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Phase I-II

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

  • Study HIC#:2000027506
  • Last Updated:06/02/2022

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.

  • Age18 years - 45 years
  • GenderBoth
  • Start Date11/10/2020
  • End Date12/31/2023

Trial Purpose and Description

This study proposes to examine the effects of CVL-562 (PF-06412562), a dopamine-1 receptor partial agonist, on the neural signal of brain regions involved in cognition in patients with schizophrenia and related psychotic disorders. The primary objective of this study is to understand the neural circuit targets of this compound as it relates to improving cognition in schizophrenia, using a spatial working memory task (sWM). The secondary objective will quantify dose-related drug effects on sWM precision based on behavioral data collected during scanning and examine effects on functional connectivity.

All patients will be psychiatrically stable with early course (psychotic symptom onset within the past 5 years) schizophrenia spectrum disorder (e.g. schizophrenia, schizoaffective disorder, or schizophreniform disorder) and will have working memory deficits (defined as below average performance on the letter n-back task of the PennCNB battery). As part of the study, they will receive oral administration of specified doses of CVL-562 (PF-06412562), in a random order with repeated functional magnetic resonance imaging and cognitive testing during those visits. The most common side effects of this compound are nausea and headache. This is a multi-site study that requires the efforts of 4 study sites in total (Columbia, State University of New York Stony Brook, UPenn, and Yale).

Eligibility Criteria

Inclusion Criteria:

  • 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).
  • 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 5 years of the onset of psychosis based on the SCID-5.
  • Treatment seeking and willing to accept the constraints on treatment entailed by the study.
  • Working memory impairment based on below average (of healthy adult normative performance) performance on the PennCNB letter nback task (1).
  • Demonstrate a premorbid IQ of ≥80 based on the Penn Reading Assessment (PRA) (2). 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.
  • Be predominantly right-handed.
  • Clinically stable treatment for at least two months prior to randomization (no Emergency Room visits, 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 study, and willing to maintain an unchanged regimen during the study. If on depot anti-psychotics, participants must have stable dosing for at least two consecutive injections 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. non-copper 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.

Exclusion Criteria:

  • Any unstable medical, psychiatric, or neurological condition (including active or otherwise remarkable suicidal or homicidal ideation) that may necessitate urgent treatment. Active medical conditions that are minor or well controlled are not exclusionary if they do not affect risk to the patient, metabolism of study drug, or the study results (e.g. well controlled type II diabetes or hypertension) as per the judgement of the investigator.
  • 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 > 15 minutes, or of psychosurgery.
  • History of significant cardiac disease (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.
  • Current history of attention-deficit/hyperactivity disorder (ADHD) with pharmacologic treatment.
  • Meeting SCID-5 moderate or severe substance use disorder for any substance other than nicotine within the 3 months prior to the initial assessment. If substance use is positive on urine toxicology testing, participants will be excluded if unwilling to abstain until urine clears for the duration of the proposed enrollment period.
  • Positive urine toxicology testing for any substance other than marijuana at Visits 3-6.
  • Pregnancy or intention to become pregnant during the study.
  • Lactating/breast-feeding or intending to do so during the study
  • Any metal in the body (including a copper IUD) or other contraindication to MR imaging.
  • Severe claustrophobia, back pain, morbid obesity, or other condition that may make an extended MR session difficult or lead to excessive movement during the imaging session. Color blindness, strabismus or other uncorrectable visual problems. Those wearing glasses would be asked to use MRI-safe glasses.
  • Use of the following medication for at least 3 weeks prior to the study or during the study: Long-acting nighttime or daytime gamma aminobutyric acid-A (GABA-A) receptor facilitators; anticonvulsant medications except for those indicated for mood stabilization, or psychostimulants or medical cannabis. Participants can be reassessed for eligibility once they have been free of these medications for >3 weeks. Participants may take non-GABAergic sleep medications, short-acting GABA-A receptor facilitators (benzodiazepine, non-benzodiazepine) prior to and during the study.
  • Any change in type or dose of psychotropic medications within 3 weeks prior to initial visit or during study to avoid transient effects of medication regimen change. Medication type and dose will be carefully recorded and used as a covariate in analyses. Participants can be reassessed for eligibility once they have been on a stable dose of medication for >3 weeks.
  • PF-06412562 is metabolized by P450 CYP3A4. In order to avoid pharmacokinetic interactions, medications or substances that induce (barbiturate, carbamazepine, etc.) or are moderate-strong inhibitors (ketoconazole, etc.; grapefruit juice) are excluded if used for 3 weeks prior to and during study.
  • Active attempts to discontinue smoking, vaping or other nicotine products within the 3 weeks prior to study or during the study. Participants can be reassessed once quit attempt is stable.
  • Diastolic blood pressure >95 or <50 mmHg or systolic blood pressure > 170 or <80 mmHg with repeat measurement showing the same abnormality. History of allergy or other contraindication to the proposed pharmacotherapy.
  • Other medication treatment with which proposed pharmacotherapy is contraindicated, in the opinion of study psychiatrists or of a subject's prescribing psychiatrist.

Sub-Investigators

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