time frame: From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 68 weeks)
Population: SEMRI analysis set included all participants in SE analysis set who had at least one post-baseline safety MRI scan. In DBT period, 4 participants randomized to placebo arm received at least one dose of gantenerumab and were considered in gantenerumab arm for SE analysis set, of which 1 participant entered OLE period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global - DBT Period: Placebo | OLE Period: Number of Participants With at Least One ARIA-H MRI Finding | 1 Participants |
| Global - DBT Period: Gantenerumab | OLE Period: Number of Participants With at Least One ARIA-H MRI Finding | 1 Participants |
Secondary
OLE Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS
C-SSRS=assessment tool used to assess lifetime suicidality of a participant (at baseline) as well as any new instances of suicidality (C-SSRS since last visit). Structured interview prompts recollection of suicidal ideation, including intensity of ideation, behavior, & attempts with actual/potential lethality. Categories have binary responses (yes/no) & include Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation/behavior is indicated by a yes answer to any of the listed categories. Score of 0 is assigned if no suicide risk is present. Score of 1 or higher= suicidal ideation or behavior. Categories with non-zero values are only reported here.
Time frame: From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 68 weeks)
Population: SE analysis set included all participants randomized during the global phase who received at least one dose of study drug. In the DBT period, 4 participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety analysis set, of which one participant entered OLE period. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Global - DBT Period: Placebo | OLE Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Active-Method, but no intent or plan | 0 Participants |
| Global - DBT Period: Placebo | OLE Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: No Event | 6 Participants |
| Global - DBT Period: Placebo | OLE Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Behavior: No Event | 6 Participants |
| Global - DBT Period: Placebo | OLE Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Self-injurious Behavior Without Suicidal Intent: No event | 6 Participants |
| Global - DBT Period: Gantenerumab | OLE Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Self-injurious Behavior Without Suicidal Intent: No event | 19 Participants |
| Global - DBT Period: Gantenerumab | OLE Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Active-Method, but no intent or plan | 1 Participants |
| Global - DBT Period: Gantenerumab | OLE Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Behavior: No Event | 19 Participants |
| Global - DBT Period: Gantenerumab | OLE Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: No Event | 18 Participants |