A Translational and Neurocomputational Evaluation of a Dopamine Receptor 1 Partial Agonist for Schizophrenia
Phase: PHASE2
Conditions: Early Course Schizophrenia Spectrum Disorder
Sponsor: Yale University

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STUDY PROTOCOL 
 
 
 
STUDY TITLE:  A Translational and Neurocomputational Evaluation of a D1R 
Partial Agonist for Schizophrenia 
 
Collaborating Sites: Columbia University/Research Foundation for Mental 
Hygiene (RFMH), State University of New York (SUNY) Stony Brook, University 
of Pennsylvania, Yale University 
  
  
 
ClinicalTrials.gov Identifier:  NCT04457310 
 
IND Number: 147842 
 
IND HOLDER:  John Krystal, M.D. 
 
Investigational Product:  CVL-562 
 
Advarra Protocol Number: Pr00041355  
 
Version and Date: Version 6.1, 08/04/2025 
 
Yale Principal Investigator:  Name: John Krystal, M.D. 
 
Address: 300 George Street, Suite 901 
  
 
 
    New Haven, CT 06511 
 
Telephone:  203-785-6396 
 
Fax: 203-785-6196 
 
email: john.krystal@yale.edu 
 
 
 
 
 
 
 

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1. ACKNOWLEDGMENT OF THE INVESTIGATORS 
 
 
 
 
PROTOCOL TITLE: A Translational and Neurocomputational Evaluation of a 
D1R Partial Agonist for Schizophrenia 
 
 
Version Date: __________________ 
 
 
Acknowledgement of the Investigator: 
 
1.) I have read this protocol and agree that the study is ethical 
 
2.) I agree to conduct the study as outlined and in accordance with all 
applicable regulations and guidelines 
 
3.) I agree to maintain the confidentiality of all information received or 
developed in connection with this protocol 
 
 
            
        
Signature of Investigator:                                               Date:  
 
 
 
Name of Investigator (Printed or Typed) 
 
 
 
 

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2. TABLE OF CONTENTS 
1. Acknowledgment of the Investigators 
2 
2. TABLE OF CONTENTS 
3 
3. ABBREVIATIONS 
5 
4. TRIAL SUMMARY 
7 
1. TRIAL DESIGN / STUDY SCHEMA 
12 
2. RATIONALE AND BACKGROUND 
13 
2.1 
Disease 
13 
2.2 
Pharmaceutical and Therapeutic Background 
14 
2.3 
Rationale for Selected Patients 
17 
2.4 
Rationale for Dose Selection/Regimen 
18 
3. STATEMENT OF PURPOSE/OBJECTIVES 
19 
3.1 
Primary Endpoint 
19 
3.2 
Secondary Endpoint 1  
19 
3.4 
Secondary Endpoint 3 
19 
3.5 
Secondary Endpoint 4 
19 
3.6 
Secondary Endpoint 5 
20 
3.7 
Secondary Endpoint 6 
20 
3.8 
Exploratory Endpoint 
20 
4. STUDY PLAN AND PROCEDURES 
20 
4.1 
Study Design Overview 
20 
4.2 
Treatment Regimen 
23 
4.3 
Special Procedures Related to COVID-19 
26 
4.4 
Randomization 
27 
4.5 
Side Effect Profiles from Prior Studies 
27 
5. Concomitant Medications 
28 
5.1 
Diet and Other Considerations 
28 
5.2 
Rescue Medication and Supportive Care 
29 
6. PATIENT POPULATION 
29 
6.1 
Inclusion Criteria 
29 
6.2 
Exclusion Criteria 
30 
7. Description of Procedures 
32 
7.1 
Study Entry / Registration 
32 
7.2 
Safety and Data Capture of Laboratory Procedures and Assessments 
32 
7.3 
Special Safety Considerations 
37 
8. SCHEDULE OF ASSESSMENTS 
41 
9. ASSESSING AND REPORTING ADVERSE EVENTS 
43 
9.1 
Definition 
43 
9.2 
Evaluating Adverse Events Including Serious Adverse Events 
44 
9.3 
Procedures 
45 
10. STATISTICAL CONSIDERATIONS 
47 
10.1 
Statistical Design and Power 
47 

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11. ADMINISTRATIVE AND REGULATORY 
51 
11.1 
Multicenter Management and Coordination 
51 
11.2 
Data safety and monitoring plan (DSMP) 
51 
11.3 
Confidentiality & Security of Data 
53 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. ABBREVIATIONS 
 
