A Study to Evaluate the Efficacy and Safety of Gantenerumab in Participants at Risk for or at the Earliest Stages of Alzheimer's Disease (AD)

NCT05256134 | Terminated Phase 3 Results FDA Drug

• 2 other identifiers: WN424442021-001184-25
• Study Type: interventional
• Target: 25
• Locations: 10 countries
• Sites: 63

Brief 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).

Conditions

Alzheimers Disease

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in PACC-5 Score

  The PACC-5 is computed as the average of z-scores of the following cognitive measures: 1. Wechsler Memory Scale (WMS LM I-II) - Total Score LM II Delayed Recall; 2. Free \& Cued Selective Reminding Test (FCSRT) -Immediate and Delayed Recall - Trials 1-3: Total Recall; 3. Wechsler Adult Intelligence Scale (WAIS) - IV Coding - Total Raw Score; 4. Mini Mental State Examination (MMSE) - Total Score; 5. Category Fluency Test (CFT) - 3 categories - Vegetables, Fruits and Animals - Total Admissible Words. The z-score was defined as the difference between the assessment and the mean of baseline assessments, divided by the standard deviation of baseline assessments. Z-scores range from -3 to +3 with higher scores indicating better cognitive performance.

  Baseline to early termination visit (up to 225 days from start of treatment)

Secondary Outcomes (21)

• 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)

Other Outcomes (4)

• Change in Blood Aβ 1-42 Over Time in All Participants

  Baseline to safety follow-up visit (up to 310 days from start of treatment)

• Change in Blood Aβ 1-40 Over Time in All Participants

  Baseline to safety follow-up visit (up to 310 days from start of treatment)

• Change in Blood NFL Over Time in All Participants

  Baseline to safety follow-up visit (up to 310 days from start of treatment)

Study Arms (2)

Gantenerumab

EXPERIMENTAL

Gantenerumab will be administered as subcutaneous (SC) injection with gradual uptitration.

Drug: Gantenerumab

Placebo

PLACEBO COMPARATOR

Placebo will be administered as SC injection with gradual uptitration.

Drug: Placebo

Interventions

Gantenerumab DRUG

Gantenerumab will be administered as per the dosing schedule described in the Arm description.

Gantenerumab

Placebo DRUG

Placebo will be administered as per the dosing schedule described in the Arm description.

Placebo

Eligibility Criteria

• Age: 60 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (63)

Banner Alzheimer?s Institute

Phoenix, Arizona, 85006, United States

Location

Banner Sun Health Research Insitute

Sun City, Arizona, 85351, United States

Location

Banner Alzheimer's Institute

Tucson, Arizona, 85718, United States

Location

California Neuroscience Research Medical Group, Inc

Sherman Oaks, California, 91403, United States

Location

JEM Research LLC

Atlantis, Florida, 33462, United States

Location

Visionary Investigators Network - Neurology Aventura

Aventura, Florida, 33180, United States

Location

Bradenton Research Center

Bradenton, Florida, 34205, United States

Location

Brain Matters Research, Inc.

