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 matching to gantenerumab 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 |
|---|---|---|
| OLE Period: Number of Participants With Injection-Site Reactions | From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 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: 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. |
| OLE Period: Number of Participants With Adverse Events (AEs) | From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 weeks) | An adverse event 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 Columbia-Suicide Severity Rating Scale (C-SSRS) | From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 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 Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) Confirmed by MRI | From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 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 Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by Magnetic Resonance Imaging (MRI) | From day of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 AEs | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 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 C-SSRS | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 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 ARIA-E Confirmed by MRI | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 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 ARIA-H Confirmed by MRI | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 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 Anti-Drug Antibodies (ADA) to Gantenerumab | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 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. |
| 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. |
| 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. Tau PET radioligand used was \[18F\] GTP1. Tau load was measured using SUVR in 4 composite target ROIs: Temporal target region included (both left & right)=anterior &posterior superior temporal gyrus, posterior temporal lobe, fusiform gyrus, &middle &inferior temporal gyrus; Medial temporal region excluding hippocampus included (both left & right): amygdala, parahippocampus & anterior medial & lateral temporal lobe; Frontal lobe (both left & right) & Parietal lobe (both left & right). Inferior cerebellar grey matter=reference region for calculating SUVRs for 4 target regions. Tau-PET-mITT analysis set=all participants in ITT analysis set who participated in Tau PET sub-study & had at least one Tau PET scan with 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 - 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: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Neurogranin | Baseline, Week 116 | — |
| DBT Period: Percent Change From Baseline to Week 116 in 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: Number of Participants With Injection-Site Reactions | From Day 1 up to 14 weeks after the last dose of blinded study drug (up to 128 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: 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. |
| 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. |
| 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. |
Other
| Measure | Time frame |
|---|---|
| Plasma Concentration of Gantenerumab | Pre-dose on Days 1, Weeks 24, 52 and 76; Post-dose on Day 4, Weeks 41, 103, and 115 |
Countries
Argentina, Belgium, Chile, Croatia, Denmark, Finland, Japan, Mexico, Netherlands, Poland, Portugal, Puerto Rico, Singapore, South Korea, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled in the study across 151 investigative sites in 18 countries from 22 August 2018 to 28 November 2022.
Pre-assignment details
A total of 975 participants with early (prodromal to mild) Alzheimer's Disease (AD) were randomized to either the gantenerumab (n=498) or placebo arm (n=477) to enter the double-blind treatment (DBT) period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo: DBT Participants received, gantenerumab matching placebo, SC injections, Q4W up to Week 36 and then Q2W up to Week 114 of the DBT period. | 477 |
| Gantenerumab: DBT Participants received gantenerumab, SC injections 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 injections, at a dose of 510 mg, Q2W up to Week 114 of the DBT period. | 498 |
| Total | 975 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind Treatment Period | Adverse Event | 5 | 19 | 0 | 0 |
| Double-blind Treatment Period | Death | 5 | 7 | 0 | 0 |
| Double-blind Treatment Period | Lack of Efficacy | 1 | 1 | 0 | 0 |
| Double-blind Treatment Period | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Double-blind Treatment Period | Physician Decision | 5 | 6 | 0 | 0 |
| Double-blind Treatment Period | Protocol Deviation | 1 | 2 | 0 | 0 |
| Double-blind Treatment Period | Reason Not Specified | 9 | 11 | 0 | 0 |
| Double-blind Treatment Period | Withdrawal by Subject | 54 | 79 | 0 | 0 |
| Open-label Extension Period | Reason Not Specified | 0 | 0 | 3 | 0 |
| Open-label Extension Period | Withdrawal by Subject | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo: DBT | Gantenerumab: DBT | Total |
|---|---|---|---|
| Age, Continuous | 71.8 years STANDARD_DEVIATION 7.4 | 71.6 years STANDARD_DEVIATION 7.8 | 71.7 years STANDARD_DEVIATION 7.6 |
| Clinical Dementia Rating-Sum of Boxes (CDR-SB) | 3.52 score on a scale STANDARD_DEVIATION 1.54 | 3.67 score on a scale STANDARD_DEVIATION 1.61 | 3.60 score on a scale STANDARD_DEVIATION 1.58 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 119 Participants | 112 Participants | 231 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 358 Participants | 386 Participants | 744 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 13 Participants | 13 Participants | 26 Participants |
| Race (NIH/OMB) Asian | 75 Participants | 56 Participants | 131 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 385 Participants | 424 Participants | 809 Participants |
| Sex: Female, Male Female | 285 Participants | 288 Participants | 573 Participants |
