Safety and Efficacy Study of Gantenerumab in Participants With Early Alzheimer's Disease (AD)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy, and Safety Study of Gantenerumab in Patients With Early (Prodromal to Mild) Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Gantenerumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gantenerumab<br>Gantenerumab will be administered as SC injections with gradual uptitration. | Drug: Gantenerumab<br>* Gantenerumab will be administered as per the schedule specified in the respective arm.<br>* Other names: RO4909832;|
| Placebo Comparator: Placebo<br>Placebo will be administered as SC injections with gradual uptitration. | Drug: Placebo<br>* Placebo matching to gantenerumab will be administered as per the schedule specified in the respective arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 116 in Global Outcome, as Measured by Clinical Dementia Rating-Sum of Boxes (CDR-SOB) |  | Baseline up to Week 116 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score |  | Baseline up to Week 116 | 
| Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Subscale Score |  | Baseline up to Week 116 | 
| Change from Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition, Subscale 13 (ADAS-Cog13) |  | Baseline up to Week 116 | 
| Change From Baseline to Week 116 in Verbal Fluency Task Score |  | Baseline up to Week 116 | 
| Change From Baseline to Week 116 in Coding |  | Change from baseline to Week 116 in the Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV) coding subtest. | 
| Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score |  | Baseline to Week 116 | 
| Change From Baseline to Week 116 in Alzheimer Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) Total Score |  | Baseline up to Week 116 | 
| Percentage of Participants With Adverse Events (AEs) |  | Baseline up to end of study (week 164) or Week 35 (Open label extension) | 
| Change in Columbia-Suicide Severity Rating Scale (C-SSRS) Score |  | Baseline up to Week 116 or Week 24 in Open label extension | 
| Percentage of Participants with Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by Magnetic Resonance Imaging (MRI) |  | Baseline up to end of study (week 164) or Week 35 (Open label extension) | 
| Percentage of Participants with Amyloid-Related Imaging Abnormalities-Haemosiderin deposition (ARIA-H) Confirmed by Magnetic Resonance Imaging (MRI) |  | Baseline up to end of study (week 164) or Week 35 (Open label extension) | 
| Percentage of Participants with Injection-Site Reactions |  | Baseline up to end of study (week 164) or Week 35 (Open label extension) | 
| Percentage of Participants With Anti-Drug Antibodies (ADA) to Gantenerumab |  | Baseline up to end of study (week 164) or Week 35 (Open label extension) | 
| Change from Baseline in Brain Amyloid Load as Measured by Amyloid Positron Emission Tomography (PET) Scan in a subset of patients up to Week 116 |  | Baseline up to Week 116 | 
| Change From Baseline in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Patients up to Week 116 |  | Baseline up to Week 116 | 
| Change From Baseline in CSF Marker of Disease in a Subset of Patients - Total Tau up to Week 116 |  | Baseline up to Week 116 | 
| Change From Baseline in CSF Marker of Disease in a Subset of Patients - Phosphorylated Tau up to Week 116 |  | Baseline up to Week 116 |