Clinical trial NCT05644977: A Multiple Dose Trial of Emraclidine in Elderly Participants and in Participants With Dementia Due to Alzheimer's Disease
Official title: A Phase 1, Randomized, Placebo-controlled Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Emraclidine Following Multiple Oral Doses in Healthy Elderly Participants (Part A) and to Evaluate the Safety and Tolerability of Emraclidine in Participants With Dementia Due to Alzheimer's Disease (Part B)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Participants
Alzheimer's Disease Dementia
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2022-12-09
Enrollment: 17
Sex: ALL
Minimum age (years): 55
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The primary purpose of the study is to evaluate the safety and tolerability of emraclidine administered orally to healthy elderly participants in Part A (multiple ascending doses) and participants with dementia due to Alzheimer's disease (AD) in Part B.


Eligibility criteria: Inclusion Criteria:

Cohorts 1 to 5 (Part A)

1. Male participants and female participants of nonchildbearing potential, ages 65 to 85 years, inclusive.
2. Healthy as determined by medical evaluation, including medical and psychiatric history, physical and neurological examinations, ECG, vital sign measurements, and laboratory test results, as evaluated by the investigator.
3. Body mass index of 17.5 to 32.0 kilograms per square meter (kg/m\^2), inclusive, and total body weight \>45 kg (100 pounds \[lb\]) at Screening.
4. Female participants will be of nonchildbearing potential, defined as follows:

   • Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause, and confirmed with a serum follicle-stimulating hormone level \>40 international units per milliliter (IU/mL).
5. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the full protocol.

Cohort 6 (Part B)

1. Male participants and female participants of nonchildbearing potential, ages 55 to 90 years, inclusive.
2. Have a clinical diagnosis of possible or probable Alzheimer's disease dementia according to the 2011 National Institute on Aging - Alzheimer's Association (NIA-AA) clinical criteria at the Screening Visit; diagnosis must be stable for at least 6 months prior to signing the ICF.
3. Have a Mini-Mental State Examination (MMSE) score of 8 through 26, inclusive, at the Screening Visit.
4. Have prior neuroimaging evidence (Computed Tomography \[CT\] or Magnetic resonance imaging \[MRI\] completed within the 3 years prior to signing the ICF) collected during or subsequent to the onset of dementia symptoms to rule out other central nervous system disorders that could account for the dementia syndrome.
5. Currently receiving oral symptomatic treatment for dementia (i.e., cholinesterase inhibitor and/or memantine), must have been on a stable regimen for at least 6 weeks prior to signing ICF and be willing to maintain a stable dose for the duration of the trial.
6. Body mass index of 17.5 to 40.0 kg/m2, inclusive, and total body weight \>45 kg (100 lb) at Screening.

Exclusion Criteria:

All Cohorts

1. "Yes" responses for any of the following items on the C-SSRS (within the past 6 months):

   * Suicidal Ideation Item 4 (Active Suicidal Ideation with Some Intent to Act, without Specific Plan)
   * Suicidal Ideation Item 5 (Active Suicidal Ideation with Specific Plan and Intent) "Yes" responses for any of the following items on the C-SSRS (within past 2 years):
   * Any of the Suicidal Behavior items (Actual Attempt, Interrupted Attempt, Aborted Attempt, Preparatory Acts or Behavior). Serious risk of suicide in the opinion of the investigator is also exclusionary.
2. Diagnosis of moderate to severe substance or alcohol-use disorder (excluding nicotine or caffeine) as per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria within 12 months prior to signing the ICF.
3. Positive drug screen or a positive test for alcohol at Screening or Baseline Visits.
4. Any of the following clinical laboratory test results at the Screening Visit (as assessed by the central laboratory) and at Check-in (Day -1; as assessed by the local laboratory), and confirmed by a single repeat measurement, if deemed necessary:

   * aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.0 × upper limit normal (ULN)
   * Total bilirubin \>1.5 × ULN. If Gilbert's syndrome is suspected, total bilirubin \>1.5 × ULN is acceptable if the conjugated or direct bilirubin fraction is \<20% of total bilirubin.

Cohorts 1 to 5 (Part A)

1. Current or past history of significant pulmonary, gastrointestinal, renal, hepatic, metabolic, genitourinary, endocrine (including diabetes mellitus), malignancy (except for basal cell carcinoma of the skin and cervical carcinoma in situ, at the discretion of the investigator), hematological, immunological, neurological, or psychiatric disease that, in the opinion of the investigator or medical monitor, could compromise either participant safety or the results of the trial.
2. Current or past history of significant cardiovascular disease.
3. Estimated glomerular filtration rate \<60 milliliters per minute (mL/min)/1.73 m\^2, as calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2021) equation at the Screening Visit or Check-in (Day -1).