| Sex: Female, Male Male | 192 Participants | 210 Participants | 402 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 477 | 7 / 498 | 0 / 13 | 0 / 14 |
| other Total, other adverse events | 296 / 474 | 358 / 501 | 8 / 13 | 6 / 14 |
| serious Total, serious adverse events | 63 / 474 | 61 / 501 | 1 / 13 | 0 / 14 |
Outcome results
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. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: DBT | DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB | 3.01 score on a scale | Standard Error 0.15 |
| Gantenerumab: DBT | DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB | 2.82 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 ADAS COG13 + Baseline Alzheimer Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL).p-value: 0.299895% CI: [-0.55, 0.17]ANCOVA
Primary
OLE Period: Number of Participants With Adverse Events (AEs)
An adverse event 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 48 weeks)
Population: OLE safety-evaluable set included all participants randomized during the global enrollment phase who received at least one dose of study drug and who entered the OLE period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo: DBT | OLE Period: Number of Participants With Adverse Events (AEs) | 8 Participants |
| Gantenerumab: DBT | OLE Period: Number of Participants With Adverse Events (AEs) | 6 Participants |
Primary
OLE Period: Number of Participants With Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by Magnetic Resonance Imaging (MRI)
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 48 weeks)
Population: MRI Safety-evaluable analysis set included all participants in the Safety-evaluable analysis set who had at least one post-baseline safety MRI scan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo: DBT | OLE Period: Number of Participants With Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by Magnetic Resonance Imaging (MRI) | 0 Participants |
| Gantenerumab: DBT | OLE Period: Number of Participants With Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by Magnetic Resonance Imaging (MRI) | 1 Participants |
Primary
OLE Period : Number of Participants With Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) Confirmed by MRI
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 48 weeks)
Population: MRI Safety-evaluable analysis set included all participants in the Safety-evaluable analysis set who had at least one post-baseline safety MRI scan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo: DBT | OLE Period : Number of Participants With Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) Confirmed by MRI | 2 Participants |
| Gantenerumab: DBT | OLE Period : Number of Participants With Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) Confirmed by MRI | 1 Participants |
Primary
OLE 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 of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 weeks)
Population: OLE safety-evaluable set included all participants randomized during the global enrollment phase who received at least one dose of study drug and who entered the OLE period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo: DBT | OLE Period: Number of Participants With Injection-Site Reactions | 0 Participants |
| Gantenerumab: DBT | OLE Period: Number of Participants With Injection-Site Reactions | 1 Participants |
Primary
OLE 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 of first dose in OLE period up to 14 weeks after the last OLE dose (up to 48 weeks)
Population: OLE safety-evaluable set included all participants randomized during the global enrollment phase who received at least one dose of study drug and who entered the OLE period. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo: DBT | OLE 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 | 12 Participants |
| Placebo: DBT | OLE 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 | 10 Participants |
| Placebo: DBT | OLE 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 | 12 Participants |
| Placebo: DBT | OLE 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 | 1 Participants |
| Placebo: DBT | OLE 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 | 1 Participants |
| Gantenerumab: DBT | OLE 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 | 13 Participants |
| Gantenerumab: DBT | OLE 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 | 0 Participants |
| Gantenerumab: DBT | OLE 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 | 0 Participants |
| Gantenerumab: DBT | OLE 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 | 13 Participants |
| Gantenerumab: DBT | OLE 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 | 13 Participants |
Secondary
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) included all participants in the ITT analysis set who participated in the Amyloid PET sub-study 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 |
|---|---|---|---|
| Placebo: DBT | Change From Baseline to Week 116 in Brain Amyloid Load as Measured by Amyloid Positron Emission Tomography (PET) Scan in a Subset of Participants | 8.46 score on a scale | Standard Error 2.768 |
| Gantenerumab: DBT | Change From Baseline to Week 116 in Brain Amyloid Load as Measured by Amyloid Positron Emission Tomography (PET) Scan in a Subset of Participants | -48.00 score on a scale | Standard Error 2.845 |
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: [-64.36, -48.56]Mixed Model for Repeated Measures
Secondary
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. Tau PET radioligand used was \[18F\] GTP1. Tau load was measured using SUVR in 4 composite target ROIs: Temporal target region included (both left & right)=anterior &posterior superior temporal gyrus, posterior temporal lobe, fusiform gyrus, &middle &inferior temporal gyrus; Medial temporal region excluding hippocampus included (both left & right): amygdala, parahippocampus & anterior medial & lateral temporal lobe; Frontal lobe (both left & right) & Parietal lobe (both left & right). Inferior cerebellar grey matter=reference region for calculating SUVRs for 4 target regions. Tau-PET-mITT analysis set=all participants in ITT analysis set who participated in Tau PET sub-study & had at least one Tau PET scan with 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 one tau PET substudy for participants willing to consent to the procedure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo: DBT | 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 |
