A Phase II/III Multicenter Randomized, Double-Blind, Placebo-Controlled, Two-Stage Adaptive Design, Platform Trial of Investigational Treatments for Primary Prevention of Disease Progression in Dominantly Inherited Alzheimer's Disease

Plain English Summary

A Study of a Potential Disease Modifying Treatment in Individuals at Risk for or With a Type of Early Onset AD Caused by a Genetic Mutation is a Phase 3 clinical trial sponsored by Washington University School of Medicine studying Alzheimers Disease, Dementia, Alzheimers Disease, Familial. This trial is testing a new drug called remternetug to see if it can prevent or slow down Alzheimer's disease in people who have a specific genetic mutation. It is for individuals aged 18 and older who have a genetic mutation known to cause early-onset Alzheimer's disease, or are at high risk of inheriting it, and are currently free of cognitive symptoms. Participants will receive either the study drug or a placebo (a dummy treatment) by injection every 12 weeks for several years, and will undergo regular medical check-ups, brain scans, and cognitive tests. Currently, there are no approved treatments specifically for preventing the progression of Alzheimer's disease in individuals with these genetic mutations before symptoms appear. The trial aims to enroll 280 participants.

Official Summary

The purpose of this research study is to test the study drug, referred to as remternetug, to determine its effectiveness for the study treatment of asymptomatic (at risk) Alzheimer disease in individuals with AD-causing mutations. This study will also investigate the effects of remternetug on biomarkers (measures of the disease including brain scans, blood and spinal fluid tests), examine safety data to identify any potential benefits or risks, and examine how well participants can tolerate remternetug. Stage 1 will determine if treatment with the study drug prevents or reverses amyloid beta (Aβ) accumulation compared with placebo in participants with dominantly inherited Alzheimer's disease (DIAD). Stage 2 will evaluate the effect of early anti-amyloid treatment on downstream biomarkers of AD in treated participants compared to external control groups.

Who Can Participate

Here is what you need to know about eligibility for this trial. You can join if you are 18 or older and have a confirmed genetic mutation (in APP, PSEN1, or PSEN2 genes) that causes early-onset Alzheimer's, or if you have a family history of this mutation and are at risk. You must have normal cognitive function (no symptoms of Alzheimer's) and a study partner who can provide information about your daily life. You cannot join if you have other significant neurological or psychiatric conditions, are at high risk for suicide, or have had a recent stroke. Women of childbearing potential must have a negative pregnancy test and agree to use effective contraception during the study. This trial is studying Alzheimers Disease, Dementia, Alzheimers Disease, Familial, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures how the drug affects the buildup of amyloid protein in the brain, which is a key marker of Alzheimer's disease, indicating whether the treatment can reduce or clear this h The specific primary outcome measures are: Stage 1: Change in amyloid load as measured by centiloid (CL) [11C]PiB-PET as biomarker endpoint for DIAN-TU-002 remternetug arm (Baseline and Week 192). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial addresses a critical unmet need by investigating a potential disease-modifying treatment for individuals at high genetic risk for early-onset Alzheimer's disease, aiming to prevent or delay As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Alzheimers Disease, Dementia, Alzheimers Disease, Familial, where improved treatment options are needed.

Investor Insight

This trial targets a specific, high-risk population for Alzheimer's, potentially offering a first-in-class preventative treatment, which could represent a significant market opportunity if successful, Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor about the study drug, remternetug, and how it might affect you, as well as the potential risks and benefits. Be prepared for regular visits over several years, which will include injections, blood tests, brain imaging (PET scans), and cognitive assessments. Ensure you have a reliable study partner who can attend visits and accurately report on your daily functioning and cognitive status. This trial is currently recruiting participants. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: QUADRUPLE
• Enrollment: 280 participants

Interventions

• DRUG: Remternetug — Administered subcutaneously every 12 weeks
• DRUG: Matching Placebo (Remternetug) — Administered as subcutaneous injection of placebo every 12 weeks

Primary Outcomes

• Stage 1: Change in amyloid load as measured by centiloid (CL) [11C]PiB-PET as biomarker endpoint for DIAN-TU-002 remternetug arm (Baseline and Week 192)

Secondary Outcomes

• Stage 2: Odds ratio between the drug-treated and control groups of being in the lower biomarker disease progression stage based on two-stage modeling of 6 biomarkers. (Weeks 0, 48, 96, 144, and 192)
• Stage 1: The proportion of participants who are amyloid positive (CL level ≥ 16.3) at the end of Stage 1 (Baseline and Week 104)
• Stage 1: Change in CSF pTau217/Tau217 ratio (Baseline and Week 104)
• Stage 1: Change in CSF pTau231/Tau231 ratio (Baseline and week 104)
• Stage 1: Change in CSF 3-repeat isoform of MTBR (MTBR-3R) (Baseline and week 104)

Full Eligibility Criteria

Inclusion Criteria:

