Alzheimer DiseaseEarly Phase 1NCT04057807
Peripheral Benzodiazepine Receptors (PBR28) Brain PET Imaging With Lipopolysaccharide Challenge for the Study of Microglia Function in Alzheimer's Disease
A Early Phase 1 study testing LPS in people with Alzheimer Disease, run by Yale University at 1 site in United States.
Trial summary
To examine the differences in the capacity to activate microglia in patients with Alzheimer's Disease (AD) compared to age-comparable cognitively normal subjects and younger healthy controls. Read more about this study
- Who is it for?
- Ages 55 to 90 yearsHealthy volunteers can take part
- Conditions the study is for
- Alzheimer Disease
- What is being tested?
- LPS
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Apr 2018to 27 Jul 2022
- Phase
- Early Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 55 to 90 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Mild AD Subjects:
- National Institute on Aging (NIA)-Alzheimer's Association core clinical criteria for probable AD
- Age between 55 and 90 (inclusive)
- Score on the Montreal Cognitive Assessment (MOCA) greater than or equal to 17
- Presence of a responsible caregiver who will accompany AD subjects to all procedures.
- Biomarker evidence of Alzheimer's disease via an amyloid PET scan or cerebrospinal fluid (CSF) amyloid Beta measurement.
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- The patient should have the capacity to consent.
- Clinical Dementia Rating (CDR) global score greater than 0.
- Cognitively normal elderly Subjects:
- Absence of National Institute on Aging-Alzheimer's Association core clinical criteria for probable AD
- Objective memory scores within the normal range for age (do not meet MCI Subjects criterion 2)
- Age between 55 and 90 (inclusive)
- Clinical Dementia Rating (CDR) global score of 0.0
Who cannot join
- Any significant neurologic disease (other than probable AD in the AD Subjects group), such as stroke, Parkinson's disease, brain tumor, seizure disorder, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits.
- Any significant systemic disease including hepatic failure, heart failure, renal failure, chronic obstructive pulmonary disease (COPD), active infection and autoimmune disease.
- Screening/baseline MRI scan with evidence of infection, infarction, or other focal lesions. Subjects with multiple lacunes or lacunes in a critical memory structure are excluded.
- Any significant systemic illness or unstable medical condition, including uncontrolled or insulin- dependent diabetes mellitus, uncorrected hypothyroidism or hyperthyroidism, or systemic cancer.
- Current or regular use of over-the-counter medication that may affect the immune system (e.g., ibuprofen), including corticosteroids or immunosuppressant drugs; no use in 3 weeks prior to the PET scan
- Investigational agents are prohibited 4 weeks prior to entry and for the duration of the study.
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- Previous treatment with an investigational small molecule with anti-amyloid properties or passive immunization against amyloid within 1 year of study entry.
- Previous treatment with an active immunization against amyloid.
- History of schizophrenia or other major psychiatric disorder (DSM IV criteria).
- History of alcohol or substance abuse or dependence (DSM IV criteria) within the past 2 years.
- Clinically significant abnormalities on screening laboratory tests (B12, Thyroid function tests, hematology, chemistry, urinalysis, ECG).
- Pregnancy, as determined by screening pregnancy tests for pre-menopausal females
- Impairment of visual or auditory acuity sufficient to interfere with study procedures.
- Education level < 6 years.
- Evidence of current depression as defined by a score of ≥ 5 on the Geriatric Depression Scale.
- Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body. The presence of claustrophobia, precluding MRI.
- Current or recent participation in any procedures involving radioactive agents such that the total radiation dose exposure to the subject in any given year would exceed the limits of annual and total dose commitment set forth in the US Code of Federal Regulations (CFR) Title 21 Section 361.1.
- Vaccination in the last month.
- Drink more than 5 alcoholic drinks per week or any heavy drinking days in the last 30 days.
- BMI > 35 or < 19
- Women who are pregnant or nursing, or fail to use one of the following methods of birth control unless she or partner is surgically sterile or she is postmenopausal (hormone contraceptives [oral, implant, injection, patch, or ring], contraceptive sponge, double barrier [diaphragm or condom plus spermicide], or Intrauterine Device (IUD)
- Individuals who are classified as "low binders" for the rs6971 polymorphism (<10% of the population)
- Patients on antiplatelet and anticoagulant medications will be excluded.
- Any patient without the capacity to consent will be excluded.
- Unstable hypertension. If blood pressure is greater than 160/100, the investigators will contact the subject's primary care physician to manage their blood pressure. If their blood pressure is not reduced to be consistently below 160/100 by the scanning day the subject will be excluded from the protocol.
