A Translational and Neurocomputational Evaluation of a Dopamine Receptor 1 Partial Agonist for Schizophrenia

NCT04457310 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 20000275061U01MH121766-01
• Study Type: interventional
• Target: 112
• Locations: 1 country
• Sites: 4

Brief Summary

This study will test whether CVL-562 (PF-06412562), a dopamine 1 partial agonist novel compound, affects working memory neural circuits in patients with early episode schizophrenia. The overall aim is to establish neuroimaging biomarkers of the Dopamine Receptor 1/Dopamine Receptor 5 Family (D1R/D5R) target engagement to accelerate development of D1R/D5R agonists in humans to treat cognitive impairments that underlie functional disability in schizophrenia, a key unaddressed clinical and public health concern.

Conditions

Early Course Schizophrenia Spectrum Disorder

Outcome Measures

Primary Outcomes (4)

• Neural Activity Across Brain Regions During a Spatial Working Memory (sWM) Task- Condition 2

  Neural activity will be measured by blood oxygen level dependent (BOLD) signal that will be assessed during functional magnetic resonance (fMRI) sessions. During each fMRI session, subjects will participate in a sWM task that involves the ability to keep a spatial location in mind over a short period of time. The sWM task includes four conditions: 1) only sWM; 2) a motor response without sWM; 3) sWM with a distracter presented near the original memory location; and 4) sWM with a distractor presented far away from the original memory location. For each condition, BOLD signal will be assessed over 20 timepoints, each measuring for 0.8 seconds \[total 16s\]. Each subject will undergo 5 fMRI sessions, one at each dose.

  Up to two hours for each fMRI session

• Neural Activity Across Brain Regions During a Spatial Working Memory (sWM) Task- Condition 1

  Neural activity will be measured by blood oxygen level dependent (BOLD) signal that will be assessed during functional magnetic resonance (fMRI) sessions. During each fMRI session, subjects will participate in a sWM task that involves the ability to keep a spatial location in mind over a short period of time. The sWM task includes four conditions: 1) only sWM; 2) a motor response without sWM; 3) sWM with a distracter presented near the original memory location; and 4) sWM with a distractor presented far away from the original memory location. For each condition, BOLD signal will be assessed over 20 timepoints, each measuring for 0.8 seconds \[total 16s\]. Each subject will undergo 5 fMRI sessions, one at each dose.

  Up to two hours for each fMRI session

• Neural Activity Across Brain Regions During a Spatial Working Memory (sWM) Task- Condition 3

  Neural activity will be measured by blood oxygen level dependent (BOLD) signal that will be assessed during functional magnetic resonance (fMRI) sessions. During each fMRI session, subjects will participate in a sWM task that involves the ability to keep a spatial location in mind over a short period of time. The sWM task includes four conditions: 1) only sWM; 2) a motor response without sWM; 3) sWM with a distracter presented near the original memory location; and 4) sWM with a distractor presented far away from the original memory location. For each condition, BOLD signal will be assessed over 20 timepoints, each measuring for 0.8 seconds \[total 16s\]. Each subject will undergo 5 fMRI sessions, one at each dose.

  Up to two hours for each fMRI session

• Neural Activity Across Brain Regions During a Spatial Working Memory (sWM) Task- Condition 4

  Neural activity will be measured by blood oxygen level dependent (BOLD) signal that will be assessed during functional magnetic resonance (fMRI) sessions. During each fMRI session, subjects will participate in a sWM task that involves the ability to keep a spatial location in mind over a short period of time. The sWM task includes four conditions: 1) only sWM; 2) a motor response without sWM; 3) sWM with a distracter presented near the original memory location; and 4) sWM with a distractor presented far away from the original memory location. For each condition, BOLD signal will be assessed over 20 timepoints, each measuring for 0.8 seconds \[total 16s\]. Each subject will undergo 5 fMRI sessions, one at each dose.

  Up to two hours for each fMRI session

Secondary Outcomes (6)

• Performance During Spatial Working Memory (sWM) Task

  Up to two hours for each fMRI session.

• Association Between Neural Activity and Task Performance

  Up to two hours for each fMRI session.

• Functional Connectivity Across Brain Regions With the Fronto-parietal Network During sWM Task

  Up to two hours for each fMRI session.

• Resting State Global Brain Functional Connectivity

  Up to two hours for each fMRI session.

• Proportion of Participants With Change in Blood Oxygen Level Dependent (BOLD) Signal During Spatial Working Memory (sWM) Task.

  Up to two hours for each fMRI session.

Study Arms (5)

CVL-562 (PF-06412562) 1 mg

EXPERIMENTAL

Each subject will complete 5 test visits each involving the administration of CVL-562 (PF-06412562) (at different doses) or placebo. Subjects will be randomized to the order of doses of CVL-562 (PF-06412562) (1 mg, 4 mg, 15 mg, or 25 mg) or placebo for the next 5 visits. The randomization will assign 75% of patients to the highest dose on the last visit and 25% would receive the highest dose on one of the other four visits. Only the highest dose (25 mg) will be subject to this pseudo-randomization strategy; all other doses will be randomly distributed.

Drug: CVL-562 (PF-06412562) 1 mg

CVL-562 (PF-06412562) 4 mg

EXPERIMENTAL

Each subject will complete 5 test visits each involving the administration of CVL-562 (PF-06412562) (at different doses) or placebo. Subjects will be randomized to the order of doses of CVL-562 (PF-06412562) (1 mg, 4 mg, 15 mg, or 25 mg) or placebo for the next 5 visits. The randomization will assign 75% of patients to the highest dose on the last visit and 25% would receive the highest dose on one of the other four visits. Only the highest dose (25 mg) will be subject to this pseudo-randomization strategy; all other doses will be randomly distributed.

Drug: CVL-562 (PF-06412562) 4 mg

CVL-562 (PF-06412562) 15 mg

EXPERIMENTAL

Each subject will complete 5 test visits each involving the administration of CVL-562 (PF-06412562) (at different doses) or placebo. Subjects will be randomized to the order of doses of CVL-562 (PF-06412562) (1 mg, 4 mg, 15 mg, or 25 mg) or placebo for the next 5 visits. The randomization will assign 75% of patients to the highest dose on the last visit and 25% would receive the highest dose on one of the other four visits. Only the highest dose (25 mg) will be subject to this pseudo-randomization strategy; all other doses will be randomly distributed.

Drug: CVL-562 (PF-06412562) 15 mg

CVL-562 (PF-06412562) 25 mg

EXPERIMENTAL

Each subject will complete 5 test visits each involving the administration of CVL-562 (PF-06412562) (at different doses) or placebo. Subjects will be randomized to the order of doses of CVL-562 (PF-06412562) (1 mg, 4 mg, 15 mg, or 25 mg) or placebo for the next 5 visits. The randomization will assign 75% of patients to the highest dose on the last visit and 25% would receive the highest dose on one of the other four visits. Only the highest dose (25 mg) will be subject to this pseudo-randomization strategy; all other doses will be randomly distributed.

Drug: CVL-562 (PF-06412562) 25 mg

Placebo

PLACEBO COMPARATOR

Each subject will complete 5 test visits each involving the administration of CVL-562 (PF-06412562) (at different doses) or placebo. Subjects will be randomized to the order of doses of CVL-562 (PF-06412562) (1 mg, 4 mg, 15 mg, or 25 mg) or placebo for the next 5 visits. The randomization will assign 75% of patients to the highest dose on the last visit and 25% would receive the highest dose on one of the other four visits. Only the highest dose (25 mg) will be subject to this pseudo-randomization strategy; all other doses will be randomly distributed.

Other: Placebo

Interventions

CVL-562 (PF-06412562) 1 mg DRUG

Each subject will complete 5 test visits each involving the administration of CVL-562 (PF-06412562) (at different doses) or placebo. Each test visit will be separated by at least 48 hours (six half-lives of CVL-562 (PF-06412562)).

CVL-562 (PF-06412562) 1 mg

CVL-562 (PF-06412562) 4 mg DRUG

Each subject will complete 5 test visits each involving the administration of CVL-562 (PF-06412562) (at different doses) or placebo. Each test visit will be separated by at least 48 hours (six half-lives of CVL-562 (PF-06412562)).

CVL-562 (PF-06412562) 4 mg

CVL-562 (PF-06412562) 15 mg DRUG

Each subject will complete 5 test visits each involving the administration of CVL-562 (PF-06412562) (at different doses) or placebo. Each test visit will be separated by at least 48 hours (six half-lives of CVL-562 (PF-06412562)).

CVL-562 (PF-06412562) 15 mg

CVL-562 (PF-06412562) 25 mg DRUG

Each subject will complete 5 test visits each involving the administration of CVL-562 (PF-06412562) (at different doses) or placebo. Each test visit will be separated by at least 48 hours (six half-lives of CVL-562 (PF-06412562)).

CVL-562 (PF-06412562) 25 mg

Placebo OTHER

Each subject will complete 5 test visits each involving the administration of CVL-562 (PF-06412562) (at different doses) or placebo. Each test visit will be separated by at least 48 hours (six half-lives of CVL-562 (PF-06412562)).

Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Between the ages of 18 (including 18 years of age) and 45 (up to 45 years and 11 months) at the time of baseline study visit.
• Able to provide informed consent (as established by consent interview), and voluntary, signed informed consent prior to the performance of any study-specific procedures
• Willing and able to perform study-relevant clinical assessments and Magnetic Resonance Imaging (MRI) as assessed by research staff.
• Meet Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for schizophrenia, schizoaffective disorder, or schizophreniform disorder on the basis of the Structured Clinical Interview for DSM-5 (SCID-5).
• Be within 10 years of the onset of psychosis based on clinical assessment at the time of Visit 1.
• Treatment seeking and willing to accept the constraints on treatment entailed by the study.
• Able to demonstrate a basic ability to follow spatial working memory task instructions and perform necessary related motor functions.
• Demonstrate a premorbid IQ of ≥80 based on the Penn Reading Assessment (PRA). The PRA correlates with other measures of IQ including the Wide Range Achievement Test (WRAT), but is computerized, based in the laboratory of co-investigators Ruben C. Gur and Raquel E. Gur, and brief to administer, allowing us to lessen the assessment burden on an already lengthy first visit.
• Be fluent in English as assessed by research staff.
• Clinically stable treatment for at least two months prior to Visit 1 (no hospitalizations, or current suicidal/homicidal active ideation, intent, or plan).
• On a stable psychotropic medication regimen (can include no psychotropic medications) for at least 3 weeks prior to Visit 1, and willing to maintain an unchanged regimen during the study. If on depot antipsychotics, participants must have stable dosing for at least two consecutive injections (including the most recent one) as the most recent injections. If on Invega Trinza, there must be no plans to change dosing during the course of the study.
• For women of child bearing potential, no intention to become pregnant during the study period, and agreement to use a reliable method of birth control (e.g. Intra-Uterine Device (IUD), hormonal contraception, abstinence, condoms) during the study period. Women will be asked to continue their method of contraception for 1 month after receiving their final dose of medication. Any individual who becomes pregnant during the study will be immediately removed, and discussion of the risks and benefits of ongoing pharmacotherapy will proceed on purely clinical grounds.

You may not qualify if:

• Be currently treated with any of the following: olanzapine, clozapine, ziprasidone or asenapine, in order to avoid prominent D1 receptor effects.
• Any major neurological disease, brain injury, epilepsy, or history of severe head trauma, including concussion with loss of consciousness greater than or equal to \> 15 minutes, or of psychosurgery.
• History of significant cardiac disease (ex: ischemia, arrhythmia).
• Any clinically significant abnormality on baseline medical screening tests (electrocardiogram (EKG), complete blood count with differential (CBC), complete metabolic profile (CMP).
• Hepatitis B or C (by report or testing) in the presence of abnormal liver function tests
• Human Immunodeficiency Virus (HIV) or Acquired Immune Deficiency Syndrome (AIDS) (by report or by testing) due cognitive effects of HIV and AIDS.
• Baseline EKG showing prolonged QTc interval (\>450 for males, \>470 for females, Framingham correction(3)), with repeat measurement showing the same abnormality.
• Current mood episode meeting criteria for a major depressive episode or a manic or hypomanic episode.
• History of electroconvulsive therapy (ECT) or treatment with neurostimulation in the past 6 months, or with plans to begin either such treatment during the study.
• History of ADHD pre-morbid to the onset of psychosis or other psychiatric illnesses that may be accompanied by cognitive impairments.
• Meeting SCID-5 moderate or severe substance use disorder for any substance other than nicotine within the 3 months prior to the initial assessment.
• Positive urine toxicology testing for any substance other than marijuana or those prescribed for medical reasons at Visits 1-6.
• Pregnancy or intention to become pregnant during the study.
• Lactating/breast-feeding or intending to do so during the study
• Any non-MRI compatible metal in the body or other contraindication to MR imaging. A copper IUD is allowable if permitted by local MRI practices.

Sponsors & Collaborators

• Yale University: lead
• Columbia University: collaborator
• University of Pennsylvania: collaborator
• State University of New York Stony Brook: collaborator
• Cerevel Therapeutics, LLC: collaborator
• National Institute of Mental Health (NIMH): collaborator

Study Sites (4)

Yale University

New Haven, Connecticut, 06511, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Stony Brook University

Stony Brook, New York, 11794, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Limitations and Caveats

Secondary outcome data is unavailable at this time due to the ongoing restrictions at the Columbia/New York State Psychiatric Institute (NYSPI) site, preventing data access and sharing described in the approved GCE.

Results Point of Contact

• Title: John Krystal, MD
• Organization: Yale University

john.krystal@yale.edu

203-785-6396

Study Officials

• John Krystal, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 29, 2020
• First Posted: July 7, 2020
• Study Start: March 2, 2021
• Primary Completion: March 22, 2024
• Study Completion: March 22, 2024
• Last Updated: October 15, 2025
• Results First Posted: October 15, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Time Frame: Six months after publication.
• Access Criteria: All neuroimaging data will be shared through the National Institute of Mental Health Data Archive (NDA). All requests for accessing these data will be reviewed by the National Institute of Mental Health.

Locations

US (4)