A Study of Trontinemab in Cognitively Unimpaired Individuals at Risk for Progression to Symptomatic Alzheimer's Disease

Official title

A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of Trontinemab in Cognitively Unimpaired Individuals at Risk for Progression to Symptomatic Alzheimer's Disease

Overview

This study will evaluate the efficacy and safety of trontinemab in participants with biomarker evidence of Alzheimer's Disease (AD) pathology but with no cognitive or functional impairment, who are at risk for progression to mild cognitive impairment (MCI) due to AD or dementia due to AD.

Interventions

• Drug Trontinemab
  Participants will receive IV trontinemab.
• Drug Placebo
  Participants will receive IV placebo.

Primary outcome measures

• Time to Progression, defined as confirmed Clinical Dementia Rating - Global Score (CDR-GS) > 0 [Time frame: Baseline up to approximately 6 years]

Secondary outcome measures (12)

• Change from Baseline through Week 216 in Clinical Dementia Rating, Sum of Boxes (CDR-SB) [Time frame: Baseline through Week 216]
• Change from Baseline through Week 216 in Free and Cued Selective Reminding Test (FCSRT) total recall score [Time frame: Baseline through Week 216]
• Change from Baseline through Week 216 in Digit Symbol Substitution Test (DSST) coding score [Time frame: Baseline through Week 216]
• Change from Baseline through Week 216 in Cognitive Function Instrument (CFI) study partner, total score [Time frame: Baseline through Week 216]
• Change from Baseline through Week 216 in Category fluency total score [Time frame: Baseline through Week 216]
• Change from Baseline through Week 216 in Mini-Mental State Examination (MMSE) total score [Time frame: Baseline through Week 216]
• Change from Baseline through Week 216 in Wechsler Memory Scale, Logical Memory II Delayed Paragraph Recall (WMS LM II [DR]) score [Time frame: Baseline through Week 216]
• Change from Baseline through Week 216 in Amsterdam Instrumental Activities of Daily Living Questionnaire-Short Version (A-IADL-Q-SV) study partner, total score [Time frame: Baseline through Week 216]
• Change from Baseline through Week 216 in Trail Making Test (TMT) [Time frame: Baseline through Week 216]
• Time to progression to adjudicated mild cognitive impairment (MCI) diagnosis [Time frame: Baseline up to approximately 6 years]
• Incidence of adverse events [Time frame: Baseline up to approximately 6 years]
• Frequency of amyloid-related imaging abnormalities-edema/effusion (ARIA-E) and amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H) magnetic resonance imaging (MRI) findings [Time frame: Baseline up to approximately 6 years]

Eligibility criteria

Inclusion criteria

• Body weight of 150 kg or less
• Willingness and ability to complete all aspects of the study for the duration of the study
• Adequate visual and auditory acuity, in the investigator's judgment, sufficient to perform the neuropsychological testing (eyewear and hearing aids are permitted)
• Cognitively and functionally unimpaired as defined by the protocol
• Availability of a study partner as defined by the protocol
• A plasma pTau217 level consistent with a high likelihood of future clinical progression

Exclusion criteria

• Any evidence of a condition other than AD that may affect cognition, including, but not limited to, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, Parkinson disease, corticobasal syndrome, Creutzfeldt-Jakob disease, progressive supranuclear palsy, frontotemporal lobar degeneration (other than frontotemporal dementia), Huntington disease, normal pressure hydrocephalus, seizure disorder, delirium, or hypoxia
• Mild cognitive impairment (MCI; may be referred to as prodromal AD), or any form of dementia
• History or presence of clinically significant cerebrovascular disease
• History of severe, clinically significant (persistent neurologic deficit or structural brain damage) central nervous system (CNS) trauma
• History or presence of clinically significant intracranial mass
• History of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder
• History or presence of any stroke with clinical symptoms within the past 12 months, or documented history within the last 12 months of an acute event that is consistent, in the opinion of the PI, with a transient ischemic attack
• At risk for suicide in the opinion of the investigator
• Substance abuse disorder within 12 months prior to screening (nicotine use is allowed)
• Any other medical conditions (e.g., cardiovascular, hepatic, renal disease) which are not stable and adequately controlled or which in the opinion of the investigator could affect the participant's safety in the study or interfere with the study assessments
• Uncontrolled hypertension
• Impaired hepatic function
• History or presence of any clinically significant hematological diseases
• Diagnosis of a wet age-related macular degeneration (AMD)
• Abnormal thyroid function
• Abnormally low serum levels of folic acid or vitamin B12 deficiency that are judged to be clinically significant and/or may impact cognition as per the investigator's judgment
• Current HIV, hepatitis B, or hepatitis C infection that has not been adequately treated in the opinion of the investigator
• History of malignancy
• Any previous administration of active immunotherapy (vaccine) that is being evaluated to prevent or postpone cognitive decline
• Any previous or current use of passive immunotherapy (immunoglobulin) or other long-acting biologic agent that is approved or under evaluation or has been evaluated to prevent or postpone cognitive decline
• Any other investigational treatment within 5 half-lives or 4 months prior to screening, whichever is longer
• Intravenous (IV) or subcutaneous immunoglobulin therapy within 5 half-lives or 4 months prior to baseline whichever is longer
• Anticoagulation medications at screening and there should be no plans to initiate any prior to or after randomization
• Any treatment with cholinesterase inhibitors
• Antipsychotic or neuroleptic medications within 3 months of screening, except as brief treatment for a non-psychiatric indication
• Individuals with chronic use of opiates or opioids, benzodiazepines, barbiturates, or hypnotics, antidepressants or medication to treat anxiety should be on a stable dose for at least 8 weeks before baseline
• Currently enrolled in an interventional study including those requiring investigational medicinal product (IMP) or involving any type of medical research that may interfere with study cognitive assessments
• Residence in a skilled nursing facility such as a convalescent home or long-term care facility

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07717411 · WN46072

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