| Placebo: DBT | 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 |
| Placebo: DBT | 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 |
| Placebo: DBT | 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 |
| Gantenerumab: DBT | 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 |
| Gantenerumab: DBT | 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 |
| Gantenerumab: DBT | 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 |
| Gantenerumab: DBT | 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 |
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 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 |
|---|---|---|---|
| Placebo: DBT | DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Score | 6.97 score on a scale | Standard Error 0.46 |
| Gantenerumab: DBT | DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Score | 5.77 score on a scale | Standard Error 0.38 |
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: 0.02695% CI: [-2.24, -0.14]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 |
|---|---|---|---|
| Placebo: DBT | DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score | 7.94 score on a scale | Standard Error 0.49 |
| Gantenerumab: DBT | DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score | 6.66 score on a scale | Standard Error 0.42 |
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 e4p-value: 0.027395% CI: [-2.41, -0.14]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 |
|---|---|---|---|
| Placebo: DBT | DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) Total Score | -9.26 score on a scale | Standard Error 0.62 |
| Gantenerumab: DBT | DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) Total Score | -8.44 score on a scale | Standard Error 0.58 |
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 e4p-value: 0.291895% CI: [-0.7, 2.34]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 |
|---|---|---|---|
| Placebo: DBT | DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Instrumental Score | -8.22 score on a scale | Standard Error 0.53 |
| Gantenerumab: DBT | DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Instrumental Score | -7.43 score on a scale | Standard Error 0.49 |
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: 0.234895% CI: [-0.51, 2.09]ANCOVA
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 |
|---|---|---|---|
| Placebo: DBT | DBT Period: Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score | 6.72 score on a scale | Standard Error 0.33 |
| Gantenerumab: DBT | DBT Period: Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score | 5.86 score on a scale | Standard Error 0.31 |
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: 0.043895% CI: [-1.7, -0.02]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. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo: DBT | DBT Period: Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score | -4.53 score on a scale | Standard Error 0.22 |
| Gantenerumab: DBT | DBT Period: Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score | -4.00 score on a scale | Standard Error 0.2 |
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: 0.056695% CI: [-0.01, 1.06]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 |
|---|---|---|---|
| Placebo: DBT | DBT Period: Change From Baseline to Week 116 in the Coding (Digit Symbol Substitution Test [DSST]) Subtest | -6.90 score on a scale | Standard Error 0.59 |
| Gantenerumab: DBT | DBT Period: Change From Baseline to Week 116 in the Coding (Digit Symbol Substitution Test [DSST]) Subtest | -5.49 score on a scale | Standard Error 0.55 |
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: 0.062995% CI: [-0.08, 2.9]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 |
|---|---|---|---|
| Placebo: DBT | DBT Period: Change From Baseline to Week 116 in Verbal Fluency Task (VFT) Score | -2.68 score on a scale | Standard Error 0.22 |
| Gantenerumab: DBT | DBT Period: Change From Baseline to Week 116 in Verbal Fluency Task (VFT) Score | -2.71 score on a scale | Standard Error 0.21 |
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: 0.908695% CI: [-0.59, 0.52]ANCOVA
Secondary
DBT Period: Number of Participants With 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 1 up to 14 weeks after the last dose of blinded study drug (up to 128 weeks)
Population: Safety-evaluable set included all participants randomized during the global phase, who received at least one dose of study drug. In the DBT period, three participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety evaluable set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo: DBT | DBT Period: Number of Participants With AEs | 409 Participants |
| Gantenerumab: DBT | DBT Period: Number of Participants With AEs | 451 Participants |
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 128 weeks)
Population: ADA-evaluable analysis set included participants who received at least one dose of study drug and who provided at least one post-baseline ADA sample. In the DBT period, three participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm. As pre-specified in the protocol of study WN42171, ADA data for studies WN29922 and WN39658 from the OLE period will be reported in the results of study WN42171 (NCT04374253).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo: DBT | DBT Period: Number of Participants With Anti-Drug Antibodies (ADA) to Gantenerumab | 12 Participants |
Secondary
DBT Period: Number of Participants With ARIA-E Confirmed by MRI
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 128 weeks)
