Alzheimers Disease, Dementia, Alzheimers Disease, Familial
Conditions
Keywords
Alzheimer's, Alzheimer's Disease, Dementia, Mutation, Genetic Mutation, Dominantly Inherited Alzheimer's Disease, Dominantly Inherited Alzheimer Network, Autosomal Dominant Alzheimer's Disease, Early Onset Alzheimer's Disease, DIAN, DIAN-TU, DIAN TU, DIAD
Brief summary
The purpose of this study is to assess the safety, tolerability, biomarker, cognitive and clinical efficacy of investigational products in participants with an Alzheimer's disease-causing mutation by determining if treatment with the study drug slows the rate of progression of cognitive/clinical impairment or improves disease-related biomarkers.
Detailed description
Alzheimer's disease (AD) is defined by the presence of abnormal accumulations of amyloid protein (plaques) and tau protein (tangles) in the brain. The double-blind arm of DIAN-TU-001 Master protocol (NCT01760005) tested whether gantenerumab provided a clinical benefit by slowing the onset or the worsening of the disease. A clinical benefit was not observed in the double-blind part of the DIAN-TU-001 study. However, gantenerumab was associated with improvements in measures of amyloid and tau and an improvement in an overall measure of neurodegeneration (when nerve cells in the brain lose function over time). It is not known whether these changes may provide future clinical benefits. Based on this information, an exploratory Open Label Extension (OLE) will further study the effect of gantenerumab on these Alzheimer-related proteins and their relationship to disease progression. After this final evaluation of study treatment with gantenerumab used in the gantenerumab / solanezumab double-blind arm of the Master protocol (NCT01760005), eligible participants from the placebo, solanezumab, and gantenerumab treatment groups in double-blind period were invited to participate in an OLE period to receive active gantenerumab study treatment as part of the DIAN-TU-001 Master protocol. The OLE period of the study planned to provide study treatment with gantenerumab for up to 3 years (36 months). This study collected brain scans, blood, and spinal fluid tests (also called biomarkers), as well as safety, clinical and cognitive testing. The goal is to determine if gantenerumab has favorable effects on these tests to determine if and how much treatment may prevent or delay the symptoms of AD. Update: Based on the results of the completed studies of gantenerumab in sporadic AD in late 2022, it was decided to determine if dominantly inherited Alzheimer's disease (DIAD) participants in the DIAN-TU-001 OLE study were substantially clinically benefiting from gantenerumab high-dose treatment before the trial reached completion as the Gant program was being stopped. An interim efficacy analysis of the DIAN-TU-001 OLE was performed to: 1. determine if gantenerumab OLE treatment and/or long-term treatment results in clinical benefit and determine the extent of amyloid removal compared to the double-blind period. 2. determine the potential effects of gantenerumab on clinical and cognitive measures to support decision-making regarding next steps for the DIAN-TU-001 OLE.
Interventions
DRUGGantenerumab
Open-label administered Subcutaneously every 4 weeks, at escalating doses; at target, dosing was every 2 weeks
Sponsors
Hoffmann-La Roche
Alzheimer's Association
National Institute on Aging (NIA)
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Arm is Open-label as noted in the arm description
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* Between 18-80 years of age * Individuals who know they have an Alzheimer's disease-causing mutation * Individuals who have participated in the double-blind period * In the opinion of the investigator and sponsor, treatment is not contraindicated for safety * Capable of receiving drug and appropriate clinical safety assessment * Able to undergo Magnetic Resonance Imaging (MRI), Lumbar Puncture (LP), Positron Emission Tomography (PET), and complete all study related testing and evaluations. * For women of childbearing potential, if partner is not sterilized, subject must agree to use effective contraceptive measures (hormonal contraception, intra-uterine device, sexual abstinence, barrier method with spermicide). * Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments. * Has a Study Partner who in the investigator's judgment is able to provide accurate information as to the subject's cognitive and functional abilities, who agrees to provide information at the study visits which require informant input for scale completion.