Cohort 6 (Part B)

1. Has either of the following:

   * History of major depressive episode with psychotic features during the 12 months prior to signing the ICF
   * History of a diagnosis of bipolar disorder, schizophrenia, or schizoaffective disorder
2. Has evidence of a clinically relevant neurological disorder other than possible or probable Alzheimer's disease such as, but not limited to, the following:

   * History of ischemic stroke within 12 months prior to signing the ICF or any evidence of hemorrhagic stroke
   * History of cerebral amyloid angiopathy, epilepsy, or central nervous system neoplasm
3. Estimated glomerular filtration rate \<60 mL/min/1.73 m2, as calculated using the CKD-EPI 2021 equation the Screening Visit.

NOTE: Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: Up to Day 28
measure: Part A: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters
timeFrame: Up to Day 17
measure: Part A: Number of Participants With Clinically Significant Changes in Laboratory Assessments
timeFrame: Up to Day 17
measure: Part A: Number of Participants With Clinically Significant Changes in Vital Sign Measurements
timeFrame: Up to Day 17
measure: Part A: Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results
timeFrame: Up to Day 17
measure: Part A: Changes in Suicidality Assessed Using the Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: Up to Day 17
measure: Part A: Number of Participants With Clinically Significant Findings in Extrapyramidal Symptoms Evaluated Using the Simpson Angus Scale (SAS)
timeFrame: Up to Day 14
measure: Part A: Number of Participants With Clinically Significant Findings in Extrapyramidal Symptoms Evaluated Using the Abnormal Involuntary Movement Scale (AIMS)
timeFrame: Up to Day 14
measure: Part A: Number of Participants With Clinically Significant Findings in Extrapyramidal Symptoms Evaluated Using the Barnes Akathisia Rating Scale (BARS)
timeFrame: Up to Day 14
measure: Part B: Number of Participants With TEAEs, Clinically Significant Changes in ECG Parameters, Laboratory Assessments, Vital Sign Measurements, and Physical and Neurological Examination Results
timeFrame: Up to Day 28
measure: Part B: Changes in Suicidality Assessed Using the C-SSRS
timeFrame: Up to Day 28
measure: Part B: Number of Participants With Clinically Significant Findings in Extrapyramidal Symptoms
timeFrame: Up to Day 28
Secondary outcomes:
measure: Part A: Maximum Observed Plasma Concentration (Cmax) of Emraclidine and its Metabolite CV-0000364
timeFrame: Days 1 and 14
measure: Part A: Time to Maximum Plasma Concentration (Tmax) of Emraclidine and its Metabolite CV-0000364
timeFrame: Days 1 and 14
measure: Part A: Area Under the Plasma Concentration-time Curve (AUC) of Emraclidine and its Metabolite CV-0000364
timeFrame: Days 1 and 14
measure: Part A: Trough Plasma Concentration (Ctrough) of Emraclidine and its Metabolite CV-0000364
timeFrame: Days 1 and 14
measure: Part A: Peak to Trough Ratio (PTR) of Emraclidine and its Metabolite CV-0000364
timeFrame: Day 14
measure: Part A: Apparent Clearance of Drug From Plasma (CL/F) of Emraclidine
timeFrame: Days 1 and 14
measure: Part A: Apparent Volume of Distribution During Terminal Phase (Vz/F) of Emraclidine
timeFrame: Days 1 and 14
measure: Part A: Apparent Terminal Half-life (t1/2) of Emraclidine and its Metabolite CV-0000364
timeFrame: Days 1 and 14
measure: Part A: Accumulation Ratio (Rac) of Emraclidine and its Metabolite CV-0000364
timeFrame: Day 14
measure: Part A: Metabolite to Parent Ratio of Emraclidine and its Metabolite CV-0000364
timeFrame: Days 1 and 14
measure: Part B: Plasma Concentrations of Emraclidine and its Metabolite CV-0000364
timeFrame: Days 1 to 28
Other outcomes:
Locations:
city: Cypress
country: United States
facility: Cypress, California
state: California
city: San Diego
country: United States
facility: San Diego, California
state: California
city: Hialeah
country: United States
facility: Hialeah, Florida
state: Florida
city: Decatur
country: United States
facility: Decatur, Georgia
state: Georgia
city: Honolulu
country: United States
facility: Honolulu, Hawaii
state: Hawaii
city: Overland Park
country: United States
facility: Overland Park, Kansas
state: Kansas
city: Farmington Hills
country: United States
facility: Farmington Hills, Michigan
state: Michigan
city: Marlton
country: United States
facility: Marlton, New Jersey
state: New Jersey
city: Princeton
country: United States
facility: Princeton, New Jersey
state: New Jersey
city: Staten Island
country: United States
facility: Staten Island, New York
state: New York
city: North Canton
country: United States
facility: North Canton, Ohio
state: Ohio
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References: