LY3372993 for Dominantly Inherited Alzheimer's disease

Inclusion criteria

• {"criterion_text":"- 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.\n- 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.\n- In the opinion of the PI, the participant will be compliant and have a high probability of completing the study.\n- Willing to complete all study-related testing, evaluations, and procedures.\n- Participant is at least 18 years old.\n- For people of childbearing potential (POCBP): a.\tMust have a negative serum pregnancy test at screening (V1) b.\tMust agree not to try to become pregnant during the study until twenty (20) weeks after the last dose of any study drug. c.\tMust agree not to breastfeed from the time of signed ICF until twenty (20) weeks after the last dose of any study drug. d.\tIf 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.\tcombined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: •\toral •\tintravaginal •\ttransdermal ii.\tprogestogen-only hormonal contraception associated with inhibition of ovulation: •\toral •\tinjectable •\timplantable iii.\tintra-uterine device (IUD) iv.\tIntrauterine hormone-releasing systems (IUS) v.\tbilateral tubal occlusion vi.\tvasectomized partner (only when this is the only partner) vii.\ttrue 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\n- Mutation status: a.\tParticipant 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.\tParticipant 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.\n- Cognitive status of participant is normal (CDR-SB 0).\n- 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.\n- Adequate visual and auditory abilities to perform all aspects of the cognitive and clinical assessments.\n- 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).\n- 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."}

Exclusion criteria

• {"criterion_text":"- 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.\n- 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.\n- Morbid obesity with significant comorbidities or that would preclude MRI imaging.\n- Clinically relevant abnormalities in hematology, coagulation, or clinical chemistry.\n- 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.\n- Have been exposed to a monoclonal antibody targeting Aβ peptide within the past 6 months or 5 half-lives from screening, whichever is longer.\n- 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.\n- Lack of sufficient venous access.\n- 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.\n- 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.\n- 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.\n- 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\n- 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.\n- History of cancer that the investigator believes has high risk of recurrence and impacting study participation or analysis.\n- 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.\n- 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.\n- 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.\n- Alcohol or substance use sufficient to meet DSM-V criteria currently or within the past year.\n- 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.\n- 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.\n- 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.\n- Hepatic or renal abnormalities that in the opinion of the investigator would interfere with participation in or analysis of the trial.\n- 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.\n- 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.\n- Currently, or within the last month prior to screening, participated in a clinical study, including a nonpharmacological study, without prior approval.\n- Participants with the \"Dutch\" APP E693Q mutation.\n- Unable to complete baseline visit (V2) procedures with appropriate cognitive and clinical scores for eligibility\n- 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."}

Primary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"Assessment of biomarkers of early-stage disease compared with baseline in each treatment group; examples include amyloid PET, soluble amyloid, soluble phospho-tau as specified in each drug-specific appendix."}
• {"endpoint_text":"- Stage 2: If applicable, will be defined in each drug-specific appendix, and will be an assessment of the effect of anti-amyloid treatment on downstream biomarkers of AD.","definition_or_measurement_approach":"Assessment of change in progression of biomarkers representing tau, neurodegenerative, and inflammatory pathobiological events; exact measures and timing specified in drug-specific appendix."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Change from baseline in brain Aβ plaque development measured by centiloid (CL) using 11C-PiB PET."}

Secondary endpoints

• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Safety assessments: recording incidence and severity of treatment-emergent adverse events (TEAEs), MRI-detected ARIA, laboratory parameters, vital signs and ECGs as applicable."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Interim biomarker analyses specified per drug to guide dose-adjustment or stopping rules; biomarkers include soluble measures (Aβ, tau), imaging (amyloid PET), MRI atrophy, and NfL."}
• {"endpoint_text":"- Remternetug arm specific Secondary end point Stage 1: Secondary efficacy endpoints include: •\tThe proportion of participants who are amyloid positive (CL level ≥ 16.3) at the end of Stage 1, •\tChange in CSF pTau217/Tau217 ratio, •\tChange in CSF pTau231/Tau231 ratio, and •\tChange in CSF 3-repeat isoform of MTBR (MTBR-3R).","definition_or_measurement_approach":"Efficacy measured by proportion with amyloid positivity (CL ≥16.3) and CSF biomarker ratio changes (pTau217/Tau217, pTau231/Tau231) and MTBR-3R changes."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Stage 2 efficacy assessed via odds ratio comparing treated group vs external control (DIAN Obs and DIAN-TU-001 placebo) using two-stage modelling of six biomarkers (pTau153/Tau153, pTau205/Tau205, MTBR-tau243, hippocampal volume, CSF NfL, precuneus thickness)."}
• {"endpoint_text":"- Remternetug arm specific Secondary end point Stage 2: Other secondary endpoints for Stage 2 include: •\tFluid and Imaging Biomarker Efficacy Endpoints o\tCSF pTau217/Tau217 ratio, CSF pTau231/Tau231, CSF MTBR-3R •\tClinical and Cognitive Efficacy Endpoints o\tA 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\tCDR-SB","definition_or_measurement_approach":"Additional Stage 2 endpoints include CSF and imaging biomarkers (pTau217/Tau217, pTau231/Tau231, MTBR-3R) and clinical/cognitive endpoints including a composite average of MAC-Q, Category Fluency, FCSRT-IR, WAIS-R DSST, MMSE, and CDR-SB."}