ADHD 
Attention Deficit Hyperactivity Disorder 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ANOVA 
Analysis of Variance 
BOLD 
Blood Oxygen Level Dependent 
CBC 
Complete Blood Count 
CDSS 
Calgary Depression Scale for Schizophrenia 
CIFTI 
Connectivity Informatics Technology Initiative 
CMP 
Complete Metabolic Profile 
CNS 
Central Nervous System 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
D1R 
Dopamine Receptor 1 
D1R/D5R 
Dopamine Receptor 1/Dopamine Receptor 5 Family 
DICOM 
Digital Imaging and Communications in Medicine 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders-5 
DSMB 
Data Safety Monitoring Board 
EKG 
Electrocardiogram 
FC 
Functional Connectivity 
FDA 
Food and Drug Administration 
fMRI 
Functional Magnetic Resonance Imaging 
FTND 
Fagerstrom Test for Nicotine Dependence 
GABA-A 
gamma aminobutyric acid-A 
GBC 
Global Brain Connectivity 
GCP 
Good Clinical Practice 
GUID 
Globally Unique Identifier 
hcG 
Human Chorionic Gonadotropin 
HIC 
Human Investigations Committee 
HIV 
Human Immunodeficiency Virus 
HCP 
Human Connectome Project 
HRF 
Hemodynamic Response Function 
ICH 
International Conference on Harmonization 
IRB 
Investigational Review Board 
IRF 
Impulse Response Function 
IUD 
Intrauterine Device 
Ki 
Inhibitory constant 
MRI 
Magnetic Resonance Imaging 
NDA 
NIMH Data Archive 
NIFTI 
Neuroimaging Informatics Technology Initiative  
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
PANSS 
Positive and Negative Syndrome Scale 
PennCNB 
Penn Computerized Neurocognitive Battery 
PFC 
Prefrontal Cortex 

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PI 
Principal Investigator 
PRA 
Penn Reading Assessment 
QTc 
Corrected QT interval on an electrocardiogram 
rsfMRI 
Resting State Functional Magnetic Resonance Imaging 
SAE 
Serious Adverse Event 
SCID-V 
Structured Clinical Interview for DSM-5 
sWM 
Spatial Working Memory 
SCZ 
Schizophrenia 
XNAT 
Extensible Neuroimaging Archive Toolkit 
YCCI 
Yale Center for Clinical Investigation 
 
 
 

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4. TRIAL SUMMARY 
 
Title 
A Translational and Neurocomputational Evaluation of a D1R 
Partial Agonist for Schizophrenia 
Protocol Short Title 
TRANSCENDS 
Funding Sponsor 
National Institutes of Health (NIH)/ National Institute of 
Mental Health (NIMH) 
IND Holder 
John H. Krystal, M.D. 
Principal Investigators, 
Site Program Directors 
Principal Investigators: John H. Krystal, M.D., Alan 
Anticevic, Ph.D. 
Site Program Directors:  
Columbia University/Research Foundation for Mental 
Hygiene (RFMH): Joshua T. Kantrowitz M.D. 
State University of New York (SUNY) Stony Brook: Anissa 
Abi-Dargham, M.D. 
University of Pennsylvania: Raquel Gur, M.D., Ph.D. 
Yale University: John H. Krystal, M.D., Alan Anticevic, Ph.D. 
Medical condition under 
investigation 
Early Episode Schizophrenia 
Purpose of study 
To test if CVL-562, a D1 partial agonist novel compound, 
affects working memory neural circuits in patients with early 
episode schizophrenia. 
Study Intervention 
CVL-562 in doses of 1 mg, 4 mg, 15 mg and 25 mg, or 
placebo 
Primary objective 
To assess the response of cognitive neural circuits to CVL-
562 in early episode schizophrenia 
Secondary objectives 
To assess changes in spatial working memory performance, 
additional responses of cognitive neural circuits, and to 
assess factors contributing to individual responses to CVL-
562. 
Endpoints 
Primary Endpoint: Spatial working memory neural circuit 
blood oxygen level dependent (BOLD) signal change. 
 
