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

Official 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.

Eligibility Requirements

• Minimum Age: 50 Years
• Maximum Age: 90 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: DOUBLE
• Enrollment: 975 participants

Study Arms

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

Interventions

• DRUG: Gantenerumab — Gantenerumab will be administered as per the schedule specified in the respective arm.
• DRUG: Placebo — Placebo matching to gantenerumab will be administered as per the schedule specified in the respective arm.

Primary Outcomes

• DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB (Baseline, Week 116)
• 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))
• 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))
• 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))
• 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))

Secondary Outcomes

• DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score (Baseline, Week 116)
• DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) Total Score (Baseline, Week 116)
• DBT Period: Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score (Baseline, Week 116)
• DBT Period: Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score (Baseline, Week 116)
• DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Score (Baseline, Week 116)

Eligibility 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

Trial Locations

• Banner Alzheimer?s Institute, Phoenix, Arizona, United States
• Barrow Neurological Institute, Phoenix, Arizona, United States
• Banner Sun Health Research Insitute, Sun City, Arizona, United States
• Health Initiatives Research, PLLC, Fayetteville, Arkansas, United States
• Fullerton Neurology and Headache Center, Fullerton, California, United States
• Neurology Center of North Orange County, Fullerton, California, United States
• Irvine Center for Clinical Research, Irvine, California, United States
• Desert Valley Research, Redlands, California, United States
• Southern California Research LLC, Simi Valley, California, United States
• Yale University School Of Medicine, New Haven, Connecticut, United States
• ...and 10 more locations

Study Officials

• Clinical Trials — STUDY_DIRECTOR
  Hoffmann-La Roche

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