Exclusion criteria
* History or presence of brain MRI scans indicative of any other significant abnormality * Alcohol or drug dependence currently or within the past 1 year * Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin or body which would preclude MRI scan. * History or presence of clinically significant cardiovascular disease, hepatic/renal disorders, infectious disease or immune disorder, or metabolic/endocrine disorders * Anticoagulants except low dose (≤ 325 mg) aspirin. * Have been exposed to a monoclonal antibody targeting beta amyloid peptide within the past six months. * History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years. * Positive urine or serum pregnancy test or plans or desires to become pregnant during the course of the trial. * Subjects unable to complete all study related testing, including implanted metal that cannot be removed for MRI scanning, required anticoagulation and pregnancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156 | Baseline (Day 1) and Weeks 52, 104 and 156 | The composite PiB partial volume corrected C-SUVR was used as the biomarker endpoint for amyloid deposition using PET. The C-SUVR of precuneus, caudate, gyrus rectus, occipital cortex, parietal cortex, prefrontal cortex, and temporal cortex of brain regions was analyzed. Higher ratio indicate worse disease stage. Baseline was defined as the last non-missing measurement prior to OLE study drug administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156 | Baseline (Day 1) and Weeks 52, 104 and 156 | The efficacy of gantenerumab in reducing disease progression was assessed by CDR - global score. The score ranges from 0 (minimum) to 3 (maximum). Higher score indicates worse performance. Baseline was defined as the last non-missing measurement prior to OLE study drug administration. |
| Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156 | Baseline (Day 1) and Weeks 52, 104 and 156 | The efficacy of gantenerumab in reducing disease progression was assessed by FAS. This scale measured instrumental activities of daily living such as preparing balanced meals and managing personal finances. The intent of the FAS was to assess change in an individual's functional activities, relative to previously attained abilities, that were caused by cognitive dysfunction. The score ranges from 0 (minimum) to 30 (maximum). Higher score indicates worse performance. Baseline was defined as the last non-missing measurement prior to OLE study drug administration. |
| Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Baseline (Day 1) and Weeks 24, 52, 76, 104, 128 and 156 | The efficacy of gantenerumab in reducing disease progression was assessed by MMSE. The MMSE is a brief, quantitative measure of cognitive status in adults used to screen for cognitive impairment. The score ranges from 0 (minimum) to 30 (maximum). Lower score indicates worse performance. Baseline was defined as the last non-missing measurement prior to OLE study drug administration. |
| Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156 | Baseline (Day 1) and Weeks 52, 104 and 156 | The efficacy of gantenerumab in reducing disease progression was assessed by Tau PET SUVR. Baseline was defined as the last non-missing measurement prior to OLE study drug administration. |
| Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156 | Baseline (Day 1) and Weeks 52, 104 and 156 | The efficacy of gantenerumab in reducing disease progression was assessed by CDR - sum of boxes. The CDR-SB score is considered a more detailed quantitative general index of cognition and function than the global CDR score. The CDR - sum of boxes is the sum score of 6 domains of cognitive function (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care), with the score of each domain ranging from 0 (no impairment) to 3 (severe impairment). The total score ranges from 0 (no impairment) to 18 (severe impairment). Higher score indicates worse performance. Baseline was defined as the last non-missing measurement prior to OLE study drug administration. |
| Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Baseline (Day 1) and Weeks 52, 104 and 156 | The efficacy of gantenerumab in reducing disease progression was assessed by CSF NfL. Baseline was defined as the last non-missing measurement prior to OLE study drug administration. |
| Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Baseline (Day 1) and Weeks 52, 104 and 156 | The efficacy of gantenerumab in reducing disease progression was assessed by CSF Amyloid Beta1-42/40. Baseline was defined as the last non-missing measurement prior to OLE study drug administration. |
| Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156 | Baseline (Day 1) and Weeks 52, 104 and 156 | The efficacy of gantenerumab in reducing disease progression was assessed by DIAN-TU OLE Cognitive Composite. The cognitive composite was calculated based on the below 4 components, 1. The wechsler adult intelligence scale-revised digit span (backward recall). Score ranges from 0 (minimum) to 7 (maximum). 2. The category fluency (animals) value. Score ranges from 0 to unlimited. 3. The wechsler adult intelligence scale digit symbol substitution test. Score ranges from 0 (minimum) to 93 (maximum). 4. The MMSE. Score ranges from 0 (minimum) to 30 (maximum). Lower scores of each component indicate worse performance. The cognitive composite is a normalized z score and has score range - 4.11 to unlimited as one of the components has score range 0 to unlimited. Lower score indicates worse performance. Baseline was defined as last non-missing measurement prior to OLE study drug administration. |
| Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156 | Baseline (Day 1) and Weeks 52, 104 and 156 | The efficacy of gantenerumab in reducing disease progression was assessed by CSF pTau-181. Baseline was defined as the last non-missing measurement prior to OLE study drug administration. |
Countries
Australia, France, Puerto Rico, Spain, United Kingdom, United States
Participant flow
Recruitment details
This is a open-label period of the trial following a Phase II/III double-blind, placebo-controlled study conducted in participants with, or at risk for, dominantly inherited Alzheimer's disease at 17 sites in the United States, Canada, Australia and Europe between 03 June 2020 and 13 November 2023.