1. Provide written informed consent, signed, and dated by the participant and study partner, or by the participant's legally authorized representative if applicable, according to local regulations for the ICF and, if applicable, country specific ICFs.
2. Participant is at least 18 years old.
3. People of childbearing potential

   1. Must have a negative serum pregnancy test at screening (V1)
   2. Must agree not to try to become pregnant during the study until 5 half-lives after the last dose of any study drug.
   3. Must agree not to breastfeed from the time of signed ICF until 5 half-lives after the last dose of any study drug.
   4. If partner is not sterilized, must agree to use highly effective contraceptive measures from screening (V1) until 5 half lives after last dose of any study drug
4. Mutation Status:

   1. Participant is a carrier of a mutation in an APP, PSEN1, or PSEN2 gene that is associated with DIAD or does not know their mutation status and there is a mutation in their family pedigree that puts them at a direct risk of inheriting the known mutation;
   2. Participant is -25 to -11 years from predicted age of cognitive symptom onset based on their mutation type or family pedigree Note: If the at-risk parent is deemed a non-carrier through confirmed genetic testing at any time during the study, the participant will be withdrawn.
5. Cognitive status of participant is normal (CDR-SB 0).
6. Fluency in DIAN-TU trial approved language and evidence of adequate premorbid intellectual functioning. Participants must be fluent in languages for which cognitive and clinical measures have been translated and validated for use in the DIAN-TU. Fluency is generally defined as daily or frequent functional use of a language generally from birth or a young age. In cultures where multiple languages are spoken or for participants who are multilingual, determination as to whether a participant's level of fluency in languages for which clinical and cognitive measures are available meets qualification for the study should be made by the site PI.
7. Participant has adequate visual and auditory abilities to perform all aspects of the cognitive and clinical assessments.
8. Participant is receiving stable doses of medication(s) for the treatment of non-excluded medical condition(s) for at least 30 days prior to baseline visit (V2) except for medications taken for episodic conditions (e.g., migraine abortive therapy, antibiotics, and other medications for upper respiratory and gastrointestinal ailments).
9. Participant has a study partner who in the PI's judgment can provide accurate information as to the participant's cognitive and functional abilities, who agrees to provide information at the study visits that require study partner input for scale completion, and who signs the necessary ICF, if applicable.
10. The participant agrees not to donate blood or blood products for transfusion from the time of Screening (V1) for a study drug arm, for the duration of the study, and for 5 half lives after the final dose of study drug.
11. In the opinion of the PI, the participant will be compliant and have a high probability of completing the study.
12. The participant is able and willing to complete all study-related testing, evaluations, and procedures.

Exclusion Criteria:

1. Significant neurologic disease (other than AD) or psychiatric disease that may currently or during the study affect cognition or the participant's ability to complete the study. This would include disorders such as: recent or severe head trauma causing cognitive change, seizure disorder, neurodegenerative disease other than DIAD, hydrocephalus, cerebral/spinal hematoma, inflammatory disease, CNS infection (e.g., encephalitis or meningitis), neoplasm, toxic exposure, metabolic disorder (including hypoxic or hypoglycemic episodes) or endocrine disorder; psychiatric disorders such as schizophrenia, schizoaffective disorder, bipolar disorder or major depression, or any other psychiatric condition/disorder which could significantly interfere with the participant's cooperative participation (e.g., prominent anxiety, agitation or behavioral problems). Disorders that are controlled medically or remote history of these disorders (e.g., history of febrile seizures in childhood) that are not likely to interfere with cognitive function and compliance with study procedures are not exclusionary.
2. At high risk for suicide, e.g., significant suicidal ideation or attempt within last 12 months, current major depression (as defined in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition \[DSM-V\]), or increased suicide risk based on screening Columbia Suicide Severity Rating Scale (C-SSRS). Current stable mild depression or current use of antidepressant medications are not exclusionary.
3. History of clinically evident stroke or history of clinically important carotid or vertebrobasilar stenosis, plaque, or other prominent risk f

Trial Locations

• University of Alabama in Birmingham, Birmingham, Alabama, United States
• University of California San Diego Medical Center, La Jolla, California, United States
• Yale University School of Medicine, New Haven, Connecticut, United States
• Emory University, Atlanta, Georgia, United States
• Advocate Lutheran General Hospital, Park Ridge, Illinois, United States
• Indiana University School of Medicine, Indianapolis, Indiana, United States
• Washington University in St. Louis, St Louis, Missouri, United States
• New York University Medical Center, New York, New York, United States
• University of Pittsburgh, Pittsburgh, Pennsylvania, United States
• Butler Hospital, Providence, Rhode Island, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Alzheimer's Disease
• Dementia
• Alzheimer's Disease, Familial
• Early-Onset Alzheimer's Disease
• Dominantly Inherited Alzheimer's Disease (DIAD)
• Genetic Neurological Disorders
• Neurodegenerative Diseases
• Cognitive Impairment
• Amyloidosis
• Preventative Neurology

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