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
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.
Study details:
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive decline in cognitive function and the ability to perform activities of daily living. The amyloid hypothesis of AD postulates that the accumulation of amyloid beta (Aβ) is an early and necessary event in the pathogenesis of AD. This hypothesis suggests that interventions that slow the accumulation of Aβ plaque in the brain or increase clearance of Aβ may be able to slow the progression of the AD clinical syndrome.
AD occurs on a continuum from asymptomatic (preclinical) to mild cognitive impairment (MCI), and then to dementia in mild, moderate, and severe stages. Evidence from both genetic at-risk and age at-risk cohorts, such as in dominantly inherited AD (DIAD) suggests that the pathophysiological process of AD begins well more than a decade before the clinical stage now recognized as AD dementia, and that neurodegeneration is already apparent on MRI by the stage of mild cognitive impairment. Recent clinical trial data suggest that treating AD during the earlier stages could have the greatest potential benefit on the disease by slowing progression.
The ability to identify individuals destined to develop Alzheimer's disease (AD) with a high degree of confidence provides a unique opportunity to assess the efficacy of therapies at asymptomatic and very early stages of dementia. Families with known disease-causing mutations are extremely rare and are geographically dispersed throughout the world. Participants in this study will not yet have developed any clinical symptoms of AD; they will be "asymptomatic" carriers of mutations that cause DIAD and would be expected to perform normally on standard cognitive and functional testing.
Further, most mutation carriers will have levels of AD-associated amyloid beta (Aβ) and non-Aβ biomarkers that are the same as non-carriers. Amyloid beta is a protein that accumulates in the brain of people with AD. Although we do not understand exactly what causes AD, the abnormal accumulation of amyloid beta protein in the brain is thought to play an important role in the symptoms of AD.
Recent research studies indicate that amyloid beta may start building up in the brain 15 years or more before the onset of memory loss. Imaging and fluid biomarkers will be used to demonstrate that the treatment compounds have engaged their therapeutic targets. A set of cognitive measures designed to assess the very earliest and most subtle cognitive changes will be collected.
The overall objectives of this study are to evaluate the biomarker effect, safety, and tolerability of investigational study drugs in participants who are known to have an AD-causing mutation. The primary objective of Stage 1 is to determine if treatment with the study drug prevents or slows the rate of Aβ pathological disease accumulation demonstrated by Aβ PiB positron emission tomography (PET) imaging. The primary objective of Stage 2 is to evaluate the effect of early anti-amyloid treatment on disease progression by assessing downstream non-Aβ biomarkers of AD (e.
g. , CSF total tau, NfL, MRI volume) compared to a control group from the DIAN Obs natural history study and the DIAN-TU-001 placebo-treated participants. Remternetug is a monoclonal antibody.
The mechanism of action of remternetug is to target and remove aggregated amyloid plaque, a key pathological hallmark of AD, via microglial-mediated clearance. Remternetug has demonstrated the ability to reduce brain amyloid plaque. The remternetug arm is part of Master Protocol DIAN-TU-002 (NCT05552157).
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
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.
- People of childbearing potential must have a negative serum pregnancy test at screening (V1). Must agree not to try to become pregnant during the study until 5 half-lives after the last dose of any study drug. Must agree not to breastfeed from the time of signed ICF until 5 half-lives after the last dose of any study drug. 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.
- 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.
- Participant is -25 to -11 years from predicted age of cognitive symptom onset based on their mutation type or family pedigree.
- 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.
- Participant has adequate visual and auditory abilities to perform all aspects of the cognitive and clinical assessments.
- 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).
- Participant has a study partner who in the PI's judgment can provide accurate information as to the participant's cognitive and functional abilities.
- 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.
- In the opinion of the PI, the participant will be compliant and have a high probability of completing the study.
- The participant is able and 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.
- At high risk for suicide, e.g., significant suicidal ideation or attempt within last 12 months, current major depression.
- History of clinically evident stroke or history of clinically important carotid or vertebrobasilar stenosis.
- 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.
- Presence of certain implanted medical devices, such as some pacemakers, aneurysm clips, artificial heart valves.
- Cardiovascular complications such as uncontrolled hypertension.
- 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/C infection.
- History of clinically significant multiple or severe drug allergies.
- Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within 90 days prior to Baseline (V2) visit.
- Current clinically significant abnormalities of thyroid function, or clinically significant deficiency in vitamin B12.
- Unstable or poorly controlled diabetes which the investigator believes may interfere with participation in or analysis of the study protocol.
- Morbid obesity with significant comorbidities or that would preclude MRI imaging.
- Current use of anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, or apixaban).
- Have been exposed to a monoclonal antibody targeting Aβ peptide within the past 6 months or 5 half-lives from screening.
- Received any other investigational pharmacological treatment within 3 months of Screening or 5 half-lives.
- Lack of sufficient venous access.
- Clinically relevant abnormalities in hematology, coagulation, or clinical chemistry.
- History of cancer that the investigator believes has high risk of recurrence and impacting study participation or analysis.
- 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.
- Currently, or within the last month prior to screening, participated in a clinical study, including a nonpharmacological study.
- Participants with the 'Dutch' APP E693Q mutation.
- Unable to complete baseline visit (V2) procedures with appropriate cognitive and clinical scores for eligibility.
- A centrally read MRI demonstrating presence of ARIA-E, > 4 cerebral microhemorrhages, or severe white matter disease at screening.
- Exposure to lecanemab, donanemab, or other investigational amyloid lowering agents within the past 6 months or five half-lives from screening.
- Investigator site personnel directly affiliated with this trial and/or their immediate families.
- Lilly employees or employees of a third-party organization (TPO) involved in this study.
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE2PHASE3
Study ID
NCT06647498
Intervention or treatment
DRUG: Remternetug
DRUG: Matching Placebo (Remternetug)
Conditions
- Alzheimers Disease
- Dementia
- Alzheimers Disease, Familial
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Research sites nearby
Closest Location:
Neuroscience Research Australia
Select from list below to view details:
Neuroscience Research Australia
Randwick, New South Wales, Australia
Mental Health Research Institute
Melbourne, Victoria, Australia
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Who is running the clinical trial?
Washington University School of Medicine
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: Stage 1: Remternetug
| Drug: Remternetug |
PLACEBO_COMPARATOR: Stage 1: Matching placebo (Remternetug)
| Drug: Matching Placebo (Remternetug) |
ACTIVE_COMPARATOR: Stage 2: Remternetug Open Label
| Drug: Remternetug |
What is the study measuring?
Primary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Stage 1: Change in amyloid load as measured by centiloid (CL) [11C]PiB-PET as biomarker endpoint for DIAN-TU-002 remternetug arm | CL calculated using \[11C\] PiB PET non-partial volume corrected (regional spread function) standardized uptake value ratio cortical composite (PiB PET SUVR) is the primary outcome and change from baseline at 2 years is the primary endpoint. | Baseline and Week 192 |
Secondary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| 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. | The key secondary efficacy endpoint for Stage 2 is the 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 neurofilament light chain (NfL), and MRI precuneus thickness). | 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 | For participants in the active treatment group, the amyloid positivity status is defined using the last available PiB-PET CL value during Stage 1: amyloid positive if CL\>=16.3 and amyloid negative if CL\<16.3. For participants in the placebo group, the amyloid positivity status: (i) is either defined using the last available PiB-PET CL value during Stage 1 (amyloid positive if CL\>=16.3 and amyloid negative if CL\<16.3) | Baseline and Week 104 |
| Stage 1: Change in CSF pTau217/Tau217 ratio | Not Specified | Baseline and Week 104 |
| Stage 1: Change in CSF pTau231/Tau231 ratio | Not Specified | Baseline and week 104 |
| Stage 1: Change in CSF 3-repeat isoform of MTBR (MTBR-3R) | Not Specified | Baseline and week 104 |
| Stage 2: Change in CSF pTau217/Tau217 ratio CSF pTau231/Tau231 ratio, and CSF MTBR-3R | Not Specified | Weeks 0, 48, 96, 144, and 192 |
| Stage 2: Change in Cognitive Composite Score | A cognitive composite derived as an average of these four tests: Memory Complaint Questionnaire (MAC-Q), Category Fluency (Animals), Buschke and Grober Free and Cued Selective Reminding Test - Immediate Recall (FCSRT-IR), Wechsler Adult Intelligence Scale - Revised (WAIS-R) Digit Symbol Substitution Test, and Mini-Mental State Examination (MMSE). Each of the four tests will be converted to a z-score using the mean (SD) of the baseline score in Stage 1 of both the treatment arm and the placebo arm, and then equally weighted to obtain the composite. | Weeks 0, 48, 96, 144, and 192 |
References
Clinical Trials Gov: 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 MutationOther trials to consider
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