Evaluation of N-Methyl-2-(4'-Methylaminophenyl)-6-Hydroxybenzothiazole and LY3372993 in Preventing Progression of Dominantly Inherited Alzheimer's Disease
- Trial ID
- 2024-517187-36-01
- Protocol
- DIAN-TU-002
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the ability of the investigational drug to prevent or slow the rate of **Aβ accumulation** compared with placebo in participants with mutations that cause **Dominantly Inherited Alzheimer’s Disease (DIAD)** during Stage 1. In Stage 2, the study aims to evaluate the effect of anti-amyloid treatment on downstream biomarkers of Alzheimer's Disease. These objectives are clinically relevant as they address the potential for early intervention in DIAD, which could alter the disease trajectory and improve patient outcomes.
Secondary objectives include:
- Evaluating the safety and tolerability of the study drug in all participants who received the study drug or placebo during both Stage 1 and Stage 2.
- Assessing target engagement in interim analysis/analyses in participants with DIAD mutations.
Participants
The clinical trial involves a total of **274 participants** who are being studied for **Dominantly Inherited Alzheimer’s Disease (DIAD)**. The study population includes both male and female subjects, with an age range that encompasses adults. Participants were selected based on their genetic predisposition to DIAD, specifically those who are carriers of mutations in the APP, PSEN1, or PSEN2 genes, or those with a family history indicating a direct risk of inheriting such mutations. The trial includes individuals who are at least 18 years old and have normal cognitive status as indicated by a Clinical Dementia Rating-Sum of Boxes (CDR-SB) score of 0. Participants are required to have adequate visual and auditory abilities to perform cognitive and clinical assessments and must be fluent in a language approved for the DIAN-TU trial. The study population is characterized by a stable health status, with participants receiving consistent medication for non-excluded medical conditions. Lifestyle considerations such as diet and physical activity are not specified, but participants must have a study partner capable of providing accurate information regarding their cognitive and functional abilities. The trial includes a vulnerable population, as it involves individuals with a genetic predisposition to a serious condition. Key inclusion criteria include the ability to provide informed consent and compliance with study procedures, while exclusion criteria are not detailed in the provided data.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study with a two-stage adaptive platform to evaluate investigational treatments for the primary prevention of disease progression in individuals with **Dominantly Inherited Alzheimer’s Disease (DIAD)**. The trial aims to assess the ability of the study drug to prevent or slow the rate of amyloid-beta (Aβ) accumulation and evaluate the effect of anti-amyloid treatment on downstream biomarkers of Alzheimer's Disease (AD). The trial is expected to commence recruitment in August 2025 and conclude by November 2034, with a maximum treatment period of 108 weeks for participants.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as mutation status, cognitive status, and other health parameters. Following successful screening, participants will be randomized to receive either the investigational drug, **Remternetug**, or a placebo. The investigational drug will be administered as a **subcutaneous injection**, while the placebo will match the investigational drug in appearance. The study will include regular follow-up visits to monitor the incidence and severity of treatment-emergent adverse events (TEAEs), assess laboratory parameters, and conduct imaging studies such as amyloid PET scans to evaluate biomarker changes.
The primary endpoints will focus on the change in brain Aβ plaque development and other biomarkers of early-stage disease, while secondary endpoints will include the incidence of TEAEs, changes in cognitive and clinical measures, and biomarker analyses. Participants are expected to be involved in the study for the entire duration of the treatment period unless conditions arise that necessitate early termination, such as non-compliance, withdrawal of consent, or adverse events that compromise participant safety. The study is structured to ensure rigorous monitoring and evaluation of both efficacy and safety outcomes, with interim analyses to guide potential dose adjustments or discontinuation of a study drug arm based on efficacy and/or futility.
Treatment
The clinical trial involves the administration of **PiB** (Pittsburgh compound B), a chemical compound with the active substance **N-Methyl-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole**. PiB is provided in the form of an **injection** and is administered via **intravenous bolus use**. The maximum daily dose is 18 mCi, with a total maximum dose of 162 mCi over a treatment period of 108 days. This compound is utilized to evaluate its ability to prevent or slow the rate of Aβ accumulation in participants with mutations causing Dominantly Inherited Alzheimer's Disease (DIAD).
The trial also includes a **placebo** designed to match LY3372993, which serves as a control to assess the efficacy of the investigational treatments. The placebo does not contain any active substance and is used to maintain the double-blind nature of the study. The pharmaceutical form and route of administration for the placebo are not specified.
**Remternetug**, with the active substance **LY3372993**, is another investigational treatment in the trial. It is a **solution for injection** and is administered via **subcutaneous injection**. Although the maximum daily and total doses are not specified, the treatment period is set for 108 days. Remternetug is classified as a biological medicinal product and is evaluated for its effect on downstream biomarkers of Alzheimer's Disease.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the impact of investigational treatments on **Dominantly Inherited Alzheimer's Disease** (DIAD). The primary endpoints for Stage 1 include the assessment of biomarkers of early-stage disease, such as amyloid PET, soluble amyloid, and soluble phospho-tau, compared with baseline in each treatment group. Specifically, for the Remternetug arm, the primary endpoint will focus on the change from baseline in brain Aβ plaque development as measured by centiloid (CL) using [11C]-Pittsburgh compound B (PiB) PET.
Secondary endpoints for both Stage 1 and Stage 2 encompass a range of safety and efficacy measures. These include the incidence and severity of treatment-emergent adverse events (TEAEs), ARIA noted by MRI, laboratory parameters, vital signs, and ECGs. Biomarker interim analyses may be conducted for dose adjustment or to determine the efficacy and/or futility of a study drug arm. For the Remternetug arm, specific secondary endpoints in Stage 1 include the proportion of participants who are amyloid positive at the end of Stage 1, and changes in cerebrospinal fluid (CSF) biomarkers such as pTau217/Tau217 ratio, pTau231/Tau231 ratio, and the 3-repeat isoform of MTBR (MTBR-3R).
In Stage 2, the Remternetug arm will assess the odds ratio between the treated group and an external control group regarding biomarker disease progression stages. This will be based on two-stage modeling of six biomarkers, including CSF tau phosphorylated tau at residue 153 (pTau153)/Tau153 ratio, CSF pTau205/Tau205 ratio, CSF MTBR-tau243, MRI hippocampal volume, CSF NfL, and MRI precuneus thickness. Additional secondary endpoints for Stage 2 include fluid and imaging biomarker efficacy endpoints, as well as clinical and cognitive efficacy endpoints, which involve a cognitive composite derived from tests such as MAC-Q, Category Fluency (Animals), FCSRT-IR, WAIS-R Digit Symbol Substitution Test, and MMSE, along with CDR-SB.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- Participant is at least 18 years old.
- 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
- 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.
- Cognitive status of participant is normal (CDR-SB 0).
- 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.
- Adequate visual and auditory abilities to perform all aspects of the cognitive and clinical assessments.
- 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).
- 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.
- 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.
- In the opinion of the PI, the participant will be compliant and have a high probability of completing the study.
- Willing to complete all study-related testing, evaluations, and procedures.
Exclusion Criteria
- 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.
- 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
- Hepatic or renal abnormalities that in the opinion of the investigator would interfere with participation in or analysis of the trial.
- 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.
- 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.
- Currently, or within the last month prior to screening, participated in a clinical study, including a nonpharmacological study, without prior approval.
- Participants with the "Dutch" APP E693Q mutation.
- Unable to complete baseline visit (V2) procedures with appropriate cognitive and clinical scores for eligibility
- 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.
- 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.
- Morbid obesity with significant comorbidities or that would preclude MRI imaging.
- Clinically relevant abnormalities in hematology, coagulation, or clinical chemistry.
- 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.
- Have been exposed to a monoclonal antibody targeting Aβ peptide within the past 6 months or 5 half-lives from screening, whichever is longer.
- 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.
- Lack of sufficient venous access.
- 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.
- 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.
- 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.
- 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.
- History of cancer that the investigator believes has high risk of recurrence and impacting study participation or analysis.
- 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.
- 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.
- 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.
- Alcohol or substance use sufficient to meet DSM-V criteria currently or within the past year.
- 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.
- 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.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 01 Aug 2025 | 10 |
 Germany | Recruiting | 01 Aug 2025 | 6 |
 Italy | Recruiting | 01 Aug 2025 | 5 |
 The Netherlands | Not Yet Recruiting | 01 Aug 2025 | — |
 Spain | Recruiting | 01 Aug 2025 | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PiB | Other | INJECTION | INTRAVENOUS BOLUS USE | 18 | 108 | PRD11332950 |
Placebo to match LY3372993 | Placebo | N/A | — | — | — | N/A |
Remternetug | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 0 | 108 | PRD10036527 |