Clinical trial NCT04805983: Evaluating the Safety, Tolerability, Pharmacokinetics and Receptor Occupancy of BMS-984923
Official title: An Open-Label, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Receptor Occupancy of BMS-984923
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Alzheimer Disease
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2021-03-18
Enrollment: 36
Sex: ALL
Minimum age (years): 50
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study will enroll four cohorts of 6 participants each. Study drug will be administered in sequentially increasing dose groups. For all 6 participants at a dose cohort, a safety assessment review will be completed prior to advancing the next higher dose level.
Primary purpose: BASIC_SCIENCE

Brief summary: This project seeks to develop a novel disease-modifying compound for Alzheimer's disease (AD).

Detailed description: The primary objective of this study is to evaluate the safety, tolerability, and pharmacokinetics of BMS-984923 in healthy participants. A secondary objective of this study is to conduct a receptor occupancy sub-study aimed at determining drug receptor occupancy at each dose using \[18F\]FPEB Positron Emission Tomography.

Eligibility criteria: Inclusion Criteria:

* No history of cognitive impairment
* Capable of providing written informed consent and willing to comply with all study requirements and procedures
* Participant is not pregnant, lactating, or of childbearing potential

  1. Non-childbearing potential for women is defined as postmenopausal (last natural menses greater than 24 months; menopausal status will be documented with serum follicle stimulating hormone (FSH) or documentation of bilateral tubal ligation or hysterectomy
  2. Male participants who are sexually active with a woman of child-bearing potential must agree to use condoms during the trial and for 3 months after the last dose unless the woman is using an acceptable means of birth control. Acceptable forms of birth control include abstinence, birth control pills, or any double combination of: intrauterine device (IUD), male or female condom, diaphragm, sponge, and cervical cap.
  3. Male participants must also agree not to donate sperm for 90 days after the last dose. -
* Glasgow Coma Scale Score of 15 (97)
* Clinical Dementia Rating Score of 0 (93)
* Has a reliable study partner who has frequent contact with the participant (e.g., average of 10 hours per week or more), who can be available for study partner assessments, who can accompany the participant for 48 hours, without absence, after discharge from Visit 2.

Score on the Mini Mental Status Exam \> 26 (95)

* Objective memory scores within normal range for age evidenced by a score no more than 1.5 standard deviations below the education adjusted cutoff on the Logical Memory II subscale (Delayed Paragraph Recall) from the Wechsler Memory Scale - Revised (the maximum score is 25).

  1. \>8 for 16 or more years of education
  2. \>4 for 8-15 years of education
  3. \>2 for 0-7 years of education

Receptor Occupancy Substudy Eligibility Criteria

* Eligibility for and enrollment in Main Study
* Participant consent to the optional substudy

Exclusion Criteria:

* Body mass index (BMI) ≥ 35 kg/m2 or body weight \< 50 kg.
* Significant cerebrovascular disease: Modified Hachinski score \> 4.
* Any significant neurologic disease, such as AD, Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities.
* Major depression, bipolar disorder as described in DSM-IV within the past 1 year.
* Psychotic features, agitation or behavioral problems within 3 months, which could lead to difficulty complying with the protocol.
* History of schizophrenia (DSM IV criteria).
* History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria).
* Clinically significant or unstable medical condition, including uncontrolled hypertension, uncontrolled diabetes, or significant cardiac, pulmonary, renal, hepatic, endocrine, or other systemic disease in the opinion of the PI, may either put the patient at risk because of participation in the study, or influence the results, or the patient's ability to participate in the study.
* Clinically significant abnormalities in B12 or Thyroid Function Tests that might interfere with the study.

Use of psychoactive medications (typical neuroleptics, narcotic analgesics, antiparkinsonian medications, systemic corticosteroids, or medications with significant central anticholinergic activity) within 2 weeks or 5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial.

* Use of medications with significant CYP1A2, 2D6, or 3A4 inhibitor or inducer activity (See appendix for a list of these medications) within 2 weeks or 5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial.
* Use of anticoagulants within 30 days or 5 half-lives (whichever is greater) prior to study drug administration and for the duration of the trial.
* Use of investigational amyloid lowering therapies within 2 months prior to study drug administration and for the duration of the trial.
* Use of another investigational agent within 30 days or 5 half-lives (whichever is greater) prior to screening and for the duration of the trial.
* Neutropenia defined as absolute neutrophils count of \< 1,500/microliter.
* Thrombocytopenia defined as platelet count \< 100,000/microliter.
* Clinically significant abnormalities in screening laboratories, including Aspartate aminotransferase (AST) \>1.5 times upper limit of normal (ULN); Alanine aminotransferase (ALT) \>1.5 times ULN; Total bilirubin \>1.5 times ULN; Serum creatinine \>2.0 times ULN.

Primary outcomes:
measure: Count of Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to 7 days after last dose
measure: Count of Lab Abnormalities
timeFrame: Up to 7 days after last dose
measure: Count of Clinically Significant Changes in Safety Assessments
timeFrame: Up to 7 days after last dose
measure: Maximum Plasma Concentration (Cmax)
timeFrame: Up to 7 days after last dose
measure: Time of Cmax (Tmax)
timeFrame: Up to 7 days after last dose
measure: Area Under the Curve From 0 to 24h (AUC 24h)
timeFrame: Up to 7 days after last dose
Secondary outcomes:
measure: Receptor Occupancy
timeFrame: Up to 24 hours after last dose
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University
state: Connecticut
Study officials:
affiliation: Assistant Professor of Psychiatry; Associate Director, Alzheimer's Disease Research Unit; Faculty, Alzheimer's Disease Research Center (ADRC)
name: Adam Mecca, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: