A Study of Treatments for the Prevention of Disease Progression in Individuals at Risk for or With Early Onset Alzheimer’s Disease Caused by a Genetic Mutation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Washington University School Of Medicine

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Decision date (initial)

2025-10-20

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

National Institutes of Health (NIH) · Eli Lilly and Company · The Alzheimer's Association · Washington University in St. Louis

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis, Safety, Efficacy

Stage 1: Evaluate the ability of study drug to prevent or slow the rate of Aβ accumulation compared with placebo in participants with mutations that cause DIAD
Stage 2: Evaluate the effect of anti-amyloid treatment on downstream biomarkers of AD.

Secondary objectives 2

1. Stage 1 and Stage 2: Evaluate the safety and tolerability of study drug in all participants who received study drug or placebo.
2. Assess target engagement in interim analysis/analyses in participants with DIAD mutations.

Conditions and MedDRA coding

Dominantly Inherited Alzheimer’s Disease (DIAD)

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Access to DIAN-TU trial data will follow the DIAN-TU data access policy, which complies with the guidelines established by the Collaboration for Alzheimer's Prevention [CAP REF].

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

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. For people of childbearing potential (POCBP): a. Must have a negative serum pregnancy test at screening (V1) b. Must agree not to try to become pregnant during the study until twenty (20) weeks after the last dose of any study drug. c. Must agree not to breastfeed from the time of signed ICF until twenty (20) weeks after the last dose of any study drug. d. If partner is not sterilized, must agree to use highly effective contraceptive measures, methods that can achieve a failure rate of less than 1% per year when used consistently and correctly from screening (V1) until twenty (20) weeks after last dose of any study drug. Such methods include: i. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: • oral • intravaginal • transdermal ii. progestogen-only hormonal contraception associated with inhibition of ovulation: • oral • injectable • implantable iii. intra-uterine device (IUD) iv. Intrauterine hormone-releasing systems (IUS) v. bilateral tubal occlusion vi. vasectomized partner (only when this is the only partner) vii. true sexual abstinence when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of exposure to IMP, and withdrawal are not acceptable methods of contraception
4. Mutation status: a. 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; b. 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. Adequate visual and auditory abilities to perform all aspects of the cognitive and clinical assessments.
8. 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. 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. 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. Willing to complete all study-related testing, evaluations, and procedures.

Exclusion criteria 28

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. Cardiovascular complications such as uncontrolled hypertension, history of myocardial infarcts, heart failure, atrial fibrillation, long QT interval on ECG likely to interfere with participation in or analysis of the trial in the opinion of the investigator
3. Hepatic or renal abnormalities that in the opinion of the investigator would interfere with participation in or analysis of the trial.
4. History of Human Immunodeficiency Virus (HIV) infection, history of Hepatitis B infection within the past year, history of Hepatitis C infection which has not been adequately treated, history of untreated spirochete infection (e.g., syphilis, Lyme) of the CNS, or history of other infection with high risk for interfering with participation or interpretation of the study in the opinion of the investigator.
5. Any other medical condition that could be expected to progress, recur, or change to such an extent that it could bias the assessment of the clinical or mental status of the participant to a significant degree or put the participant at special risk.
6. Currently, or within the last month prior to screening, participated in a clinical study, including a nonpharmacological study, without prior approval.
7. Participants with the "Dutch" APP E693Q mutation.
8. Unable to complete baseline visit (V2) procedures with appropriate cognitive and clinical scores for eligibility
9. Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within 90 days prior to Baseline (V2) visit (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted) or chemotherapeutic agents for malignancy within the last 3 years.
10. Current clinically significant abnormalities of thyroid function, or clinically significant deficiency in vitamin B12. Vitamin B12 less than the lower limits of normal with normal methylmalonic acid (MMA)/homocysteine is not deemed clinically significant, therefore not exclusionary.
11. Morbid obesity with significant comorbidities or that would preclude MRI imaging.
12. Clinically relevant abnormalities in hematology, coagulation, or clinical chemistry.
13. Current use of anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, or apixaban). Daily use of low dose (≤ 325 mg) aspirin or antiplatelet medications are not exclusionary.
14. Have been exposed to a monoclonal antibody targeting Aβ peptide within the past 6 months or 5 half-lives from screening, whichever is longer.
15. Received any other investigational pharmacological treatment within 3 months of Screening or 5 half-lives, whichever is longer. Note: Use of approved treatments for AD and other medications may be permitted in this study in accordance with the guidelines in the Concomitant Medications, Section 5.1 of the protocol.
16. Lack of sufficient venous access.
17. Remternetug arm specific exclusion criteria 1. A centrally read MRI demonstrating presence of ARIA-E, > 4 cerebral microhemorrhages, any superficial siderosis, any macrohemorrhage, or severe white matter disease at screening.
18. Remternetug arm specific exclusion criteria 2. Exposure to lecanemab, donanemab, or other investigational amyloid lowering agents within the past 6 months or five half-lives from screening, whichever is longer. Note: Use of approved treatments for AD and other medications may be permitted in this study in accordance with the guidelines in the Concomitant Medications, Section 5.1 of the main protocol.
19. Remternetug arm specific exclusion criteria 3. Investigator site personnel directly affiliated with this trial and/or their immediate families, defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
20. Remternetug arm specific exclusion criteria 4. Lilly employees or employees of a third-party organization (TPO) involved in this study that requires exclusion of their employees or have study partners who are Lilly employees or are employees of TPOs involved in this study that require exclusion of their employees.
21. History of cancer that the investigator believes has high risk of recurrence and impacting study participation or analysis.
22. History of clinically significant multiple or severe drug allergies, significant atopy, or severe post-treatment hypersensitivity reactions (including but not limited to erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, and/or exfoliative dermatitis) or sensitivity to study-drug specific PET imaging agents with a high risk for interfering with participation or interpretation of the study in the opinion of the investigator.
23. 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.
24. History of clinically evident stroke or history of clinically important carotid or vertebrobasilar stenosis, plaque, or other prominent risk factor for stroke or cerebral hemorrhage (including atrial fibrillation and anticoagulation, documented transient ischemic attack [TIA] in the last 12 months) that may be interfering with cognition or is likely to impact with the participant’s ability to complete the study.
25. Alcohol or substance use sufficient to meet DSM-V criteria currently or within the past year.
26. History of or Baseline (V2) visit brain MRI scan indicative of any other significant abnormality, definite microhemorrhages (per criteria defined in the drug-specific appendix), evidence of a cerebral contusion, encephalomalacia, or aneurysms. Minor or clinically insignificant imaging findings are not exclusionary.
27. Presence of certain implanted medical devices, such as some pacemakers, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or body which would preclude MRI scan.
28. Unstable or poorly controlled diabetes which the investigator believes may interfere with participation in or analysis of the study protocol. Participants may be rescreened after 3 months to allow optimization of diabetic control.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Stage 1: Defined in each drug-specific appendix; will be an assessment of biomarkers of early-stage disease (e.g., amyloid PET, soluble amyloid, soluble phospho-tau) compared with baseline in each treatment group
2. Stage 2: If applicable, will be defined in each drug-specific appendix, and will be an assessment of the change in progression of biomarkers representing tau, neurodegenerative, and inflammatory pathobiological events in the disease cascade for temporally different periods of the presymptomatic phases of the disease.
3. Remternetug arm specific Primary end point Stage 1: The primary endpoint will only use data collected from Stage 1, and will be the change from baseline in brain Aβ plaque development as measured by centiloid (CL) [11C]-Pittsburgh compound B (PiB) PET.

Secondary endpoints 5

1. Stage 1 and Stage 2: • Incidence and severity of TEAEs, o serious TEAEs, o serious drug related TEAEs, o TEAEs leading to discontinuation, o TEAEs resulting in death • ARIA noted by MRI • laboratory parameters • vital signs • ECGs (if done)
2. Biomarker interim analyses may be used for dose-adjustment, remediation, or stopping a study drug arm for efficacy and/or futility. Biomarkers are specified for each drug based on mechanism of action and may include soluble biochemical measures (e.g., Aβ and tau), imaging measures of pathology (e.g., amyloid PET), and AD biomarker changes (e.g., atrophy measured by MRI, and neurodegeneration measured by NfL).
3. Remternetug arm specific Secondary end point Stage 1: Secondary efficacy endpoints include: • The proportion of participants who are amyloid positive (CL level ≥ 16.3) at the end of Stage 1, • Change in CSF pTau217/Tau217 ratio, • Change in CSF pTau231/Tau231 ratio, and • Change in CSF 3-repeat isoform of MTBR (MTBR-3R).
4. Remternetug arm specific Secondary end point Stage 2: Odds ratio between the treated group and the external control group (DIAN Obs and DIAN-TU-001 placebo) of being in the lower biomarker disease progression stage based on two-stage modeling of 6 biomarkers (CSF tau phosphorylated tau at residue 153 (pTau153)/Tau153 ratio, CSF pTau205/Tau205 ratio, CSF microtubule binding region of tau 243 amino acids long (MTBR-tau243), MRI hippocampal volume, CSF NfL, and MRI precuneus thickness).
5. Remternetug arm specific Secondary end point Stage 2: Other secondary endpoints for Stage 2 include: • Fluid and Imaging Biomarker Efficacy Endpoints o CSF pTau217/Tau217 ratio, CSF pTau231/Tau231, CSF MTBR-3R • Clinical and Cognitive Efficacy Endpoints o A cognitive composite derived as an average of these four tests: MAC-Q, Category Fluency (Animals), FCSRT-IR, WAIS-R Digit Symbol Substitution Test, and MMSE. o CDR-SB

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Washington University School Of Medicine

Sponsor organisation

Washington University School Of Medicine

Address

660 South Euclid Avenue 8056

City

Saint Louis

Postcode

63110-1010

Country

United States

Scientific contact point

Organisation

Washington University School Of Medicine

Contact name

Stephanie Belyew, Assoc Director, Clin Trials Operations

Public contact point

Organisation

Washington University School Of Medicine

Contact name

Susan Mills, Senior Director, Clin Trials Operations

Third parties 11

Locations

4 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 175 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications