A Multiple Ascending Dose Trial of Emraclidine in Elderly Participants

Study Overview
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Brief Summary
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The primary purpose of the study is to evaluate the safety and tolerability of multiple ascending doses of emraclidine administered orally to elderly participants.

Official Title
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A Phase 1, Randomized, Placebo-controlled, Multiple Ascending Dose Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Emraclidine in Elderly Participants

Conditions
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Healthy Participants

Intervention / Treatment
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* Drug: Emraclidine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. 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). 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. Exclusion Criteria: 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. Current or past history of significant cardiovascular disease. 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. 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. Positive drug screen or a positive test for alcohol at Screening or Baseline Visits. 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 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). NOTE: Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Emraclidine Dose 1<br>Participants will receive emraclidine dose 1 or emraclidine-matching placebo tablets, orally, once daily (QD) up to Day 14. | Drug: Emraclidine<br>* Oral tablets<br>* Other names: PF-06852231;Drug: Placebo<br>* Oral tablets<br>|
| Experimental: Cohort 2: Emraclidine Dose 2<br>Participants will receive emraclidine dose 2 or emraclidine-matching placebo tablets, orally, QD up to Day 14. | Drug: Emraclidine<br>* Oral tablets<br>* Other names: PF-06852231;Drug: Placebo<br>* Oral tablets<br>|
| Experimental: Cohort 3: Emraclidine Dose 3<br>Participants will receive emraclidine dose 3 or emraclidine-matching placebo tablets, orally, QD up to Day 14. | Drug: Emraclidine<br>* Oral tablets<br>* Other names: PF-06852231;Drug: Placebo<br>* Oral tablets<br>|
| Experimental: Cohort 4: Emraclidine Dose 4<br>Participants will receive emraclidine dose 4 or emraclidine-matching placebo tablets, orally, QD up to Day 14. | Drug: Emraclidine<br>* Oral tablets<br>* Other names: PF-06852231;Drug: Placebo<br>* Oral tablets<br>|
| Experimental: Cohort 5: Emraclidine Dose 5<br>Participants will receive emraclidine dose 5 or emraclidine-matching placebo tablets, orally, QD up to Day 14. | Drug: Emraclidine<br>* Oral tablets<br>* Other names: PF-06852231;Drug: Placebo<br>* Oral tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) |  | Up to Day 28 | 
| Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters |  | Up to Day 17 | 
| Number of Participants With Clinically Significant Changes in Laboratory Assessments |  | Up to Day 17 | 
| Number of Participants With Clinically Significant Changes in Vital Sign Measurements |  | Up to Day 17 | 
| Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results |  | Up to Day 17 | 
| Changes in Suicidality Assessed Using the Columbia-Suicide Severity Rating Scale (C-SSRS) | The C-SSRS includes 'yes' or 'no' responses for assessment of suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe). Greater lethality or potential lethality of suicidal behaviors (endorsed on the behavior subscale) indicates increased risk. | Up to Day 17 | 
| Number of Participants With Clinically Significant Findings in Extrapyramidal Symptoms Evaluated Using the Simpson Angus Scale (SAS) | The SAS consists of a list of 10 symptoms of parkinsonism. Each item is rated on a 5-point scale, with a score of 0 representing absence of symptoms and a score of 4 representing a severe condition. The SAS total score is the sum of the scores for all 10 items. | Up to Day 14 | 
| Number of Participants With Clinically Significant Findings in Extrapyramidal Symptoms Evaluated Using the Abnormal Involuntary Movement Scale (AIMS) | The AIMS assessment consists of 10 items describing symptoms of dyskinesia. Each item is rated on a 5-point scale, with a score of 0 representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 10, awareness, severe distress). In addition, the AIMS includes 2 yes/no questions that address the participant's dental status. | Up to Day 14 | 
| Number of Participants With Clinically Significant Findings in Extrapyramidal Symptoms Evaluated Using the Barnes Akathisia Rating Scale (BARS) | The BARS consists of 4 items related to akathisia. The first 3 items are rated on a 4-point scale, with a score of 0 representing absence of symptoms and a score of 3 representing a severe condition. The global clinical evaluation is made on a 6-point scale, with a score of 0 representing absence of symptom and a score of 5 representing severe akathisia. | Up to Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Emraclidine and its Metabolite CV-0000364 |  | Days 1 and 14 | 
| Time to Maximum Plasma Concentration (Tmax) of Emraclidine and its Metabolite CV-0000364 |  | Days 1 and 14 | 
| Area Under the Plasma Concentration-time Curve (AUC) of Emraclidine and its Metabolite CV-0000364 |  | Days 1 and 14 | 
| Trough Plasma Concentration (Ctrough) of Emraclidine and its Metabolite CV-0000364 |  | Days 1 and 14 | 
| Peak to Trough Ratio (PTR) of Emraclidine and its Metabolite CV-0000364 |  | Day 14 | 
| Apparent Clearance of Drug From Plasma (CL/F) of Emraclidine |  | Days 1 and 14 | 
| Apparent Volume of Distribution During Terminal Phase (Vz/F) of Emraclidine |  | Days 1 and 14 | 
| Apparent Terminal Half-life (t1/2) of Emraclidine and its Metabolite CV-0000364 |  | Days 1 and 14 | 
| Accumulation Ratio (Rac) of Emraclidine and its Metabolite CV-0000364 | Rac would be calculated from AUC and Cmax of emraclidine and its metabolite. | Day 14 | 
| Metabolite to Parent Ratio of Emraclidine and its Metabolite CV-0000364 |  | Days 1 and 14 |