Pre-assignment details
All eligible participants from DIAN-TU-001 trial sites were offered the opportunity to receive gantenerumab for up to 3 years in an open-label extension (OLE). A total of 74 participants were enrolled in the OLE period of which, 1 participant was screen failure.
Participants by arm
| Arm | Count |
|---|---|
| Double-blind Placebo - OLE Gantenerumab Eligible participants from placebo treatment group in double-blind period entered OLE period to receive gantenerumab up to 1500 mg SC infusion Q2W for 3 years. | 18 |
| Double-blind Solanezumab - OLE Gantenerumab Eligible participants from solanezumab treatment group in double-blind period entered OLE period to receive gantenerumab up to 1500 mg SC infusion Q2W for 3 years. | 27 |
| Double-blind Gantenerumab - OLE Gantenerumab Eligible participants from gantenerumab treatment group in double-blind period entered OLE period to continue to receive gantenerumab up to 1500 mg SC infusion Q2W for 3 years. | 28 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Disease Progression | 0 | 1 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Other | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Study Terminated by Sponsor | 11 | 20 | 16 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 2 |
Baseline characteristics
| Characteristic | Double-blind Placebo - OLE Gantenerumab | Double-blind Solanezumab - OLE Gantenerumab | Double-blind Gantenerumab - OLE Gantenerumab | Total |
|---|---|---|---|---|
| Age, Continuous | 49.7 years STANDARD_DEVIATION 9.62 | 47.0 years STANDARD_DEVIATION 8.6 | 50.3 years STANDARD_DEVIATION 7.97 | 48.9 years STANDARD_DEVIATION 8.64 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 1 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 26 Participants | 24 Participants | 64 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islanders | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 1 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 14 Participants | 26 Participants | 26 Participants | 66 Participants |
| Sex: Female, Male Female | 11 Participants | 14 Participants | 13 Participants | 38 Participants |
| Sex: Female, Male Male | 7 Participants | 13 Participants | 15 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 27 | 0 / 28 |
| other Total, other adverse events | 17 / 18 | 27 / 27 | 27 / 28 |
| serious Total, serious adverse events | 2 / 18 | 4 / 27 | 3 / 28 |
Outcome results
Primary
Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156
The composite PiB partial volume corrected C-SUVR was used as the biomarker endpoint for amyloid deposition using PET. The C-SUVR of precuneus, caudate, gyrus rectus, occipital cortex, parietal cortex, prefrontal cortex, and temporal cortex of brain regions was analyzed. Higher ratio indicate worse disease stage. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Time frame: Baseline (Day 1) and Weeks 52, 104 and 156
Population: The OLE gantenerumab modified intent-to-treat (mITT) analysis set included all participants in the OLE who met mITT criteria using OLE baseline as the baseline reference point. Only participants analyzed at baseline and specific timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156 | Week 104 | -0.4843 ratio | Standard Deviation 0.55217 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156 | Week 52 | -0.1382 ratio | Standard Deviation 0.22606 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156 | Week 156 | -0.7660 ratio | Standard Deviation 0.64108 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156 | Week 104 | -0.7026 ratio | Standard Deviation 0.63641 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156 | Week 52 | -0.3318 ratio | Standard Deviation 0.40538 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156 | Week 156 | -1.1761 ratio | Standard Deviation 0.96831 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156 | Week 52 | 0.1201 ratio | Standard Deviation 0.15142 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156 | Week 156 | -0.2748 ratio | Standard Deviation 0.41027 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156 | Week 104 | -0.1880 ratio | Standard Deviation 0.26639 |
Comparison: Week 52: Treatment group and visit were treated as categorical fixed effects factors and OLE baseline Composite \[11C\] PiB-PET SUVR score as continuous. An unstructured correlation pattern was used to estimate the variance-covariance of the within participant repeated measures. The Kenward-Roger method was used to estimate the denominator degrees of freedom.p-value: 0.011795% CI: [-0.206, -0.0272]Mixed Model for Repeated Measures (MMRM)
Comparison: Week 104: Treatment group and visit were treated as categorical fixed effects factors and OLE baseline Composite \[11C\] PiB-PET SUVR score as continuous. An unstructured correlation pattern was used to estimate the variance-covariance of the within participant repeated measures. The Kenward-Roger method was used to estimate the denominator degrees of freedom.p-value: <0.000195% CI: [-0.5971, -0.3326]MMRM