- Patients with contraindications for lumbar puncture procedure can be still involved and will be excluded from the optional portion of the study with the lumbar puncture. These include existing intracranial space-occupying lesion with mass effect, posterior fossa mass, risk of cerebral herniation by increased CSF pressure or Arnold chiari malformation, as well as anticoagulant medication, coagulopathies and uncorrected bleeding diathesis, congenital spine abnormalities, and local skin infection at the puncture site.
Trial locations and contacts
1 site in 1 country.
United States1 site
Alzheimer's Disease Research Unit
New Haven, Connecticut, 06510
About this study
Official title: PBR28 Brain Positron Emission Tomography Imaging With Lipopolysaccharide (LPS) Challenge for the Study of Microglia Function in Alzheimer's Disease
To examine the differences in the capacity to activate microglia in patients with Alzheimer's Disease (AD) compared to age-comparable cognitively normal subjects and younger healthy controls.
Read the detailed description
The primary outcome is Microglia Activation Reserve Index (MARI) (calculated in the parietal region of interest (ROIs)) in AD patients compared to elderly controls. The researchers will recruit up to 20 participants. The investigators will use 7 AD and 7 comparably aged cognitively normal successfully scanned subjects to calculate the microglial activation reserve index. The expectations are significant differences between the two groups suggesting altered reactivity of the microglia in AD. The result would be an exciting one suggesting at least one mechanism by which some patients with significant amyloid load have progressive dementia while comparable others are either cognitively normal or have stable Mild Cognitive Impairment (MCI). It will also suggest avenues for intervention in amyloid positive MCIs to prevent progression to Alzheimer's dementia. The exploratory analysis will include:
- Effects of aging on MARI: The researchers will evaluate the effects of aging on MARI. Comparisons will be made for MARI between cognitively normal elderly and the 8 healthy individuals to whom the investigators applied this protocol in an earlier study. The reactivity of microglia is reported to change with age and so the investigators expect MARI to change in the cognitively normal elderly. However, the expectation is that the differences between the young and elderly cognitively normal subjects to be small relative to the comparison of AD and elderly normal controls.
- Effects of amyloid on MARI: The researchers will look at the relationship of regional and global amyloid load to MARI. The presence of a relationship suggests that one of the reasons for altered microglial reactivity might be interactions of microglia with pathologic amyloid.
- Effects of MARI on cognition: The researchers will explore whether MARI would correlate with the measure of disease stage, with higher MARIs associated with worse neuropsychological score and more severe disease. The researchers will look for correlations between MARI and the individual neuropsychological scores. This would determine if disease severity is correlated with microglial activation reserve.
- Conditions
- Alzheimer Disease
- Being tested
- LPS
- Medical subject headings
- Alzheimer Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LPSDrug
LPS (0.4 ng/kg)
| Study group | Role | What they receive |
|---|---|---|
| Patients receiving endotoxin | Experimental | The 20 enrolled subjects will have LPS (0.4 ng/kg) administered intravenously Receives: Drug: LPS |
What is being measured
The primary outcome is the main question the study is designed to answer.
Microglial Activation Reserve Index (MARI)
Participants will undergo [11C]PBR PET scanning both before and then after LPS injection. Parametric images of volume of distribution (VT)were generated for each using multilinear analysis (MA1) and MARI was calculated in the parietal cortex using the equation [(VT post LPS - VT pre LPS)/VT post LPS] x 100%. Higher values of MARI are thought to represent higher levels of microglial activation. There are no clinically relevant thresholds for this measure.
Measured: 180 minutes post intervention
Secondary outcomes (1)
Effects of MARI on Cognition
The Pearson's correlation between MARI and performance on the Montreal Cognitive Assessment (MOCA) will be calculated. The MOCA is a global assessment of cognitive function ranging from 0 to 30 where higher scores represent better cognitive performance.
Measured: 180 minutes post intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Aug 2019
- Study start15 Apr 2018
- Primary completion27 Jul 2022
- Study completion27 Jul 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Alzheimer DiseaseStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Sponsor
- Investigators
- Adam Mecca, M.D., Ph.D., Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04057807
- Sponsor's protocol ID
- 1611018611
- Other IDs
- 1K23AG057794-01
- Status last verified
- Feb 2024
- First submitted
- 13 Aug 2019
- Last updated
- 5 Feb 2024
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 5 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- PBR28 Brain Positron Emission Tomography Imaging With Lipopolysaccharide (LPS) Challenge for the Study of Microglia Function in Alzheimer's Disease
- ClinicalTrials.gov ID
- NCT04057807
- Acronym / sponsor ID
- 1611018611
- Conditions
- Alzheimer Disease
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Study start
- 15 Apr 2018 (actual)
- Primary completion
- 27 Jul 2022 (actual)
- Study completion
- 27 Jul 2022 (actual)
- First posted
- 15 Aug 2019 (actual)
- Results
- Posted 18 Oct 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
To examine the differences in the capacity to activate microglia in patients with Alzheimer's Disease (AD) compared to age-comparable cognitively normal subjects and younger healthy controls.