Secondary Endpoints:  
1. Identification of a proportion of participants with a BOLD 
signal response to CVL-562  
2.  Spatial working memory performance change 
3. Change in BOLD signal regression with trial-by-trial 
spatial working memory performance 
4. Functional connectivity during spatial working memory 
performance change 
5. Global brain connectivity change 
6. Global brain connectivity change comparison with 

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genomic maps relevant to psychotic disease processes  
 
Exploratory Endpoint: Association of genetics with 
treatment response 
Sample size 
100 (120 who are eligible for full study procedures will be 
recruited) 
Summary of eligibility 
criteria 
Inclusion:  
- 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) (1). 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 

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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: 
- 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 judgment 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 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 to 
cognitive effects of HIV and AIDS. 
- Baseline EKG showing prolonged QTc interval (>450 for males, 
>470 for females, Framingham correction(2)), 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 

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contraindication to MR imaging. A copper IUD is allowable if 
permitted by local MRI practices. 
- 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. 
- Daily use of the following medication within 10 days prior to the 
initial visit or during the study: Long-acting nighttime or daytime 
gamma aminobutyric acid-A (GABA-A) receptor facilitators; 
anticonvulsant medications used at high doses or for seizure 
control, or psychostimulants or medical cannabis. Participants 
can be re-assessed for eligibility once they have been free of 
daily use of these medications for >10 days. Participants may 
take non-GABAergic sleep medications, short-acting GABA 
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 re-assessed for eligibility once 
they have been on a stable dose of medication for >3 weeks. 
- CVL-562 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 within 10 days prior to or during study. 
Participants can be re-assessed for eligibility once they have 
been free of these medications/substances for >10 days.  
- Active attempts to discontinue smoking, vaping or other nicotine 
products within the 3 weeks prior to study or during the study. 
Participants can be re-assessed 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. 
Assessments 
- Structured clinical interview (SCID-V) 
- Spatial working memory task 
- The Positive and Negative Syndrome Scale (PANSS) 
- Penn Computerized Neurocognitive Battery (PennCNB) 
- Urine toxicology 
- Urine pregnancy 
- Baseline bloodwork (complete blood count with differential, 

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comprehensive metabolic panel, Hepatitis B, Hepatitis C) 
- Electrocardiogram (EKG) 
- Vital signs 
- Physical exam 
- Penn Reading Assessment (PRA) 
- Fagerstrom Test for Nicotine Dependence (FTND) 
- Calgary Depression Rating Scale 
- Beck Anxiety Inventory 
- Columbia-Suicide Severity Rating Scale (C-SSRS; 
baseline/screening and since last visit versions) 
- Edinburgh Handedness Inventory 
- Lifestyle Questionnaire 
- Drug assay bloodwork 
- fMRI scans  
 
 
 

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1. TRIAL DESIGN / STUDY SCHEMA 
 
Patients (n=120 who are eligible for full study procedures) will be recruited from 
four centers experienced in recruiting and enrolling patients with early episode 
psychosis into research (Columbia University/Research Foundation for Mental 
Hygiene (RFMH), SUNY Stony Brook, University of Pennsylvania, Yale 
University). Patients will be recruited over a two-three year period. Study 
participation for patients will last approximately one-two months. 
  
Upon successfully completing the initial phone screening process, participants will 
be invited to complete a baseline assessment to determine eligibility. Including this 
baseline assessment, all eligible participants would complete 7 total study visits 
(of which some may occur over multiple days). Five of these will be test visits 
involving the administration of CVL-562 (immediate release formulation) or 
placebo. Each test visit start time will be separated by at least 48 hours (six half-
lives of CVL-562). The baseline visit will involve informed consent and screening 
assessments to determine eligibility, including a structured clinical interview 
(SCID-V), Penn Reading Assessment (PRA), Edinburgh Handedness Inventory, 
PANSS, PennCNB letter n-back task, Calgary Depression Scale for 
Schizophrenia,  Beck Anxiety Inventory, Columbia-Suicide Severity Rating 
Scale—baseline/screening 
version 
(C-SSRS, 
baseline/screening), 
urine 
toxicology/pregnancy, baseline bloodwork (complete blood count (CBC) with 
differential, comprehensive metabolic panel (CMP), Hepatitis B & C, HIV, genetics 
(optional)), EKG, vital signs, health history, physical exam, practice spatial working 
memory task, practice flashing checkerboard task, MRI safety assessment and an 
optional  mock scanner experience. Subjects will be randomized to the order of 
doses of CVL-562 (1 mg, 4 mg, 15 mg, or 25 mg) or placebo for the next 5 visits. 
The randomization would occur after eligibility for full study procedures is 
confirmed, and would assign 75% of patients to the highest dose on the last visit. 
25% of patients would receive the highest dose on one of the other four visits. This 
randomization strategy is intended to minimize the impact of association of the 25 
mg dose with nausea in approximately 30% of subjects, which may unblind 
subjects and lead to study discontinuation. All female participants will be required 
to be on birth control (or abstinence) and will receive pregnancy tests at the start 
of each visit. Information on nicotine use, the amount and duration of use will be 
collected at the start of the study using the Fagerstrom Test for Nicotine 
Dependence Questionnaire. All subjects will be tested for COVID-19 as part of 
Visit 1. COVID-19 testing may be repeated after Visit 1 based on symptoms. 
  
Each test visit will begin with clinical assessment to confirm continued eligibility for 
the study, including urine sample for toxicology/pregnancy exam, Positive and 
Negative Syndrome Scale (PANSS), Columbia-Suicide Severity Rating Scale—
since last visit (C-SSRS, since last visit), MRI safety assessment, and vital signs. 
If participants have not eaten a meal within two hours prior to the start of the study 
visit, they will be given a small meal to induce a fed state, as the effects of the 
study drug have a different timeline during a fed vs. fasting state. A lifestyle 

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questionnaire will be administered to understand basic events that occurred in the 
hours before the scan. A brief refresher session on the spatial working memory 
task will be presented to the participants to remind them of the task instructions at 
this point or after drug administration prior to the start of scanning. After these 
procedures, the test visit medication will be administered and the subject will enter 
the fMRI scanner to perform the spatial working memory task. Vital signs will be 
taken after drug administration and prior to scanning. Scanning is timed to have 
functional imaging coincide with peak CVL-562 plasma levels, i.e., it will begin 
approximately 75 minutes following medication administration and last for 
approximately 90 minutes (up to 2 hours). Plasma levels of CVL-562 will be 
obtained prior to and following imaging with a blood draw or IV continued during 
the scan to minimize frequency of needlesticks. Vital signs, PANSS, C-SSRS—
since last visit, and PennCNB will be administered immediately following removal 
from the scanner. All subjects will be observed for at least 2 hours following dosing, 
and provided follow-up (see below, Protection Against CVL-562 Risks). 
  
After completion of the 5 treatment visits, participants will be scheduled for a final 
in-person follow-up visit to conduct an exit interview with debriefing of the study.  
 
2. RATIONALE AND BACKGROUND 
 
2.1 
Disease 
 
Schizophrenia (SCZ) is a disabling neuropsychiatric illness characterized by 
disturbances in perception of reality and substantial cognitive impairment (3). The 
illness affects approximately 1% of the population, and is highly debilitating given 
the effects of the illness on cognition, sensory perception and social/motivational 
functioning. Cognitive disturbances are considered to be one of the main reasons 
for enormous functional disability in patients with schizophrenia and associated 
psychotic illnesses.  The overarching aim of this protocol is to further investigate 
areas of cognition impaired in schizophrenia, particularly spatial working memory 
as assessed with functional neuroimaging (4, 5). This study proposes to examine 
the effects of CVL-562, 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 
and related psychotic disorders. A secondary outcome will be to measure the effect 
on spatial working memory performance, and secondary outcomes will examine 
effects on functional connectivity. All patients will be between 18-45 years old, and 
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 in a random order with repeated functional magnetic resonance imaging and 
cognitive testing during those visits. The most common side effects of 

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this compound are nausea and headache.  This is a multi-site study that requires 
the efforts of 4 study sites in total (Columbia, SUNY Stony Brook, UPenn, and 
Yale), and we aim to have a total recruitment effort of 120 subjects who are eligible 
for full study procedures. 
 
2.2 
Pharmaceutical and Therapeutic Background 
 
2.2.1 D1 and D5 receptor function are critical for optimal cortical function.  
 
All D1R agonists studied to date activate both D1 and D5 receptors. D1R/D5R 
agonism is one of the most intensively studied therapeutic mechanisms from a 
basic neuroscience perspective, but least understood mechanisms from a clinical 
perspective. Patricia Goldman-Rakic first identified procognitive effects of 
D1R/D5R agonism in non-human primates (6). Yet, we have not succeeded in 
developing D1R/D5R treatments for schizophrenia for reasons that may include: i) 
only very recent development of D1R/D5R agonists with good CNS bioavailability, 
ii) steep inverted-U dose-related effects of D1R/D5R agonists on working memory 
(WM) make optimal dose selection difficult (7), ii) the acute behavioral effects of 
D1R agonists may not be indicative of their effects in D1R-sensitized networks (8), 
iv) chronic antipsychotic treatment may downregulate D1Rs and complicate the 
optimal dosing of D1R agonists in patients (7), v) preclinical and computational 
studies make specific predictions about D1R/D5R agonist effects (9-11) but clinical 
studies have tested these drugs using standard neuropsychological tests that were 
not optimized to detect D1R agonist effects (12), and vi) illness phase may 
influence D1R/D5R agonist response (13). For instance, there is evidence that 
early course patients may exhibit more severe cortical functional hyperconnectivity 
(14, 15) but less of the progressive cortical volume loss, and presumably synaptic 
loss, associated with chronic illness (16-18). Below, we address strategies arising 
from translational neuroscience, computational neuroscience, and precision 
medicine that may help to address limitations of prior efforts to develop D1R/D5R 
agonist treatments for cognitive impairment in schizophrenia. 
 
2.2.2 The role of D1 receptors in cognitive impairment in schizophrenia.  
 
The translational framework underlying this application is that D1R/D5R agonists 
improve cognition and, more specifically, working memory (WM) in schizophrenia 
by restoring deficient inhibitory tuning of prefrontal cortical (PFC) networks. Both 
early course schizophrenia and healthy subjects administered ketamine exhibit 
increased resting PFC functional connectivity (FC) (14, 19) and reduced precision 
of information encoded in WM (20, 21). PFC inhibitory tuning deficits in 
schizophrenia might arise, in part, from deficits in excitatory drive to interneurons 
(22). However, these tuning deficits may be exacerbated by deficient PFC 
D1R/D5R signaling. A Consortium co-investigator, Dr. Abi-Dargham and 
colleagues showed that schizophrenia patients have deficits in prefrontal cortex 
(PFC) dopamine release and upregulation of D1R/D5Rs in association with WM 
deficits, implicating deficits in D1R/D5R signaling in cognitive dysfunction in 

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schizophrenia (23-25). Goldman-Rakic, Arnsten, and colleagues showed in non-
human primates that deficits in D1R/D5R signaling reduce neural tuning during 
WM (26). In turn, they demonstrated that D1R/D5R agonists restore the sculpting 
of neural activity associated with spatial WM (sWM) and suppress FC of 
neighboring pyramidal neurons (i.e. unwanted hyperconnectivity) (27, 28). Using a 
delayed response sWM task, they also showed that D1R/D5R agonists attenuated 
sWM disruption produced by chronic haloperidol administration (29)(, 
amphetamine sensitization (11), ketamine administration (30), and aging (31). 
Computational models of this circuit show that, while enhancing tuning, D1R/D5R 
agonism stabilizes recurrent neural activity and reduces effects of distractors (32). 
The aims below test translational hypotheses designed to validate biomarkers for 
future human D1R agonist trial development.  
 
Therefore, we hypothesize that the D1R/D5R partial agonist CVL-562 will have 
pro-cognitive effects in schizophrenia by restoring inhibitory tuning of prefrontal 
cortical activity, thereby increasing sWM behavioral precision and reducing the 
impact of distractors.  Prior studies from investigators within this Consortium (AA, 
JL, RG, JVS) using the full D1R/D5R agonist, DAR-100A described promising 
behavioral effects in schizophrenia and schizotypy, but they were unable to 
validate a neural functional biomarker of target engagement (12, 33). Moreover, 
clinical effects in these initial studies were insufficiently robust to drive further 
development. CVL-562 presents many advantages for psychopharmacology 
research relative to DAR-100A. Thus, we are at a key junction where we need to 
identify biomarkers sensitive to changes in D1R/D5R function that can definitively 
guide drug development, leading to clear Go/No-Go decisions with respect to 
subsequent, full-scale clinical trials. 
 
2.2.3 CVL-562 is a long-awaited selective D1R/D5R partial agonist.  
 
Prior D1R/D5R agonists studied in schizophrenia included SKF38393, a weak 
partial agonist with poor CNS bioavailability (34) that produced ambiguous results 
(35), and dihydrexidine/DAR-100A, a full agonist at both receptors (35) with very 
steep inverted U dose-related effects and unclear benefits (12). D1R full agonists 
are limited by tachyphylaxis and tolerance. CVL-562 is a partial agonist that is 
relatively resistant to engaging the b-arrestin pathway and has substantially 
reduced liability to produce tachyphylaxis and tolerance (36). CVL-562 has high 
selectivity for D1R/D5R and moderate binding affinity for both recombinant hD1R 
(Ki = 95 nM) and hD5R (Ki = 175 nM) (37) (unpublished Pfizer data). In vitro 
functional testing against recombinant hD1 and hD5 receptors established that the 
compound is an agonist, which stimulates cAMP formation with EC50 values of 
580 nM and 220 nM, respectively. Comparison of the cAMP response to the full 
agonist, dopamine, indicated that CVL-562 is a partial agonist at D1Rs and D5Rs 
with intrinsic activity values of 44% and 74% for the hD1 and hD5 receptors, 
respectively. With oral administration, it has a Tmax of 60-90 min, half-life of 7.5 h, 
and it is provided in 1, 3 and 5 mg tablets. Its tolerability and efficacy was 
demonstrated preliminarily in a positive study in Parkinson disease where a single 

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administration produced 12 hours of clinical improvement (35). It was developed 
by Pfizer, Inc. and recently acquired by Cerevel Therapeutics, who have agreed to 
support the proposed trial. As noted above, CVL-562, like all prior pro-cognitive 
D1R agonists, also stimulates D5R.  D5Rs are located on proximal dendrites, while 
D1Rs are located on dendritic spines and distal dendrites (38). D5R, like D1R, 
plays an important role in sWM (39). We are taking several steps in this study to 
address potential implications of the dual actions of CVL-562. First, we are densely 
mapping the dose-response curve for CVL-562 from marginal occupancy to the 
limits of tolerability to determine whether there are non-linear (inverted-U) dose-
related effects. The moderate intrinsic activity of CVL-562 at D1R may protect 
against detrimental effects of cognition related to overstimulation of D1R and direct 
impairment of cognition was not observed in the Pfizer Phase IB SCZ trial. 
However, it is still possible that this drug produces detrimental effects on cognition 
(inverted-U dose-response) at given doses due to overstimulation of D5R. 
Therefore, our study design incorporates a wide range of doses to identify 
individual responses to each dose and allow us to map individual pharmacologic 
dose-response profiles.  
 
2.2.4 Ability of responses to single doses to predict the effects of chronic 
dosing.  
 
Unfortunately, the initial Phase IB study of CVL-562 in schizophrenia produced 
negative results and did not provide guidance for dose-selection. Differences 
between this earlier study and the current study are that we believe that we would 
optimize patient selection, use more sensitive outcome measures, and map the 
dose-response relationship more precisely. Prior non-human primate studies, 
though, describe dose-related improvements in sWM (40), and with chronic 
intermittent administration, even lower doses of D1R/D5R agonists that were 
without initial benefit also came to have procognitive effects (32). Thus, we are 
confident that doses of CVL-562 that produce acute neural signatures of 
improvement, and secondarily, improvement in sWM would be likely to produce 
clinical benefits in a subsequent longer clinical trial.  As our primary endpoints are 
imaging in nature, we are also testing to see whether D1 partial agonism affects 
sWM circuits, with improved sWM performance and the identification of a subset 
of those who respond to CVL-562 as secondary endpoints. Using these as 
secondary endpoints could be used in subsequent full-scale clinical trials if our 
study demonstrates single-dose effects of CVL-562 on associated neural circuits. 
 
2.2.5 Adjusting for antipsychotic effects.  
 
Antipsychotics could complicate this study in three ways: directly competing with 
dopamine for D1Rs, down-regulating D1Rs and D5Rs (7) and reducing cortical 
structural connectivity, which might be reflected in antipsychotic-related reductions 
in cortical volumes (41, 42). To reduce the first risk, we are excluding 
antipsychotics with high D1R affinity, including olanzapine, clozapine, ziprasidone 
and asenapine. The second risk is somewhat unavoidable, as D1R/D5R down 

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regulation occurs as early as 6 months of antipsychotic treatment (7). Nonetheless, 
it is essential to determine the benefits of adjunctive CVL-562 in patients engaged 
in antipsychotic treatment so that findings can generalize to typical treatment 
settings.  However, to minimize the second and third risks, we will limit this study 
to people early in the course of schizophrenia to limit the cumulative impact of 
antipsychotic exposure. One additional potential risk is of pharmacokinetic 
interactions of CVL-562 and antipsychotic medications. CVL-562 is primarily 
metabolized by the P450 enzyme CYP3A4 (Investigator Brochure). We do not 
anticipate drug-drug interactions with antipsychotics because neither CVL-562 or 
the antipsychotics allowed for patients in this project are P450 enzyme inhibitors 
or inducers (Investigator Brochure).  Nonetheless, we will measure plasma CVL-
562 levels on each test visit and we will explore whether plasma level is a better 
predictor than dose of drug effects on our primary and secondary outcome 
measures. If plasma level is significantly better than dose in predicting biomarker 
changes, the subsequent clinical trial could target plasma level rather than dose, 
a strategy that seems to be optimal for some other medications (43). 
  