Comparison: Week 156: Treatment group and visit were treated as categorical fixed effects factors and OLE baseline Composite \[11C\] PiB-PET SUVR score as continuous. An unstructured correlation pattern was used to estimate the variance-covariance of the within participant repeated measures. The Kenward-Roger method was used to estimate the denominator degrees of freedom.p-value: <0.000195% CI: [-0.8821, -0.5303]MMRM
Secondary
Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156
The efficacy of gantenerumab in reducing disease progression was assessed by CSF Amyloid Beta1-42/40. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Time frame: Baseline (Day 1) and Weeks 52, 104 and 156
Population: The OLE gantenerumab mITT analysis set included all participants in the OLE who met mITT criteria using OLE baseline as the baseline reference point. Only participants analyzed at baseline and specific timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 104 | 0.02961 ratio | Standard Deviation 0.022677 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 52 | 0.00669 ratio | Standard Deviation 0.015517 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 156 | 0.04400 ratio | Standard Deviation 0.024807 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 104 | 0.03588 ratio | Standard Deviation 0.025329 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 52 | 0.01217 ratio | Standard Deviation 0.013657 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 156 | 0.05304 ratio | Standard Deviation 0.037927 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 52 | -0.00060 ratio | Standard Deviation 0.00828 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 156 | 0.01182 ratio | Standard Deviation 0.022581 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 104 | 0.00571 ratio | Standard Deviation 0.010013 |
Comparison: Week 52: Treatment group and visit were treated as categorical fixed effects factors and OLE baseline CSF Amyloid Beta1-42/40 score as continuous. An unstructured correlation pattern was used to estimate the variance-covariance of the within participant repeated measures. The Kenward-Roger method was used to estimate the denominator degrees of freedom.p-value: 0.000195% CI: [0.0034, 0.01]MMRM
Comparison: Week 104: Treatment group and visit were treated as categorical fixed effects factors and OLE baseline CSF Amyloid Beta1-42/40 score as continuous. An unstructured correlation pattern was used to estimate the variance-covariance of the within participant repeated measures. The Kenward-Roger method was used to estimate the denominator degrees of freedom.p-value: <0.000195% CI: [0.0189, 0.0312]MMRM
Comparison: Week 156: Treatment group and visit were treated as categorical fixed effects factors and OLE baseline CSF Amyloid Beta1-42/40 score as continuous. An unstructured correlation pattern was used to estimate the variance-covariance of the within participant repeated measures. The Kenward-Roger method was used to estimate the denominator degrees of freedom.p-value: <0.000195% CI: [0.0266, 0.0447]MMRM
Secondary
Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156
The efficacy of gantenerumab in reducing disease progression was assessed by CDR - sum of boxes. The CDR-SB score is considered a more detailed quantitative general index of cognition and function than the global CDR score. The CDR - sum of boxes is the sum score of 6 domains of cognitive function (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care), with the score of each domain ranging from 0 (no impairment) to 3 (severe impairment). The total score ranges from 0 (no impairment) to 18 (severe impairment). Higher score indicates worse performance. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Time frame: Baseline (Day 1) and Weeks 52, 104 and 156
Population: The OLE gantenerumab mITT analysis set included all participants in the OLE who met mITT criteria using OLE baseline as the baseline reference point. Only participants analyzed at baseline and specific timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156 | Week 104 | 1.47 score on a scale | Standard Deviation 2.191 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156 | Week 52 | 1.12 score on a scale | Standard Deviation 2.147 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156 | Week 156 | 2.15 score on a scale | Standard Deviation 3.504 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156 | Week 104 | 1.31 score on a scale | Standard Deviation 2.507 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156 | Week 52 | 0.91 score on a scale | Standard Deviation 1.497 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156 | Week 156 | 0.40 score on a scale | Standard Deviation 0.907 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156 | Week 52 | 0.09 score on a scale | Standard Deviation 0.666 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156 | Week 156 | 1.14 score on a scale | Standard Deviation 2.405 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156 | Week 104 | 0.50 score on a scale | Standard Deviation 1.504 |
