Clinical Trials

Trontinemab for Early Alzheimer’s Disease

Trontinemab is a bispecific monoclonal antibody that is directed against the amyloid-β protein and has a Brainshuttle™ module to enable greater central nervous system exposure and enhanced amyloid plaque removal. It therefore has the potential to improve the overall benefit-risk profile in comparison to currently available amyloid-β antibodies. This Phase 3 study will evaluate the efficacy and safety of trontinemab in participants aged 50 to 90 with early Alzheimer’s disease. Participants will be randomly assigned in a 1:1 ratio to receive either 3.6 mg/kg of trontinemab or placebo intravenously every 4 weeks for a total of seven doses. During the maintenance phase participants will receive 3.6 mg/kg of trontinemab or placebo intravenously every 12 weeks. The total duration of each subject’s participation is approximately 80 weeks, including a screening period of up to 8 weeks and a double-blind treatment period of 72 weeks. All participants will receive 6 MRI scans and 3 amyloid PET scans and may enroll in an optional tau PET substudy. Participants who complete the double-blind treatment phase may be eligible to enter a separate open-label extension study in which all subjects will receive trontinemab. Permits concurrent treatment with cholinesterase inhibitors and/or memantine, providing they have been on a stable dose for at least 8 weeks prior to screening. HIC# 2000040901.

MK-2214 for Early Alzheimer’s Disease

MK-2214 is a monoclonal antibody directed against extracellular tau protein, thereby slowing the toxic spread of this protein in Alzheimer’s disease. This phase 2 study will evaluate the efficacy, safety, and tolerability of MK-2214 in participants aged 50 to 85 with early Alzheimer’s disease. Participants will be randomly assigned in a 3:2 ratio to receive either 160mg of MK-2214 or placebo (60% probability of receiving active MK-2214). Infusions will occur every 4 weeks for about 100 weeks. All participants will receive up to 4 MRI scans and 5 tau PET scans and will have the option to participate in a lumbar puncture substudy. Participants who complete the double-blind treatment phase may be eligible to enter a separate open-label extension study in which all subjects will receive MK-2214. Permits concurrent treatment with cholinesterase inhibitors and/or memantine, providing they have been on a stable dose for at least 3 months prior to screening. HIC# 2000040425.

Remternetug, an Investigational Treatment for Primary Prevention of Disease Progression in Dominantly Inherited Alzheimer’s Disease

Remternetug is a monoclonal antibody directed to target amyloid plaques with the potential to provide clinical benefit in Alzheimer’s disease. This is a Phase II/III, double-blind, placebo-controlled, two-stage adaptive design study designed to assess the safety, tolerability and biomarker efficacy of remternetug in cognitively normal participants who are known to have or at risk of having an Alzheimer’s disease-causing mutation. Participants will receive blinded remternetug or placebo in Stage 1 for a minimum of 2 years. If it demonstrates a potential clinical benefit at the end of Stage 1, eligible participants who are known to have a disease-causing mutation may be offered to enter Stage 2 for 4 years. In Stage 1, participants will be randomly assigned to receive either placebo (any patients) or remternetug (mutation carriers only) every 12 weeks through a subcutaneous injection. In Stages 1 and 2, participants will be required to have up to 20 brain MRI scans, 9 11C-PiB PET scans, and 9 lumbar punctures during the study. HIC# 2000033904.

JNJ-64042056 for Individuals at Risk for Alzheimer’s Dementia

A stage of “preclinical Alzheimer’s disease” has been defined based on biomarker evidence of elevated tau proteins before the stage of clinical symptoms. Clinically “normal” older individuals with elevated tau pathology (by blood test and PET scan) are at increased risk for cognitive decline and progression to Alzheimer’s dementia. JNJ-64042056 is a vaccine targeted to pathological forms of the tau protein. This is a Phase 2, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of JNJ-64042056 in cognitively normal participants aged 55 to 75 who are at risk of developing Alzheimer’s disease. Participants will be randomly assigned in a 1:1 ratio to receive either placebo or 900 µg of JNJ-64042056 intramuscularly every 6 months (50% chance of receiving active study drug). All participants will receive up to 12 MRI scans and up to 6 tau PET scans. HIC# 2000038564.