2.2.6 Optimizing task selection.  
 
This application builds on specific ideas of how D1R/D5R agonists enhance spatial 
working memory (sWM): 1) they stabilize persisting neural representations over 
temporal delays and in the face of distraction, 2) they optimize the inhibitory tuning 
of neural representations, sculpting more precise sWM representations. To 
optimize both features, we propose a task that is a direct translation of the spatial 
delayed response task developed by Funahashi and Goldman-Rakic and 
employed in subsequent studies of D1R/D5R agonists in the Rakic laboratory and 
others (44). The human version of the task involves having people move their eyes 
or direct a joystick to the precise spot where a target stimulus was presented in the 
presence of distractors of varying proximity to the target. Schizophrenia patients 
show relatively greater impairment in precision with increasing delay and closer 
proximity of distractors to targets (21). Using the proposed sWM framework builds 
on the rich evidence base in non-human primates implicating specific back-
translational neurophysiologic mechanisms supporting sWM (45, 46), which can 
be leveraged for understanding clinical deficits via computational modeling (47-
49).  
 
2.3 
Rationale for Selected Patients 
 
2.3.1 Precision medicine strategies for optimizing the study population.  
 
This proposal employs two precision medicine strategies: selecting patients with 
demonstrated WM impairment and limiting recruitment to patients early in their 
course of illness. Enriching for PFC signaling deficits: D1R/D5R agonists are 
targeted for SCZ because in these patients, deficits in dopamine release and 
compensatory upregulation of D1R/D5Rs are associated with WM impairments 
(23-25). Thus, to formally test whether baseline WM impairments are associated 

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with differential responses to the study drug, all subjects will be measured on the 
PennCNB letter n-back task at Visit 1. Individual performance on this task can be 
compared with drug response during analysis. Illness Phase Specificity: As noted 
earlier, D1R/D5R agonists enhance inhibitory tuning of PFC pyramidal neurons 
(32), reducing aberrant cortical functional connectivity, i.e., suppressing “noise.” 
We have previously hypothesized that drugs that have this effect may be relatively 
more efficacious early in the course of schizophrenia (22), when deficits in 
inhibitory tuning of PFC pyramidal neurons may be at its most prominent. Further, 
we had suggested that drugs that attenuate functional connectivity would lose their 
efficacy in chronic illness because these drugs would exacerbate the damaging 
impact on network function of illness progression-related loss of gray/white matter 
and synaptic connectivity (16, 50-53). This hypothesis is supported by early course 
schizophrenia studies that reported resting-state fMRI (rs-fMRI) functional hyper-
connectivity relative to later illness stages (14, 15). Importantly, focusing on the 
early course illness period reduces the impact of progressive synaptic loss due to 
advancing illness and the possible cumulative and complex impact of antipsychotic 
treatment. The notion that drugs that enhance inhibitory tuning might work 
preferentially early in the course of SCZ is supported by findings with an mGluR2 
agonist, which ameliorates symptoms at moderate doses in early course patients 
(≤3 yr), but which worsens symptoms at high doses in chronic (>10 yr) 
schizophrenia patients (54). 
 
2.4 
Rationale for Dose Selection/Regimen 
 
The trial is set up to have 5 treatment visits, each with single dosing followed by 
an fMRI scan timed to be at peak blood levels of CVL-562. Subjects will be 
randomized to the order of doses of CVL-562 (1 mg, 4 mg, 15 mg, or 25 mg, all 
immediate release formulation) 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. This randomization strategy is intended to minimize the 
impact on study completion of the association of the 25 mg dose with nausea in 
approximately 30% of subjects, which may unblind subjects and lead to study 
discontinuation. The particular doses have been chosen based on prior work using 
this drug, and in order for the group to have a range of doses to chart a purported 
‘inverted-U’ curve of drug dosing with respect to impact on cognitive functioning. 
The 1 mg dose has been included in order to catch those participants who are the 
most sensitive to D1 partial agonism. As we intend to chart the full dose-response 
for each participant, the selected doses will allow us to catch those participants 
who are either more or less sensitive to D1 partial agonism, as well as chart 
differential pharmacodynamics curves. The randomization of dose order will also 
allow for separation of practice effects, and we can test to ensure that drug effects 
are stronger than practice effects. As the timing of CVL-562’s effects is >30% 
delayed during a fed state than during a fasting state (per investigator’s brochure) 
we will offer a small meal to those who have not eaten a meal within two hours 

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prior to the visit start. This is an attempt to achieve a fed state across all 
participants, and achieve standard pharmacokinetics during the scan. 
  