Comparison: The time to recurrent progression in CDR - sum of boxes. Baseline Asymptomatic Participants: Estimate and confidence interval was based on the Cox proportional hazards regression model including treatment and baseline estimated years to symptom onset as fixed effects. The OLE gantenerumab mITT analysis set included all participants in the OLE who met mITT criteria using OLE baseline as the baseline reference point.p-value: 0.453595% CI: [0.64, 2.7]Regression, Cox
Comparison: The time to recurrent progression in CDR - sum of boxes. Baseline Symptomatic Participants: Estimate and confidence interval was based on the Cox proportional hazards regression model including treatment and baseline estimated years to symptom onset as fixed effects. The OLE gantenerumab mITT analysis set included all participants in the OLE who met mITT criteria using OLE baseline as the baseline reference point.p-value: 0.484895% CI: [0.74, 1.86]Regression, Cox
Secondary
Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156
The efficacy of gantenerumab in reducing disease progression was assessed by CDR - global score. The score ranges from 0 (minimum) to 3 (maximum). Higher score indicates worse performance. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Time frame: Baseline (Day 1) and Weeks 52, 104 and 156
Population: The OLE gantenerumab mITT analysis set included all participants in the OLE who met mITT criteria using OLE baseline as the baseline reference point. Only participants analyzed at baseline and specific timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156 | Week 104 | 0.17 score on a scale | Standard Deviation 0.309 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156 | Week 52 | 0.12 score on a scale | Standard Deviation 0.281 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156 | Week 156 | 0.25 score on a scale | Standard Deviation 0.425 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156 | Week 52 | 0.17 score on a scale | Standard Deviation 0.324 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156 | Week 104 | 0.21 score on a scale | Standard Deviation 0.514 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156 | Week 156 | 0.10 score on a scale | Standard Deviation 0.211 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156 | Week 52 | 0.02 score on a scale | Standard Deviation 0.188 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156 | Week 156 | 0.18 score on a scale | Standard Deviation 0.421 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156 | Week 104 | 0.09 score on a scale | Standard Deviation 0.366 |
Comparison: Time to first progression in CDR-Global score. Baseline Asymptomatic Participants: Estimate and confidence interval was based on Cox proportional hazards regression model including treatment and baseline estimated years to symptom onset as fixed effects. Time to first progression was defined as time from baseline to first visit where CDR-Global Score was greater than baseline value, where progression must be observed at 2 consecutive measurements unless progression occurs at last measurement.p-value: 0.885595% CI: [0.33, 2.58]Regression, Cox
Comparison: Time to first progression in CDR-Global score. Baseline Symptomatic Participants: Estimate and confidence interval was based on Cox proportional hazards regression model including treatment and baseline estimated years to symptom onset as fixed effects. Time to first progression was defined as time from baseline to first visit where CDR-Global Score was greater than baseline value, where progression must be observed at 2 consecutive measurements unless progression occurs at last measurement.p-value: 0.449795% CI: [0.3, 1.69]Regression, Cox
Secondary
Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156
The efficacy of gantenerumab in reducing disease progression was assessed by DIAN-TU OLE Cognitive Composite. The cognitive composite was calculated based on the below 4 components, 1. The wechsler adult intelligence scale-revised digit span (backward recall). Score ranges from 0 (minimum) to 7 (maximum). 2. The category fluency (animals) value. Score ranges from 0 to unlimited. 3. The wechsler adult intelligence scale digit symbol substitution test. Score ranges from 0 (minimum) to 93 (maximum). 4. The MMSE. Score ranges from 0 (minimum) to 30 (maximum). Lower scores of each component indicate worse performance. The cognitive composite is a normalized z score and has score range - 4.11 to unlimited as one of the components has score range 0 to unlimited. Lower score indicates worse performance. Baseline was defined as last non-missing measurement prior to OLE study drug administration.