BAN2401 for Individuals at Risk for Alzheimer’s Dementia (AHEAD, A3-45 Study)

A stage of “preclinical Alzheimer’s disease” has recently been defined based on biomarker evidence of amyloid-β pathology before the stage of clinical symptoms. Clinically “normal” older individuals with elevated Aβ pathology (by PET scan) are at increased risk for cognitive decline and progression to Alzheimer’s dementia. BAN2401 is a humanized monoclonal antibody with high selectivity for soluble amyloid-β protofibrils. This is a 4-year, double-blind, placebo-controlled, phase 3 study to evaluate the safety, tolerability, and efficacy of BAN2401 in cognitively normal participants ages 55-80 years who are at risk of developing Alzheimer’s dementia. Participants with intermediate (A3 study) or elevated (A45 study) levels of brain amyloid on a screening PET scan will be randomized to receive intravenous BAN2401 or placebo (50% probability of receiving active BAN2401). A3 study participants will receive BAN2401 (titrated up to 10mg/kg) or placebo every four weeks. A45 study participants will receive BAN2401 (titrated up to 10mg/kg) or placebo every 2 weeks for the first 96 weeks, then every four weeks for the remainder of the study. Participants will be required to have at least 12 MRI scans, three amyloid (18F-NAV4694) PET scans, and three tau (18F-MK6240) PET scans. Participants can also participate in an optional lumbar puncture substudy. Does NOT permit concurrent treatment with cholinesterase inhibitors and memantine. HIC# 2000027712.

CT1812 for Early Alzheimer’s Disease

CT1812 is a sigma-2 receptor modulator that is thought to displace and reduce binding of toxic beta-amyloid oligomers to neuronal synapses, with the potential to provide clinical benefit in Alzheimer’s disease. This is a Phase 2, double-blind, placebo-controlled study designed to evaluate the efficacy, safety, and tolerability of CT1812 in participants aged 50 to 85 with early Alzheimer’s disease. Participants will be randomly assigned in a 1:1:1 ratio to receive either 100mg or 200mg of CT1812 or placebo daily for 18 months (67% chance of receiving active study drug). All participants will receive 3 MRI scans and will also undergo either an amyloid PET scan or a lumbar puncture to confirm the presence of cerebral Aβ accumulation. Participants will have the option of participating in amyloid PET and/or cerebrospinal fluid (CSF) lumbar puncture substudies. Permits concurrent treatment with cholinesterase inhibitors and memantine. HIC# 2000035336.

BMS-986446 for Early Alzheimer’s Disease

BMS-986446 is a monoclonal antibody directed against extracellular tau protein, thereby slowing the toxic spread of this protein in Alzheimer’s disease. This phase 2 study will evaluate the safety, tolerability, and efficacy of BMS-986446 in participants ages 50-80 years with early Alzheimer’s disease for 76 weeks. Participants will be randomly assigned in a 4:3:3 ratio to receive either 1400 mg or 4200 mg of BMS-986446 or placebo (70% probability of receiving active BMS-986446). Infusions will occur every 4 weeks. All participants will receive 5 MRI scans and will also undergo 3 tau PET scans. Participants who complete the double-blind treatment phase may be eligible to enter a 96-week open-label extension study in which all subjects will receive BMS-986446. Permits concurrent treatment with cholinesterase inhibitors and/or memantine, providing they have been on a stable dose for at least 12 weeks prior to baseline. HIC# 2000037714.