Delray Beach, Florida, 33445, United States

Location

Neuropsychiatric Research; Center of Southwest Florida

Fort Myers, Florida, 33912, United States

Location

ClinCloud, LLC

Maitland, Florida, 32751, United States

Location

K2 Medical Research, LLC

Maitland, Florida, 32751, United States

Location

Optimus U Corp

Miami, Florida, 33125, United States

Location

Renstar Medical Research

Ocala, Florida, 34470, United States

Location

Charter Research - Winter Park/Orlando

Orlando, Florida, 32803, United States

Location

Progressive Medical Research

Port Orange, Florida, 32127, United States

Location

Alzheimer's Research and Treatment Center

Stuart, Florida, 34997, United States

Location

Charter Research - Lady Lake/The Villages

The Villages, Florida, 32162, United States

Location

Alzheimer?s Research and Treatment Center

Wellington, Florida, 33414, United States

Location

Premiere Research Institute

West Palm Beach, Florida, 33407, United States

Location

Center for Advanced Research & Education

Gainesville, Georgia, 30501, United States

Location

Great Lakes Clinical Trials

Chicago, Illinois, 60640, United States

Location

Via Christi Research

Wichita, Kansas, 67214, United States

Location

Tandem Clinical Research, LLC

Marrero, Louisiana, 70072, United States

Location

Quest Research Institute

Farmington Hills, Michigan, 48334, United States

Location

University of Nebraska Medical Center; Dept of Neurological Sciences

Omaha, Nebraska, 68198-8440, United States

Location

The Cognitive and Research Center of New Jersey

Springfield, New Jersey, 07081, United States

Location

Velocity Clinical Research

East Syracuse, New York, 13057, United States

Location

Alzheimer's Memory Center

Matthews, North Carolina, 28105, United States

Location

Ohio State University; College of Medicine

Columbus, Ohio, 43210, United States

Location

Senior Adults Specialty Research

Austin, Texas, 78757, United States

Location

Kerwin Medical Center

Dallas, Texas, 75231, United States

Location

Re:Cognition Health

Fairfax, Virginia, 22031, United States

Location

Instituto Kremer

Córdoba, X5004AOA, Argentina

Location

KaRa Institute of Neurological Diseases

Macquarie Park, New South Wales, 2113, Australia

Location

Heidelberg Repatriation Hospital; Medical and Cognitive Research Centre

Heidelberg West, Victoria, 3081, Australia

Location

Australian Alzheimer's Research Foundation

Nedlands, Western Australia, 6009, Australia

Location

Okanagan Clinical Trials

Kelowna, British Columbia, V1Y 1Z9, Canada

Location

True North Clinical Research-Halifax

Halifax, Nova Scotia, B3S 1N2, Canada

Location

Kawartha Centre - Redefining Healthy Aging

Peterborough, Ontario, K9H 2P4, Canada

Location

Toronto Memory Program

Toronto, Ontario, M3B 2S7, Canada

Location

Fondazione Santa Lucia IRCCS; Neurologia e Riabilitazione Neurologica

Rome, Lazio, 00179, Italy

Location

IRCCS Ospedale San Raffaele; U.O. di Neurologia

Milan, Lombardy, 20132, Italy

Location

IRCCS Neuromed; Neurologia I-Centro studio e cura delle demenze e UVA

Pozzilli, Molise, 86077, Italy

Location

AO di Perugia - Ospedale S. Maria della Misericordia; Clinica Neurologica

Perugia, Umbria, 06156, Italy

Location

KLIMED

Bia?ystok, 15-704, Poland

Location

NZOZ Vitamed

Bydgoszcz, 85-079, Poland

Location

NZOZ NEURO-KARD Ilkowski i Partnerzy Sp. Partn. Lek

Późna, 61-853, Poland

Location

Senior Sp. Z O.O. Poradnia Psychogeriatryczna

Sopot, 81-855, Poland

Location

Centrum Medyczne Euromedis Sp. z o.o.

Szczecin, 70-111, Poland

Location

NZOZ WCA

Wroc?aw, 53-659, Poland

Location

Dong-A University Hospital

Busan, 49201, South Korea

Location

Gachon University Gil Medical Center

Incheon, 21565, South Korea

Location

Konkuk University Medical Center

Seoul, 05030, South Korea

Location

Hospital Quiron de Madrid; Servicio de Neurologia

Pozuelo de Alarcón, Madrid, 28223, Spain

Location

BARCELONABETA BRAIN RESEARCH CENTER (BBRC); FUNDACIÓN PASQUAL MARAGALL, Servicio de Neurologia

Barcelona, 08005, Spain

Location

Fundación ACE; Servicio de Neurología

Barcelona, 08028, Spain

Location

Hospital Virgen del Rocío; Servicio de Neurología

Seville, 41013, Spain

Location

Sahlgrenska Academy University,Neuroscience and Physiology;Departmt of Psychiatry and Neurochemistry

Mölndal, 431 41, Sweden

Location

KAROLINSKA UNI HOSPITAL, HUDDINGE; Mottagning Kognitiv Forskning, M54

Stockholm, 141 86, Sweden

Location

Re-Cognition

Birmingham, B16 8QQ, United Kingdom

Location

University of Exeter; College of Medicine and Health

Exeter, EX1 2LU, United Kingdom

Location

Panthera Biopartners Sheffield

Sheffield, S2 5FX, United Kingdom

Location

Southampton General Hospital

Southampton, SO16 6YD, United Kingdom

Location

Related Publications (2)

• Hibar DP, Bauer A, Rabe C, Borlinghaus N, Jethwa A, Kollmorgen G, Di Domenico A, Zetterberg H, Blennow K, Masters CL, Sperling RA, Bittner T. Elecsys pTau217 plasma immunoassay detection of amyloid pathology in clinical cohorts. Alzheimers Dement. 2026 Jan;22(1):e71009. doi: 10.1002/alz.71009.

  PMID: 41537338 DERIVED

• Bauer A, Rabe C, Schiffman C, Rose F, Respondek G, Gullotta F, Schlieker L, Jethwa A, Schrurs I, Manuilova E, Ostrowitzki S, Bittner T. Blood-based pre-screening in the SKYLINE secondary prevention Ph3 gantenerumab study. Alzheimers Dement. 2025 Oct;21(10):e70676. doi: 10.1002/alz.70676.

  PMID: 41085131 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Interventions

gantenerumab

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Limitations and Caveats

SKYLINE study was terminated early \& limited data could be collected \& analyzed. Hence, no conclusions can be made on effectiveness of gantenerumab in treatment of people at risk for or at earliest stages of AD.

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 25, 2022
• First Posted: February 25, 2022
• Study Start: April 19, 2022
• Primary Completion: March 13, 2023
• Study Completion: March 13, 2023
• Last Updated: June 12, 2025
• Results First Posted: July 9, 2024

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

CA (4); IT (4); SE (2); KR (3); ES (4); GB (4); US (32); PL (6); AR (1); AU (3)