Time frame: Baseline (Day 1) and Weeks 52, 104 and 156
Population: The OLE gantenerumab mITT analysis set included all participants in the OLE who met mITT criteria using OLE baseline as the baseline reference point. Only participants analyzed at baseline and specific timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156 | Week 104 | -0.5535 score on a scale | Standard Deviation 0.82376 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156 | Week 52 | -0.2281 score on a scale | Standard Deviation 0.44682 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156 | Week 156 | -0.3309 score on a scale | Standard Deviation 0.60877 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156 | Week 104 | -0.2373 score on a scale | Standard Deviation 0.49333 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156 | Week 52 | -0.1462 score on a scale | Standard Deviation 0.3751 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156 | Week 156 | -0.2738 score on a scale | Standard Deviation 0.49439 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156 | Week 52 | -0.1336 score on a scale | Standard Deviation 0.26523 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156 | Week 156 | -0.1327 score on a scale | Standard Deviation 0.31666 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156 | Week 104 | -0.2493 score on a scale | Standard Deviation 0.48045 |
Comparison: Baseline Asymptomatic Participants: The statistical model included time since baseline (years), treatment arm, an interaction between treatment and time. Time was considered as continuous. Random intercepts and slopes for each participant was included as random effects with an unstructured covariance matrix.p-value: 0.64495% CI: [-0.12, 0.2]Linear Mixed Effects Model
Comparison: Baseline Symptomatic Participants: The statistical model included time since baseline (years), treatment arm, an interaction between treatment and time. Time was considered as continuous. Random intercepts and slopes for each participant was included as random effects with an unstructured covariance matrix.p-value: 0.74595% CI: [-0.18, 0.26]Linear Mixed Effects Model
Secondary
Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156
The efficacy of gantenerumab in reducing disease progression was assessed by FAS. This scale measured instrumental activities of daily living such as preparing balanced meals and managing personal finances. The intent of the FAS was to assess change in an individual's functional activities, relative to previously attained abilities, that were caused by cognitive dysfunction. The score ranges from 0 (minimum) to 30 (maximum). Higher score indicates worse performance. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Time frame: Baseline (Day 1) and Weeks 52, 104 and 156
Population: The OLE gantenerumab mITT analysis set included all participants in the OLE who met mITT criteria using OLE baseline as the baseline reference point. Only participants analyzed at baseline and specific timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156 | Week 104 | 3.1885 score on a scale | Standard Deviation 5.48051 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156 | Week 52 | 1.7555 score on a scale | Standard Deviation 3.25466 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156 | Week 156 | 2.1944 score on a scale | Standard Deviation 3.3768 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156 | Week 104 | 1.9524 score on a scale | Standard Deviation 3.85326 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156 | Week 52 | 1.1060 score on a scale | Standard Deviation 2.80472 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156 | Week 156 | 1.0000 score on a scale | Standard Deviation 2.39046 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156 | Week 52 | 0.4348 score on a scale | Standard Deviation 1.67403 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156 | Week 156 | 1.6154 score on a scale | Standard Deviation 3.3798 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156 | Week 104 | 0.8889 score on a scale | Standard Deviation 2.71006 |
Comparison: Baseline Asymptomatic Participants: The statistical model included time since baseline (years), treatment arm, an interaction between treatment and time. Time was considered as continuous. Random intercepts and slopes for each participant was included as random effects with compound symmetry covariance matrix.p-value: 0.7695% CI: [-0.46, 0.33]Linear Mixed Effects Model
Comparison: Baseline Symptomatic Participants: The statistical model included time since baseline (years), treatment arm, an interaction between treatment and time. Time was considered as continuous. Random intercepts and slopes for each participant was included as random effects with an unstructured covariance matrix.p-value: 0.09395% CI: [-2.63, 0.2]Linear Mixed Effects Model
Secondary
Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156
The efficacy of gantenerumab in reducing disease progression was assessed by MMSE. The MMSE is a brief, quantitative measure of cognitive status in adults used to screen for cognitive impairment. The score ranges from 0 (minimum) to 30 (maximum). Lower score indicates worse performance. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Time frame: Baseline (Day 1) and Weeks 24, 52, 76, 104, 128 and 156
