Using F-18 Flornaptitril PET scans to see brain protein patterns in people with MCI from suspected CTE or Alzheimer's

Visualizing Brain Proteinopathies Using [F-18]Flornaptitril-PET in the Prediction of Clinical Progression of Mild Cognitive Impairment With Either Suspected Chronic Traumatic Encephalopathy or Alzheimer's Disease

This study will test whether F-18 Flornaptitril PET scans can predict clinical worsening in people with mild cognitive impairment suspected to be due to chronic traumatic encephalopathy or Alzheimer's disease.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 230 (estimated)
• Ages: 45 Years and up
• Sex: All
• Sponsor: CereMark Pharma, LLC (Industry-sponsored)
• Drugs / interventions: aducanumab, lecanemab
• Locations: 1 site (Evanston, Illinois)
• Trial ID: NCT06254469 on ClinicalTrials.gov

What this trial studies

This Phase 3, multi-site randomized study uses F-18 Flornaptitril (F-18 FNT) PET imaging to determine whether regional brain protein patterns predict clinical decline in people with MCI suspected to result from CTE or Alzheimer's disease. Participants receive F-18 FNT-PET scans, standardized clinical assessments, and longitudinal follow-up visits at 1 and 2 years, with images read by trained readers. The primary outcomes are the accuracy of the PET scan in predicting clinical decline and the safety and tolerability of the tracer; secondary aims include differentiating suspected CTE from AD and correlating PET reads with other measures. The trial requires a trial partner for each participant and is sponsored by CereMark Pharma with site participation currently including Endeavor Health Systems in Evanston, Illinois.

Who should consider this trial

Good fit: Adults with mild cognitive impairment suspected to be due to CTE (age >45) or Alzheimer's disease (age >50) who can undergo PET scanning, have a reliable trial partner, and are willing to attend follow-up visits.

Not a fit: People without MCI, those below the study age cutoffs, those who cannot tolerate or access PET imaging, those lacking a trial partner, or those whose cognitive impairment stems from other causes are unlikely to benefit from this trial.

Why it matters

Potential benefit: If successful, this imaging approach could help identify which people with MCI are likely to worsen so clinicians and families can plan care earlier and more precisely.

How similar studies have performed: Tau PET tracers have shown diagnostic and prognostic value in Alzheimer's disease, but use of F-18 flornaptitril specifically to differentiate suspected CTE from AD and predict progression is relatively novel and less established.

Eligibility criteria

Inclusion Criteria:

Participants with MCI enrolling in the trial must meet all the following criteria:

1\. Diagnosis of MCI due to suspected CTE, and with age \>45 years, or AD, and with age \>50 years at the time of the Screening Visit (see Inclusion Criteria 9) 2. Participants must have a trial partner who has frequent interaction with them (approximately \>3-4 times per week), will be present for all clinic visits, and can assist in compliance with trial procedures 3. Participants, or in the Investigator's opinion, participant's legally acceptable representative, and a trial partner provide informed consent as required by IRB 4. Female participants must be either surgically sterilized or post-menopausal, defined as at least 1 year without menses as reported by the participant or have a negative serum pregnancy test 5. Willing to comply with trial procedures 6. Willing to communicate with trial personnel 7. Willing to undergo longitudinal follow-up visits at 1 and 2 years after the Imaging Visit (only for Part B) 8. CDR global score of 0.5 9. Participants with MCI due to suspected CTE must meet the diagnostic standards of possible traumatic encephalopathy syndrome as all the following criteria:

a. All of the following features are required: i) Persistence of symptoms for longer than 2 years; no other neurologic disorder that is more likely to account for all the clinical features; history of head trauma exposure, progressive course; and at least 1 supportive feature ii) History of head trauma exposure, typically associated with history of concussion, although may be limited to subconcussive trauma iii) Head trauma exposure is repetitive in nature iv) Demonstrated progressive course v) Delayed symptom onset vi) Self-report or observer report of cognitive dysfunction, confirmed with objective cognitive decline documented by results of formal neuropsychological testing. Cognitive decline typically affects more than 1 domain (neuropsychological tests, visuospatial, memory, and language) b. Only 1 of the following supportive features is required: i) Emotional dysregulation: including depression, anxiety, agitation, aggression, paranoid ideation, deterioration of interpersonal relationships, or suicidality ii) Behavioral change: including violence, poor impulse control, socially inappropriate behavior, avolition, apathy, change in personality, or comorbid substance abuse iii) Motor disturbance: including bradykinesia, tremor, rigidity, gait instability, dysarthria, dysphagia, or ataxia 9. Participants with MCI due to suspected AD must meet all the following criteria:

1. Diagnosis of MCI due to suspected AD according to workgroups of the Diagnostic Guidelines of the National Institute on Aging and Alzheimer's Association (NIA-AA)
2. Documented evidence of memory decline with gradual onset and slow progression for at least 1 year. If medically documented evidence is not available, an informant may provide confirmatory evidence
3. An MMSE-2 score of 22 to 30, inclusive, at the Screening Visit
4. Biomarker positive based on predefined plasma p-tau cutoff
5. Modified Hachinski Ischemic Score of ˂4 at the Screening Visit
6. Cognitive deficits do not occur exclusively in the context of delirium
7. Cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder, schizophrenia), or other medical condition (e.g., hypothyroidism)
8. Treated with a stable dosage regimen of acetylcholinesterase inhibitors (AchEI) and/or memantine for at least 4 months prior to the Screening Visit. Participants should be expected to remain on a stable dosage regimen of these medications for the duration of the trial. Participants who are not being treated with AchEI and/or memantine at the time of the Screening Visit due to contraindications or previous failed treatment with these medications are also eligible for inclusion, if it is expected that participants will not be treated with these medications for the duration of the trial.

Inclusion Criteria for Healthy Volunteers (Part A):

1. Medically healthy, at the age within 3 years of any participants with MCI due to suspected CTE or AD in Part A, and with no clinically relevant findings on physical examination or laboratory results
2. Participants must have a trial partner who has frequent interaction with them (approximately \>3-4 times per week), will be present for all clinic visits, and can assist in compliance with trial procedures
3. No cognitive impairment based upon cognitive assessment and as evaluated by the Investigator
4. No first-degree family history of early-onset AD or other neurodegenerative diseases (prior to age 65)
5. An MMSE-2 score ≥27.

Exclusion Criteria:

1. Pregnant or breastfeeding
2. Unable to remain still for duration of imaging procedure or have an inability to tolerate neuropsychological, clinical, or PET scan studies (e.g., head tremor that may cause head motion artifact, uncontrollable psychosis, acute suicidality)
3. History of stroke, transient ischemic attack, seizures, or other condition of the head or neck within 12 months prior to the Screening Visit that, in the Investigator's opinion, might affect circulation to the head or image interpretation
4. Preexisting major neurologic or other physical illness that could confound results (e.g., multiple sclerosis, diabetes, cancer)
5. Psychiatric disorder such as mania, schizophrenia, anxiety, or depression (Geriatric Depression Scale ≥10), which in the Investigator's opinion, might interfere with completing trial procedures
6. Condition or personal circumstance that, in the Investigator's opinion, might interfere with the collection of complete, good quality data
7. History of significant prescription drug, non-prescription drug, or alcohol abuse, including but not limited to marijuana, cocaine, heroin, or derivatives
8. Previously received F-18 FNT at any time, or any other investigational product (IP) within the past 30 days
9. History of allergic reactions to albumin, or severe anemia or cardiac failure in which case the use of albumin would be medically contraindicated
10. Unstable cardiac disease or uncontrolled hypertension (systolic blood pressure \[BP\] \>170 mmHg or diastolic BP \>100 mmHg)
11. Any use of benzodiazepines within 24 hours prior to all trial visits
12. Plan to take ibuprofen or naproxen within 5 days before the PET scan
13. Received any radioactive drugs or scans within the previous month or 10 half-lives of the drug, whichever is longer, or participated in imaging or other clinical research studies that might confound trial results
14. Implants (e.g., implanted cardiac pacemakers or defibrillators, insulin pumps, metallic ocular foreign body, implanted neural stimulators, CNS aneurysm clips, or other medical implants that have not been certified for MRI), a history of claustrophobia in MRI, or any contraindication for MRI
15. History of any CT/MRI finding such as mass lesions or brain infection that are unrelated to the trial
16. Participated in another clinical trial for an investigational agent (other than monoclonal antibody) and taken at least one dose of trial drug, unless confirmed as placebo, within 90 days prior to the Screening Visit. The end of a previous investigational trial is defined as the date of the last dose of trial drug
17. Monoclonal antibody treatment within the previous 180 days prior to the Screening Visit
18. Plan to receive treatment of aducanumab, lecanemab, or other potentially approved treatment options for Early AD during the trial.

Where this trial is running

Evanston, Illinois

• Endeavor Health Systems — Evanston, Illinois, United States (Recruiting)

Study contacts

• Principal investigator: Chad Yucus, MD — Endeavor Health System
• Study coordinator: Henry M Chilton, PharmD

Conditions Alzheimer Disease; Chronic Traumatic Encephalopathy