A Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Efficacy and Safety Study of Gantenerumab in Patients With Mild Alzheimer's Disease; Part II: Open-Label Extension For Participating Patients

Official Summary

Part 1 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of gantenerumab in participants with mild Alzheimer disease. Participants will be randomized to receive either gantenerumab subcutaneously every 4 weeks or placebo subcutaneously every 4 weeks. Approved Alzheimer medication is allowed if on stable dose for 3 months prior to screening. Part 2 is an open-label extension (OLE). A positron emission tomography (PET) imaging substudy will be conducted within the main study. Eligible participants who provide separate informed consent will undergo PET imaging scans using the radioligand florbetapir as a pharmacodynamic measure of changes in brain amyloid load over time.

Eligibility Requirements

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

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: DOUBLE
• Enrollment: 389 participants

Study Arms

• Part 1 (Double Blind treatment): Placebo (PLACEBO_COMPARATOR)
  Participants received matching placebo by subcutaneous (SC) injection every 4 weeks (Q4W) up to 100 weeks during Part 1 of the study.
• Part 1 (Double Blind treatment): Gantenerumab (EXPERIMENTAL)
  Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.
• Part 2 (Open-Label Extension [OLE] treatment): Placebo switched to Gantenerumab Up to 1200 mg (PLACEBO_COMPARATOR)
  Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
• Part 2 (OLE treatment): Gantenerumab up to 1200 mg (EXPERIMENTAL)
  Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.

Interventions

• DRUG: Placebo — Participants received Placebo SC injection Q4W.
• DRUG: Gantenerumab — Participants received Gantenerumab at 105 mg , 225 mg, or at doses up to 1200 mg SC injection Q4W.

Primary Outcomes

• Part 2: Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) (First dose up to 4 weeks after the last dose of study drug (up to 249 weeks))
• Part 2: Percentage of Participants With Treatment Emergent Anti-Drug Antibodies (ADAs) (First dose up to last dose (Baseline up to until maximum 5 years))
• Part 2: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment (First dose up to 4 weeks after the last dose in OLE (Up to approximately 249 weeks))

Secondary Outcomes

• Part 1: Percentage of Participants With AEs, SAEs (First dose up to last dose (Up to approximately 152 weeks))
• Part 1: Percentage of Participants With Treatment Emergent ADAs (First dose up to last dose (Up to approximately 152 weeks))
• Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints (Pre-dose: Weeks 4, 8, 12, 24, 48, 72 and Post dose: Day 4)
• Part 1: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment (First dose up to last dose (Up to approximately 152 weeks))
• Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104 (Baseline (Part 1 screening), Week 104)

Eligibility Criteria

Inclusion Criteria:

* Clinical diagnosis of probable mild Alzheimer disease (AD) based on National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria or major NCD based whether or not receiving AD approved medication
* Cerebral spinal fluid (CSF) result consistent with the presence of amyloid pathology
* Availability of a person ('caregiver') who in the investigator's judgment has frequent and sufficient contact with the participant, and is able to provide accurate information regarding the participant's cognitive and functional abilities
* Fluency in the language of the tests used at the study site
* Willingness and ability to complete all aspects of the study
* Adequate visual and auditory acuity, in the investigator's judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted)
* If currently receiving approved medications for AD, the dosing regimen must have been stable for 3 months prior to screening
* Agreement not to participate in other research studies for the duration of this trial and its associated substudies

PART 2 - All participants who have been randomized and are actively participating in the study are eligible for Part 2

Exclusion Criteria:

* Dementia or neurocognitive disorder (NCD) due to a condition other than AD, including, but not limited to, frontotemporal dementia, Parkinson disease, dementia with Lewy bodies, Huntington disease, or vascular dementia
* History or presence of clinically evident vascular disease potentially affecting the brain that in the opinion of the investigator has the potential to affect cognitive function
* History or presence of stroke within the past 2 years or documented history of transient ischemic attack within the last 12 months
* History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease with associated cognitive deficits
* History of schizophrenia, schizoaffective disorder, or bipolar disorder
* Alcohol and/or substance use disorder (according to the DSM-5) within the past 2 years (nicotine use is allowed)
* History or presence of atrial fibrillation
* Within the last 2 years, unstable or clinically significant cardiovascular disease (e.g., myocardial infarction, angina pectoris, cardiac failure New York Heart Association Class II or higher)
* Uncontrolled hypertension
* Chronic kidney disease
* Impaired hepatic function

PET imaging substudy, in addition to above:

\- Prior participation in other research study or clinical care within the last year such that the total radiation exposure would exceed the local or national annual limits

Part 2 Participants who have been discontinued from the study

Trial Locations

• Banner Sun Health Research Insitute, Sun City, Arizona, United States
• Territory Neurology and Research Institute, Tucson, Arizona, United States
• ATP Clinical Research, Inc, Costa Mesa, California, United States
• Pacific Research Network - PRN, San Diego, California, United States
• California Neuroscience Research Medical Group, Inc, Sherman Oaks, California, United States
• Meridien Research, Brooksville, Florida, United States
• Brain Matters Research, Inc., Delray Beach, Florida, United States
• Neuropsychiatric Research; Center of Southwest Florida, Fort Myers, Florida, United States
• Miami Jewish Health Systems; Clinical Research, Miami, Florida, United States
• Accelerated Enrollment Solutions, Orlando, Florida, United States
• ...and 10 more locations

Study Officials

• Clinical Trials — STUDY_DIRECTOR
  Hoffmann-La Roche

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