Longitudinal PET Imaging of Biomarkers in Alzheimer’s Disease

Since synaptic loss is a robust and consistent component of Alzheimer’s disease (AD) pathology, direct measurement of synaptic density could be an important step for understanding disease progression and monitoring therapeutic interventions. We recently developed 11C UCB-J, a PET tracer for quantitative measurement of a vesicle membrane protein present in virtually all synapses. The purpose of this research is to examine these synapses, as measured using Positron Emission Tomography (PET) scanning and the tracer 11C UCB-J, and to integrate this information with other biomarkers of disease, including Aβ and tau deposition. Participants will include individuals between the ages of 50 and 85 with mild cognitive impairment (MCI) or dementia due to AD, as well as participants without cognitive impairment. Additionally, the sample will include participants aged 40 to 75 years with and without a first-degree family history of AD. The study procedures include medical history and physical exam, blood and urine samples, memory testing, an MRI scan, and up to 4 PET scans every two years over the course of 10 years. Length of participation is approximately 10 years. HIC#2000024532.

PET Imaging of Synaptic Density in Alzheimer’s Disease

Since synaptic loss is a robust and consistent component of Alzheimer’s disease (AD) pathology, direct measurement of synaptic density could be an important step for understanding disease progression. We recently developed [11C]APP311, a PET tracer for quantitative measurement of a vesicle membrane protein present in virtually all synapses. The purpose of this research is to examine these synapses, as measured using Positron Emission Tomography (PET) scanning and the tracer [11C]APP311, in participants between the ages of 55 and 90 with mild cognitive impairment (MCI) or dementia due to AD, as well as participants without cognitive impairment. The study procedures include medical history and physical exam, blood and urine samples, memory testing, an MRI scan, and up to 3 PET scans. Length of participation is approximately 6 months. Participants will be compensated up to $800 for their time. HIC#1608018300

Alzheimer’s Disease Neuroimaging Initiative 4 (ADNI 4).

At present, the development of drugs for patients with Alzheimer’s disease is costly and time consuming. The validation of suitable biomarkers that track the progression of the disease and reflect underlying pathology is critical to streamlining this process. This is a multi-center observational research study designed to look at the relationships between clinical, cognitive, imaging, genetic, and biomarker tests in order to understand the full spectrum of Alzheimer’s disease (AD) from its earliest stage. It will enroll about 1500 participants ages 55 – 90 (inclusive) across three cohorts: cognitively normal, mild cognitive impairment, and mild AD dementia. Approximately 750 of those participants will have also been in the ADNI-3 study. At least 50-60% of newly enrolled participants will come from populations that have been underrepresented in earlier iterations of ADNI (e.g., Black, Latinx, and persons with less than 12 years of education) to enhance the generalizability of results. Study participation will last for about 4-5 years based on cohort (up to 6 visits total). All subjects will undergo MRI scans and up to 8 PET scans and can participate in optional lumbar puncture procedures (up to 3 lumbar punctures). They will also have the option to participate in a brain donation program. HIC#2000034800.

Apolipoprotein E and Other Genetic Factors in Alzheimer’s Disease

Apolipoprotein E (ApoE) is the major genetic risk factor for AD. The purpose of this research is to determine whether ApoE is related to differences among patients with AD, for example in the rate of progression, associated symptoms, and brain imaging features. We may also study other genes thought to be related to AD or brain function. Subjects participating in other studies in the ADRU may also participate in this study by providing a blood sample for genetic testing. HIC# 0505008171

Alzheimer’s Disease Research Center (ADRC) – Clinical Core

The goal of the Clinical Core of the Yale ADRC is to perform research diagnostic evaluations for a large clinical population and to follow participants longitudinally to provide data for a broad range of studies related to Alzheimer’s disease and other dementias. This research will also focus on biomarkers and their utility in the earliest stages of disease. The Clinical Core will evaluate and enroll approximately 100 participants annually from the following categories: cognitively normal individuals—both with and without a first-degree family history of Alzheimer’s disease, individuals with Mild Cognitive Impairment, individuals with mild-moderate Alzheimer’s dementia, individuals with other neurodegenerative dementias. Participants will have an initial evaluation, including cognitive tests, blood samples, and a physical and neurological examination. Participants will be asked to return for annual follow-up visits in which these assessments will be repeated. Subjects will also have the option to participate in substudies involving lumbar puncture, MRI scans, and brain autopsy. HIC#1505015818