Population: MRI Safety-evaluable analysis set included all participants in the Safety-evaluable analysis set who had at least one post-baseline safety MRI scan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo: DBT | DBT Period: Number of Participants With ARIA-E Confirmed by MRI | 18 Participants |
| Gantenerumab: DBT | DBT Period: Number of Participants With ARIA-E Confirmed by MRI | 128 Participants |
Secondary
DBT Period: Number of Participants With ARIA-H Confirmed by MRI
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 128 weeks)
Population: MRI Safety-evaluable analysis set included all participants in the Safety-evaluable analysis set who had at least one post-baseline safety MRI scan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo: DBT | DBT Period: Number of Participants With ARIA-H Confirmed by MRI | 57 Participants |
| Gantenerumab: DBT | DBT Period: Number of Participants With ARIA-H Confirmed by MRI | 109 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 128 weeks)
Population: Safety-evaluable set included all participants randomized during the global phase, who received at least one dose of study drug. In the DBT period, three participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety evaluable set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo: DBT | DBT Period: Number of Participants With Injection-Site Reactions | 31 Participants |
| Gantenerumab: DBT | DBT Period: Number of Participants With Injection-Site Reactions | 75 Participants |
Secondary
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 128 weeks)
Population: Safety-evaluable set included all participants randomized during the global phase, who received at least one dose of study drug. In the DBT period, three participants randomized to placebo arm received at least one dose of gantenerumab and were considered in the gantenerumab arm for safety evaluable set. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo: DBT | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: No Event | 437 Participants |
| Placebo: DBT | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Active-Nonspecific | 4 Participants |
| Placebo: DBT | DBT 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 | 2 Participants |
| Placebo: DBT | 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 |
| Placebo: DBT | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Behavior: No Event | 464 Participants |
| Placebo: DBT | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Self-injurious Behavior, No Suicidal Intent | 0 Participants |
| Placebo: DBT | 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 | 464 Participants |
| Placebo: DBT | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Passive | 20 Participants |
| Placebo: DBT | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Active-Method, Intent, and Plan | 0 Participants |
| Gantenerumab: DBT | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Passive | 12 Participants |
| Gantenerumab: DBT | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Behavior: No Event | 483 Participants |
| Gantenerumab: DBT | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Active-Nonspecific | 2 Participants |
| Gantenerumab: DBT | 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 | 481 Participants |
| Gantenerumab: DBT | DBT 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 | 2 Participants |
| Gantenerumab: DBT | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Self-injurious Behavior, No Suicidal Intent | 2 Participants |
| Gantenerumab: DBT | 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 |
| Gantenerumab: DBT | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: Active-Method, Intent, and Plan | 2 Participants |
| Gantenerumab: DBT | DBT Period: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using C-SSRS | Suicidal Ideation: No Event | 464 Participants |
Secondary
DBT Period: Percent Change From Baseline to Week 116 in Cerebrospinal Fluid (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 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) |
|---|---|---|
| Placebo: DBT | DBT Period: Percent Change From Baseline to Week 116 in Cerebrospinal Fluid (CSF) Marker of Disease in a Subset of Participants - Neurofilament Light Chain (NFL) | 25.5 percent change in NFL |
| Gantenerumab: DBT | DBT Period: Percent Change From Baseline to Week 116 in Cerebrospinal Fluid (CSF) Marker of Disease in a Subset of Participants - Neurofilament Light Chain (NFL) | 8.9 percent change in NFL |
p-value: 0.01495% CI: [-22.51, -2.87]ANCOVA
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 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) |
|---|---|---|
| Placebo: DBT | DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Neurogranin | -6.1 percent change in neurogranin |
| Gantenerumab: DBT | DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Neurogranin | -19.6 percent change in neurogranin |
p-value: <0.00195% CI: [-21.88, -6.21]ANCOVA
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) |
|---|---|---|
| Placebo: DBT | DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Phosphorylated Tau (pTau-181) | 0.1 percent change in pTau-181 |
| Gantenerumab: DBT | DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Phosphorylated Tau (pTau-181) | -20.9 percent change in pTau-181 |
p-value: <0.00195% CI: [-28.29, -12.97]ANCOVA
Secondary
DBT Period: Percent Change From Baseline to Week 116 in 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 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) |
|---|---|---|
| Placebo: DBT | DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Total Tau (tTau) | 1.8 percent change in tTau |
| Gantenerumab: DBT | DBT Period: Percent Change From Baseline to Week 116 in CSF Marker of Disease in a Subset of Participants - Total Tau (tTau) | -16.4 percent change in tTau |
p-value: <0.00195% CI: [-24.92, -10.11]ANCOVA
Other Pre-specified
Plasma Concentration of Gantenerumab
Time frame: Pre-dose on Days 1, Weeks 24, 52 and 76; Post-dose on Day 4, Weeks 41, 103, and 115
Population: Pharmacokinetic(PK)-evaluable analysis set included participants who received at least one dose of study drug and who provided at least one valid post-baseline PK sample.