Population: The OLE gantenerumab mITT analysis set included all participants in the OLE who met mITT criteria using OLE baseline as the baseline reference point. Only participants analyzed at baseline and specific timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 24 | -0.6 score on a scale | Standard Deviation 2.4 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 52 | -1.2 score on a scale | Standard Deviation 2.74 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 76 | -2.1 score on a scale | Standard Deviation 3.7 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 104 | -3.1 score on a scale | Standard Deviation 5.13 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 128 | -3.3 score on a scale | Standard Deviation 5.5 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 156 | -3.8 score on a scale | Standard Deviation 7.61 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 156 | 1.2 score on a scale | Standard Deviation 1.33 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 24 | -0.5 score on a scale | Standard Deviation 3 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 104 | -1.5 score on a scale | Standard Deviation 4.73 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 128 | -0.2 score on a scale | Standard Deviation 1.93 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 52 | -1.0 score on a scale | Standard Deviation 2.47 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 76 | -0.8 score on a scale | Standard Deviation 3.51 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 52 | -0.9 score on a scale | Standard Deviation 2.35 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 76 | -0.9 score on a scale | Standard Deviation 2.89 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 156 | -1.4 score on a scale | Standard Deviation 3.92 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 104 | -1.2 score on a scale | Standard Deviation 3.53 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 24 | -0.1 score on a scale | Standard Deviation 1.23 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156 | Week 128 | -2.1 score on a scale | Standard Deviation 4.71 |
Comparison: Baseline Asymptomatic Participants: The statistical model included time since baseline (years), treatment arm, an interaction between treatment and time. Time was considered as continuous. Random intercepts and slopes for each participant was included as random effects with an unstructured covariance matrix.p-value: 0.98995% CI: [-0.43, 0.44]Linear Mixed Effects Model
Comparison: Baseline Symptomatic Participants: The statistical model included time since baseline (years), treatment arm, an interaction between treatment and time. Time was considered as continuous. Random intercepts and slopes for each participant was included as random effects with an unstructured covariance matrix.p-value: 0.71495% CI: [-0.86, 1.25]Linear Mixed Effects Model
Secondary
Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156
The efficacy of gantenerumab in reducing disease progression was assessed by CSF NfL. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Time frame: Baseline (Day 1) and Weeks 52, 104 and 156
Population: The OLE gantenerumab mITT analysis set included all participants in the OLE who met mITT criteria using OLE baseline as the baseline reference point. Only participants analyzed at baseline and specific timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 104 | 263.74 pg/mL | Standard Deviation 268.343 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 52 | 176.01 pg/mL | Standard Deviation 223.432 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 156 | 233.30 pg/mL | Standard Deviation 186.805 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 104 | 351.02 pg/mL | Standard Deviation 312.203 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 52 | 283.97 pg/mL | Standard Deviation 255.009 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 156 | 609.45 pg/mL | Standard Deviation 549.253 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 52 | 106.09 pg/mL | Standard Deviation 252.328 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 156 | 402.20 pg/mL | Standard Deviation 536.504 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156 | Week 104 | 257.12 pg/mL | Standard Deviation 255.528 |
Comparison: Baseline Asymptomatic Participants: The statistical model included time since baseline (years), treatment arm, an interaction between treatment and time. Time was considered as continuous. Random intercepts and slopes for each participant was included as random effects with variance components covariance matrix.p-value: 0.05595% CI: [0, 0.09]Linear Mixed Effects Model
Comparison: Baseline Symptomatic Participants: The statistical model included time since baseline (years), treatment arm, an interaction between treatment and time. Time was considered as continuous. Random intercepts and slopes for each participant was included as random effects with an unstructured covariance matrix.p-value: 0.18895% CI: [-0.02, 0.11]Linear Mixed Effects Model
Secondary
Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156