Methods

• Phone script / sample phone screen script (titles: 'Sample phone screen script', 'K2_Recruitment material_PhoneScriptPrimaryPevention_Final_ITA_san') — used as telephone pre-screening materials (country-specific versions present: ITA, ESP, DEU).
• Primary prevention trial brochure / Trial brochure / Primary Prevention Brochure (country-specific templates and redacted versions listed for ITA, ESP, DEU, FRA) — outreach and informational brochure for potential participants.
• Brain donation program brochure and confirmation/thank you letters — targeted materials for brain donation recruitment.
• Patient GP Letter (K2_Patient_GP Letter_ITA) — engagement via general practitioners in Italy.
• Wallet-sized participant cards / Patient Trial ID Card — physical leave-behind materials for participants.
• InvARC digital materials (InvARC Script, InvARC Screenshots, Inv ARC_Privacy description) — digital/remote recruitment and screening platform described in documentation (country-specific).
• Country-specific recruitment arrangements and informed consent procedure documents (K1/K2 recruitment materials) for Spain, France, Germany, Italy.

Spain

Earliest CTIS Part Ii Submission Date

03-06-2025

Latest Decision Or Authorization Date

23-04-2026

Processing Time Days

324

Number Of Sites

1

Number Of Participants

6

France

Earliest CTIS Part Ii Submission Date

06-10-2025

Latest Decision Or Authorization Date

20-04-2026

Processing Time Days

196

Number Of Sites

5

Number Of Participants

10

Germany

Earliest CTIS Part Ii Submission Date

07-10-2025

Latest Decision Or Authorization Date

24-04-2026

Processing Time Days

199

Number Of Sites

2

Number Of Participants

6

Italy

Earliest CTIS Part Ii Submission Date

18-09-2025

Latest Decision Or Authorization Date

22-04-2026

Processing Time Days

216

Number Of Sites

2

Number Of Participants

5

Primary sponsor

Full Name

Washington University School Of Medicine

Organisation Type

Educational Institution

Country Of Registered Address

United States

Contract research organisations

Name

IQVIA Limited

Responsibilities

Multiple sponsor duties (codes: 1,12,13,2,5,8,9) — clinical operations / vendor roles as listed in sponsorDuties.

Name

Signant Health Global LLC

Responsibilities

Responsibilities include sponsor duties codes 3 and 7 (electronic data capture/eCOA/clinical data services).

Name

Medidata Solutions Inc.

Responsibilities

Sponsor duties code 7 (data platform/clinical data services).

Name

Fisher Clinical Services GmbH

Responsibilities

Sponsor duties code 14 (logistics/other vendor services).

Third parties

• {"country":"United Kingdom","full_name":"Medical Research Network Limited","duties_or_roles":"Home health nurse","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"University Of Michigan","duties_or_roles":"PET Scan QC","organisation_type":"Educational Institution"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"Sponsor duties codes: 1,12,13,2,5,8,9","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Xnat Works Inc.","duties_or_roles":"Imaging; sponsor duties codes include 6","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"Sponsor duties code: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Sage Bionetworks","duties_or_roles":"Sponsor duties code: 7","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"Sponsor duties code: 14","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"C2n Diagnostics LLC","duties_or_roles":"Sponsor duties code: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Signant Health Global LLC","duties_or_roles":"Sponsor duties codes: 3,7","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Mayo Clinic Hospital Rochester","duties_or_roles":"Imaging Image QC and central/safety reads","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"Sponsor duties code: 7","organisation_type":"Non-Pharmaceutical company"}