Trial to Study the Effect of CVL-231 on 24-Hour Ambulatory Blood Pressure in Participants With Schizophrenia

Study Overview
=================
Brief Summary
-----------------
The purpose of this trial is to characterize the effects of 2 oral doses (over 8 weeks total) of CVL-231 on ambulatory blood pressure and heart rate in patients with stable schizophrenia.

Official Title
-----------------
A Randomized, Double-Blind Trial to Study the Effect of CVL-231 on 24-Hour Ambulatory Blood Pressure in Participants With Schizophrenia

Conditions
-----------------
Blood Pressure, Schizophrenia

Intervention / Treatment
-----------------
* Drug: CVL-231


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female participants, ages 30 to 60 years, inclusive, at the time of signing the ICF. Primary diagnosis of schizophrenia per DSM-5, as confirmed by the MINI version 7.0.2. PANSS Total Score ≤70 at the time of signing the ICF and Check-in (Day -5). Exclusion Criteria: Current DSM-5 diagnosis other than schizophrenia including, but not limited to, mental retardation; schizoaffective disorder; major depressive disorder; schizophreniform disorder; psychotic depression; bipolar disorder; post-traumatic stress disorder; generalized anxiety disorder, obsessive compulsive disorder, eating disorders (bulimia, anorexia), or other anxiety disorders as a primary diagnosis (Note: Anxiety symptoms secondary to schizophrenia are allowed); delirium, dementia, amnestic, or other cognitive disorders. Acute depressive symptoms within 30 days prior to signing the ICF that require treatment with an antidepressant are exclusory. Additional excluded conditions include borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder. Any of the following: Schizophrenia considered resistant/refractory (defined as failure to respond to 2 or more courses of adequate pharmacological treatment) to antipsychotic treatment by history History of failure to respond to clozapine Response to clozapine treatment only History of extrapyramidal symptoms treated with a medication that required dose modification and/or new treatment within 6 months prior to signing the ICF. Current or past history of significant cardiovascular disease including any of the following: ischemic heart disease, myocardial infarction, cardiac valvulopathy, cardiac surgery revascularization (coronary artery bypass grafting) or stenting or percutaneous transluminal coronary angioplasty), hypertension, receiving medications to treat hypertension, orthostatic hypotension, angina, unstable angina, cerebrovascular accident or stroke or transient ischemic attack, pacemaker, atrial fibrillation, atrial flutter, paroxysmal atrial tachycardia, or non-sustained or sustained ventricular tachycardia, pulmonary arterial hypertension, sick sinus syndrome, Type 2 second-degree or third-degree atrioventricular block, congestive heart failure, personal or family history of sudden death or long QT syndrome, unexplained syncope or syncope within the last 3 years regardless of etiology. 12-lead ECG demonstrating any of the following at the Screening Visit or at Check-in (Day -5): QTcF interval >450 ms QRS interval >120 ms (unless right bundle branch block) PR interval >200 ms LVH with ST depressions and/or T wave inversions in leads with relatively tall R waves (ie, LVH with associated ST-T wave abnormalities) Type 2 second-degree or third-degree atrioventricular block Heart rate <45 bpm or >90 bpm Abnormal acute ECG changes (such as clinically significant ST depression or elevation or T wave inversion) Abnormal heart rhythm (atrial fibrillation and atrial flutter) Blood pressure measurements demonstrating any of the following at the Screening Visit and at Check-in (Day -5): Systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg o Blood pressure will be measured in a seated position after at least 3 minutes of rest. The average of 3 measurements will be used to determine eligibility. Orthostatic hypotension, defined as a decrease of ≥20 mmHg in systolic blood pressure after at least 2 minutes of standing compared with the average of the resting supine blood pressure measurement

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CVL-231 Dose Level 1<br>10 mg once daily | Drug: CVL-231<br>* CVL-231 is a brain penetrant mAChR activator that selectively binds to the M4 mAChR subtype while sparing other muscarinic receptor subtypes (M1, M2, M3, and M5). CVL-231 is being developed for treatment of psychosis in schizophrenia.<br>|
| Experimental: CVL-231 Dose Level 2<br>30 mg once daily | Drug: CVL-231<br>* CVL-231 is a brain penetrant mAChR activator that selectively binds to the M4 mAChR subtype while sparing other muscarinic receptor subtypes (M1, M2, M3, and M5). CVL-231 is being developed for treatment of psychosis in schizophrenia.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from Baseline to Week 8 in the 24-hour ambulatory SBP (Systolic Blood Pressure) |  | Baseline to week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean changes from Baseline to Weeks 4 and 8 in ambulatory SBP during daytime period |  | At weeks 4 and 8 | 
| Mean changes from Baseline to Weeks 4 and 8 in ambulatory SBP during nighttime period |  | At weeks 4 and 8 | 
| Mean change from Baseline to Week 4 in the 24-hour ambulatory SBP |  | At week 4 | 
| Mean change from Baseline to Weeks 4 and 8 in the 24-hour ambulatory DBP (Diastolic blood pressure) |  | At week 8 | 
| Mean change from Baseline to Weeks 4 and 8 in the 24-hour ambulatory HR (Heart rate) |  | At weeks 4 and 8 | 
| Number of treatment-emergent adverse events |  | Screening through day 84 | 
| Frequency of clinically significant changes in electrocardiograms |  | Baseline through day 84 | 
| Frequency of clinically significant changes in clinical laboratory assessments |  | Baseline through day 84 | 
| Frequency of clinically significant changes in vital sign measurements |  | Baseline through day 84 | 
| Frequency of clinically significant changes in physical examination results |  | Baseline through day 84 | 
| Frequency of clinically significant changes in neurological examination results |  | Baseline through day 84 | 
| Frequency of clinically significant findings in suicidality assessed using the C-SSRS (Columbia Suicide Severity Rating Scale) |  | Baseline through day 84 | 
| Frequency of clinically significant findings in extrapyramidal symptoms evaluated using the SAS (Simpson Angus Scale) |  | Baseline through day 84 | 
| Frequency of clinically significant findings in extrapyramidal symptoms evaluated using the AIMS (Abnormal Involuntary Movement Scale) |  | Baseline through day 84 | 
| Frequency of clinically significant findings in extrapyramidal symptoms evaluated using the BARS (Barnes Akathisia Rating Scale) |  | Baseline through day 84 | 
| Steady state CVL-231 Peak Plasma Concentration (Cmax) for CVL-231 and Metabolite (PF-06892787) |  | Baseline through day 84 | 
| Area under the plasma concentration-time curve over dosing interval (AUCτ) for CVL-231 and Metabolite (PF-06892787) |  | Baseline through day 84 |