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
- Conditions
- Interventions
- Registration Number
- NCT06647498
- Lead Sponsor
- Washington University School of Medicine
- Brief 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 a...
- Detailed Description
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 inte...
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 280
-
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
-
Mutation Status:
- 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 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parent is deemed a non-carrier through confirmed genetic testing at any time during the study, the participant will be withdrawn.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.
-
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, 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.
-
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.
-
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.
-
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. Low dose aspirin (≤ 325 mg daily) is not exclusionary.
-
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, 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.
-
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 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.
-
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.
-
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.
-
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
-
Morbid obesity with significant comorbidities or that would preclude MRI imaging.
-
Current use of anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, or apixaban). Daily use of low dose (< 325 mg) aspirin is 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.
-
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 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
-
A centrally read MRI demonstrating presence of ARIA-E, > 4 cerebral microhemorrhages, any superficial siderosis, any macrohemorrhage, 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, whichever is longer.
Note: Use of approved treatments for AD and other medications may be permitted.
-
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
-
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Stage 1: Remternetug Remternetug Active Remternetug- blinded Stage 1: Matching placebo (Remternetug) Matching Placebo (Remternetug) Matching placebo Stage 2: Remternetug Open Label Remternetug Open label will start after last dose of Stage 1
- Primary Outcome Measures
Name Time Method 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 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.
- Secondary Outcome Measures
Name Time Method 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 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 mic...
Stage 1: The proportion of participants who are amyloid positive (CL level ≥ 16.3) at the end of Stage 1 Baseline and Week 104 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 ...
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 Stage 2: Change in CSF pTau217/Tau217 ratio CSF pTau231/Tau231 ratio, and CSF MTBR-3R Weeks 0, 48, 96, 144, and 192 Stage 2: Change in Cognitive Composite Score Weeks 0, 48, 96, 144, and 192 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...
Trial Locations
- Locations (35)
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
🇺🇸Saint 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
Kerwin Research and Memory Center
🇺🇸Dallas, Texas, United States
University of Washington
🇺🇸Seattle, Washington, United States
Instituto de Investigaciones Neurologicas Raul Carrea, FLENI
🇦🇷Ciudad Autonoma de Buenos Aire, Argentina
Neuroscience Research Australia
🇦🇺Randwick, New South Wales, Australia
Mental Health Research Institute
🇦🇺Melbourne, Victoria, Australia
UBC Hospital
🇨🇦Vancouver, British Columbia, Canada
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
McGill Center for Studies in Aging
🇨🇦Verdun, Quebec, Canada
CHU de Quebec - Hôpital de l' Enfant Jésus
🇨🇦Québec, Canada
Grupo de Neurociencias Sede de la Universidad de Antioquia
🇨🇴Medellín, Colombia
CHU de Toulouse - Hôpital Purpan
🇫🇷Toulouse, Haute Garonne, France
Hopital Roger Salengro - CHU Lille
🇫🇷Lille, Nord, France
Groupe Hospitalier Pitie-Salpetriere
🇫🇷Paris cedex 13, Paris, France
Hopital Neurologique Pierre Wertheimer
🇫🇷Bron cedex, Rhone, France
CHU de Rouen - Hôpital Charles Nicolle
🇫🇷Rouen, Seine Maritime, France
Universitaetsklinikum Tubingen
🇩🇪Tübingen, Baden Wuerttemberg, Germany
LMU-Campus Grosshadern
🇩🇪Muenchen, Bayern, Germany
St Vincent's University Hospital
🇮🇪Dublin, Ireland
IRCCS Centro San Giovanni di Dio Fatebenefratelli
🇮🇹Brescia, Italy
Azienda Ospedaliera Universitaria Careggi
🇮🇹Firenze, Italy
Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez
🇲🇽Mexico, Distrito Federal, Mexico
Brain Research Center
🇳🇱Amsterdam, Netherlands
University of Puerto Rico, School of Medicine
🇵🇷San Juan, Puerto Rico
Hospital Clínic I Provincial de Barcelona
🇪🇸Barcelona, Spain
The National Hospital for Neurology and Neurosurgery
🇬🇧London, Greater London, United Kingdom