Detailed description
The primary outcome is Microglia Activation Reserve Index (MARI) (calculated in the parietal region of interest (ROIs)) in AD patients compared to elderly controls. The researchers will recruit up to 20 participants. The investigators will use 7 AD and 7 comparably aged cognitively normal successfully scanned subjects to calculate the microglial activation reserve index. The expectations are significant differences between the two groups suggesting altered reactivity of the microglia in AD. The result would be an exciting one suggesting at least one mechanism by which some patients with significant amyloid load have progressive dementia while comparable others are either cognitively normal or have stable Mild Cognitive Impairment (MCI). It will also suggest avenues for intervention in amyloid positive MCIs to prevent progression to Alzheimer's dementia. The exploratory analysis will include:
- Effects of aging on MARI: The researchers will evaluate the effects of aging on MARI. Comparisons will be made for MARI between cognitively normal elderly and the 8 healthy individuals to whom the investigators applied this protocol in an earlier study. The reactivity of microglia is reported to change with age and so the investigators expect MARI to change in the cognitively normal elderly. However, the expectation is that the differences between the young and elderly cognitively normal subjects to be small relative to the comparison of AD and elderly normal controls.
- Effects of amyloid on MARI: The researchers will look at the relationship of regional and global amyloid load to MARI. The presence of a relationship suggests that one of the reasons for altered microglial reactivity might be interactions of microglia with pathologic amyloid.
- Effects of MARI on cognition: The researchers will explore whether MARI would correlate with the measure of disease stage, with higher MARIs associated with worse neuropsychological score and more severe disease. The researchers will look for correlations between MARI and the individual neuropsychological scores. This would determine if disease severity is correlated with microglial activation reserve.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients receiving endotoxin | Experimental | Drug: LPSThe 20 enrolled subjects will have LPS (0.4 ng/kg) administered intravenously |
Who may qualify
- Ages
- 55 to 90 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Mild AD Subjects:
- National Institute on Aging (NIA)-Alzheimer's Association core clinical criteria for probable AD
- Age between 55 and 90 (inclusive)
- Score on the Montreal Cognitive Assessment (MOCA) greater than or equal to 17
- Presence of a responsible caregiver who will accompany AD subjects to all procedures.
Key exclusion criteria (26 listed)
- Any significant neurologic disease (other than probable AD in the AD Subjects group), such as stroke, Parkinson's disease, brain tumor, seizure disorder, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits.
- Any significant systemic disease including hepatic failure, heart failure, renal failure, chronic obstructive pulmonary disease (COPD), active infection and autoimmune disease.
- Screening/baseline MRI scan with evidence of infection, infarction, or other focal lesions. Subjects with multiple lacunes or lacunes in a critical memory structure are excluded.
- Any significant systemic illness or unstable medical condition, including uncontrolled or insulin- dependent diabetes mellitus, uncorrected hypothyroidism or hyperthyroidism, or systemic cancer.
- Current or regular use of over-the-counter medication that may affect the immune system (e.g., ibuprofen), including corticosteroids or immunosuppressant drugs; no use in 3 weeks prior to the PET scan
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LPSLPS (0.4 ng/kg) | Drug | Patients receiving endotoxin |
Primary outcome
Microglial Activation Reserve Index (MARI)
Time frame: 180 minutes post intervention
Participants will undergo [11C]PBR PET scanning both before and then after LPS injection. Parametric images of volume of distribution (VT)were generated for each using multilinear analysis (MA1) and MARI was calculated in the parietal cortex using the equation [(VT post LPS - VT pre LPS)/VT post LPS] x 100%. Higher values of MARI are thought to represent higher levels of microglial activation. There are no clinically relevant thresholds for this measure.
1 secondary outcome
Effects of MARI on Cognition
Time frame: 180 minutes post intervention
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Feb 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Adam Mecca, M.D., Ph.D. principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing LPS in people with Alzheimer Disease, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Oct 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Microglial Activation Reserve Index (MARI) (time frame: 180 minutes post intervention). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Feb 2024.