A Phase III, Multicenter, Randomized, Parallel-Group, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Gantenerumab in Participants at Risk for or at the Earliest Stages of Alzheimer's Disease

Official Summary

A study to evaluate the efficacy and safety of gantenerumab in amyloid-positive, cognitively unimpaired participants at risk for or at the earliest stages of AD. The planned number of participants for this study is approximately 1200 participants randomized in a 1:1 ratio to receive either gantenerumab or placebo (600 participants randomized to gantenerumab and 600 participants randomized to placebo).

Eligibility Requirements

• Minimum Age: 60 Years
• Maximum Age: 80 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: DOUBLE
• Enrollment: 25 participants

Study Arms

• Gantenerumab (EXPERIMENTAL)
  Gantenerumab will be administered as subcutaneous (SC) injection with gradual uptitration.
• Placebo (PLACEBO_COMPARATOR)
  Placebo will be administered as SC injection with gradual uptitration.

Interventions

• DRUG: Gantenerumab — Gantenerumab will be administered as per the dosing schedule described in the Arm description.
• DRUG: Placebo — Placebo will be administered as per the dosing schedule described in the Arm description.

Primary Outcomes

• Change From Baseline in PACC-5 Score (Baseline to early termination visit (up to 225 days from start of treatment))

Secondary Outcomes

• Time From Randomization to Clinical Progression to Mild Cognitive Impairment (MCI) or Dementia Due to AD (Randomization to early termination Visit (up to 225 days from start of treatment))
• Time to Onset of Confirmed Clinical Progression (Randomization to early termination Visit (up to 225 days from start of treatment))
• Change From Baseline in the Amsterdam Instrumental Activities of Daily Living Questionnaire Short Version (A-IADL-Q-SV) (Baseline to early termination visit (up to 225 days from start of treatment))
• Change From Baseline in the Cognitive Function Instrument Acute (CFIa) Participant Version (Baseline to early termination visit (up to 225 days from start of treatment))
• Change From Baseline in the CFIa Study Partner Version (Baseline to early termination visit (up to 225 days from start of treatment))

Eligibility Criteria

Key Inclusion Criteria:

* Willing and able to comply with the study protocol and complete all aspects of the study \[including cognitive and functional assessments, physical and neurological examinations, MRI, CSF collection, genotyping, and positron emission tomography (PET) imaging\].
* Cognitively unimpaired with a screening clinical dementia rating global score (CDR-GS) of 0, and Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index (RBANS DMI) \>=80.
* Evidence of cerebral amyloid accumulation.
* Participants who have an available person (referred to as a "study partner").
* Fluent in the language of the tests used at the study site.
* Adequate visual and auditory acuity, sufficient to perform neuropsychological testing (eye glasses and hearing aids are permitted).
* Agreed not to participate in other interventional research studies for the duration of this trial.
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \<1% per year during the treatment period and for at least 17 weeks after the final dose of study treatment.

Key Exclusion Criteria:

* Any evidence of an underlying neurological or neurodegenerative condition that may lead to cognitive impairment other than AD.
* Clinical diagnosis of mild cognitive impairment (MCI), prodromal AD, or any form of dementia.
* History or presence of intracranial or intracerebral vascular malformations, aneurysm, subarachnoid hemorrhage, or intracerebral macrohemorrhage.
* History or presence of posterior reversible encephalopathy syndrome.
* History of ischemic stroke with clinical symptoms or an acute event that is consistent with a transient ischemic attack within 12 months of screening.
* History of severe, clinically significant (i.e., resulting in persistent neurologic deficit or structural brain damage) central nervous system (CNS) trauma (e.g., cerebral contusion).
* History or presence of intracranial mass lesion (e.g., glioma, meningioma) that could potentially impair cognition or lead to progressive neurological deficits.
* Infections that may affect brain function or a history of infections that resulted in neurologic sequelae \[e.g., human immunodeficiency virus (HIV), syphilis, neuroborreliosis, and viral or bacterial meningitis and encephalitis\].
* History of major depression, schizophrenia, schizoaffective disorder, or bipolar disorder.
* At risk for suicide.
* History of alcohol and/or substance abuse or dependence.
* History or presence of clinically significant systemic vascular disease, atrial fibrillation or heart failure.
* Within the last year, experienced unstable or clinically significant cardiovascular disease (e.g., myocardial infarction).
* Uncontrolled hypertension.
* Chronic kidney disease, indicated by creatinine clearance \<30 mL/min.
* Confirmed and unexplained impaired hepatic function.
* History of, or are known to currently have an HIV infection, or hepatitis B or hepatitis C virus infection that has not been adequately treated.
* History or presence of systemic autoimmune disorders that may lead to progressive neurological impairment with associated cognitive deficits.
* Systemic immunosuppression or immunomodulation due to the continuing effects of immunosuppressant or immunomodulating medications.
* Current COVID-19 infection.
* Evidence of folic acid or vitamin B-12 deficiency.
* Any passive immunotherapy (Ig) or other long-acting biologic agent to prevent or postpone cognitive decline within 1 year of screening.
* Any other investigational treatment within 5 half-lives or 6 months (whichever is longer) prior to screening.
* Typical/Atypical anti-psychotic medications or neuroleptic medications.
* Anticoagulation medications within 3 months of screening with no plans to initiate any prior to randomization.
* Any previous treatment with cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists are exclusionary at screening.
* Pregnant or breastfeeding, or intending to become pregnant during the study or within 17 weeks after the final dose of gantenerumab.
* Impaired coagulation.
* Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins, including gantenerumab and gantenerumab excipients.
* Participants who reside in a skilled nursing facility such as a convalescent home or long-term care facility.
* Participants who require residence in such facilities during the study may continue in the study and be followed for efficacy and safety, provided that they have a study partner who meets the study partner requirements.

Trial Locations

• Banner Alzheimer?s Institute, Phoenix, Arizona, United States
• Banner Sun Health Research Insitute, Sun City, Arizona, United States
• Banner Alzheimer's Institute, Tucson, Arizona, United States
• California Neuroscience Research Medical Group, Inc, Sherman Oaks, California, United States
• JEM Research LLC, Atlantis, Florida, United States
• Visionary Investigators Network - Neurology Aventura, Aventura, Florida, United States
• Bradenton Research Center, Bradenton, Florida, United States
• Brain Matters Research, Inc., Delray Beach, Florida, United States
• Neuropsychiatric Research; Center of Southwest Florida, Fort Myers, Florida, United States
• ClinCloud, LLC, Maitland, Florida, United States
• ...and 10 more locations

Study Officials

• Clinical Trials — STUDY_DIRECTOR
  Hoffmann-La Roche

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