The efficacy of gantenerumab in reducing disease progression was assessed by CSF pTau-181. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Time frame: Baseline (Day 1) and Weeks 52, 104 and 156
Population: The OLE gantenerumab mITT analysis set included all participants in the OLE who met mITT criteria using OLE baseline as the baseline reference point. Only participants analyzed at baseline and specific timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156 | Week 104 | -7.15305 picogram per milliliter (pg/mL) | Standard Deviation 5.152265 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156 | Week 52 | -3.29012 picogram per milliliter (pg/mL) | Standard Deviation 3.301052 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156 | Week 156 | -8.13416 picogram per milliliter (pg/mL) | Standard Deviation 5.86108 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156 | Week 104 | -6.03388 picogram per milliliter (pg/mL) | Standard Deviation 4.745042 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156 | Week 52 | -2.95397 picogram per milliliter (pg/mL) | Standard Deviation 3.225444 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156 | Week 156 | -6.83542 picogram per milliliter (pg/mL) | Standard Deviation 3.548298 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156 | Week 52 | -0.28807 picogram per milliliter (pg/mL) | Standard Deviation 1.740518 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156 | Week 156 | -1.48436 picogram per milliliter (pg/mL) | Standard Deviation 2.746503 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156 | Week 104 | -1.19673 picogram per milliliter (pg/mL) | Standard Deviation 2.262092 |
Comparison: Week 56: Treatment group and visit were treated as categorical fixed effects factors and OLE baseline CSF pTau181 as continuous. An unstructured correlation pattern was used to estimate the variance-covariance of the within participant repeated measures. The Kenward-Roger method was used to estimate the denominator degrees of freedom.p-value: <0.000195% CI: [-2.9469, -1.4051]MMRM
Comparison: Week 104: Treatment group and visit were treated as categorical fixed effects factors and OLE baseline CSF pTau181 as continuous. An unstructured correlation pattern was used to estimate the variance-covariance of the within participant repeated measures. The Kenward-Roger method was used to estimate the denominator degrees of freedom.p-value: <0.000195% CI: [-5.8609, -3.826]MMRM
Comparison: Week 156: Treatment group and visit were treated as categorical fixed effects factors and OLE baseline CSF pTau181 as continuous. An unstructured correlation pattern was used to estimate the variance-covariance of the within participant repeated measures. The Kenward-Roger method was used to estimate the denominator degrees of freedom.p-value: <0.000195% CI: [-6.9679, -4.5561]MMRM
Secondary
Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156
The efficacy of gantenerumab in reducing disease progression was assessed by Tau PET SUVR. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Time frame: Baseline (Day 1) and Weeks 52, 104 and 156
Population: The OLE gantenerumab mITT analysis set included all participants in the OLE who met mITT criteria using OLE baseline as the baseline reference point. Only participants analyzed at baseline and specific timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156 | Week 104 | 0.29471 ratio | Standard Deviation 0.658922 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156 | Week 52 | 0.09032 ratio | Standard Deviation 0.337016 |
| Double-blind Placebo - OLE Gantenerumab | Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156 | Week 156 | 0.38857 ratio | Standard Deviation 0.475259 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156 | Week 104 | 0.19329 ratio | Standard Deviation 0.811715 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156 | Week 52 | -0.11554 ratio | Standard Deviation 0.537111 |
| Double-blind Solanezumab - OLE Gantenerumab | Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156 | Week 156 | -0.02390 ratio | Standard Deviation 0.860703 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156 | Week 52 | 0.12246 ratio | Standard Deviation 0.202397 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156 | Week 156 | 0.21449 ratio | Standard Deviation 0.281091 |
| Double-blind Gantenerumab - OLE Gantenerumab | Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156 | Week 104 | 0.26572 ratio | Standard Deviation 0.314147 |
Comparison: Baseline Asymptomatic Participants: The statistical model included time since baseline (years), treatment arm, an interaction between treatment and time. Time was considered as continuous. Random intercepts and slopes for each participant was included as random effects with an unstructured covariance matrix.p-value: 0.73895% CI: [-0.18, 0.13]Linear Mixed Effects Model
Comparison: Baseline Symptomatic Participants: The statistical model included time since baseline (years), treatment arm, an interaction between treatment and time. Time was considered as continuous. Random intercepts and slopes for each participant was included as random effects with an unstructured covariance matrix.p-value: 0.39595% CI: [-0.28, 0.66]Linear Mixed Effects Model