3. STATEMENT OF PURPOSE/OBJECTIVES 
 
This U01 study is a response to the NIMH Program Announcement for National 
Cooperative Drug Development Groups (NCDDG) intended to accelerate the 
development of a high priority therapeutic agent by establishing its dose-related 
pharmacodynamic effects on biomarkers designed to inform subsequent clinical 
development. The overall aim is to establish neuroimaging biomarkers of 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.  
 
3.1 
Primary Endpoint  
 
To test if CVL-562 has dose-related effects in schizophrenia patients on putative 
neural biomarkers of D1R/D5R stimulation. We will examine the dose-specific 
effects of CVL-562 on blood oxygen level dependent (BOLD) signal change 
during working memory procedures. The primary outcome measure is an 
analysis of variance of the dose-dependent effects of CVL-562 on the blood 
oxygen level dependent signal (BOLD) during spatial working memory. Post-hoc 
univariate tests will quantify directional dose-related CVL-562 effects. 
 
3.2 
Secondary Endpoint 1  
 
To test in how many participants CVL-562 produces a dose-related modulation of 
BOLD signal during working memory procedures. 
 
3.3 
Secondary Endpoint 2 
 
To test if CVL-562 produces a dose-related modulation of sWM behavioral 
performance collected during fMRI. This will be examined using the behavioral 
data generated during neuroimaging to quantify dose-related CVL-562 effects on 
sWM performance both with and without distractors. 
 
3.4 
Secondary Endpoint 3  
 
We plan to directly examine the association between trial-by-trial sWM 
performance and task-evoked BOLD signal by regressing trial-by-trial sWM 
performance with and without distractors with the relevant BOLD signal.  
 
3.5 
Secondary Endpoint 4 
 
We will examine the dose-dependent effects of CVL-562 on the functional 
connectivity of brain regions during spatial working memory.  

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3.6 
Secondary Endpoint 5 
 
We will examine the dose-dependent effects of CVL-562 on the resting state 
functional connectivity using a data-driven global brain connectivity (GBC) metric.  
 
3.7 
Secondary Endpoint 6 
We will compare the change in resting state GBC as a function of CVL-562 dose 
with the transcriptomic maps from the Allen Human Brain Atlas relevant to risk 
genes in schizophrenia.        
 
3.8 
Exploratory Endpoint 
 
We will conduct exploratory analyses to test whether genetic variants of genes 
related to dopamine or CVL-562 metabolism relate to changes in BOLD signal in 
response to CVL-562. 
 
 
4. STUDY PLAN AND PROCEDURES 
 
4.1 
Study Design Overview 
 
Patients (n=120) will be recruited from four centers experienced in recruiting and 
enrolling patients with early episode psychosis into research (Columbia 
University/RFMH, SUNY Stony Brook, University of Pennsylvania, Yale 
University). Patients will be recruited over a total of 2-3 years. Study participation 
for patients will last approximately one-two months.  After an initial phone screen 
to determine interest and general eligibility, participants will be scheduled for an 
in-person assessment to confirm full eligibility. Study procedures will be reviewed 
with the participant, and written consent will be obtained upon arrival during this 
visit.  
 
Upon successfully completing the screening evaluations, all eligible subjects will 
complete 7 total study visits (of which some may be spread over multiple days), 5 
of which will be test visits involving the administration of CVL-562 or placebo 
(Figure 1). Each test visit will be separated by at least 48 hours (six half-lives of 
CVL-562, per investigator brochure from Pfizer/Cerevel the half-life is 7.5 hours). 
Given the repeated visits required in this study, participants will be offered an 
elective inpatient admission on a research psychiatric unit, if space is available, 
for further observation or isolation (due to COVID-19 exposure risk) as needed. 
For those requiring housing, a stay at a nearby hotel will be offered. The baseline 
visit will involve informed consent and screening assessments to determine 
eligibility, including a structured clinical interview (SCID-V), Penn Reading 
Assessment (PRA), Edinburgh Handedness Inventory, PANSS, PennCNB letter 
n-back task, Calgary Depression Scale for Schizophrenia, spatial working 

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memory task, practice flashing checkerboard task, Beck Anxiety Inventory, 
Columbia-Suicide Severity Rating Scale—baseline/screening (C-SSRS, 
baseline/screening), urine toxicology/pregnancy, baseline bloodwork (complete 
blood count (CBC) with differential, comprehensive metabolic panel (CMP), 
Hepatitis B, Hepatitis C, HIV, genetics (optional)), EKG, vital signs, health history, 
physical exam,  assessment and an optional mock scanner experience. Pre-
existing health information may be used to determine eligibility if it was obtained 
within 3 weeks prior to the date of consent. Subjects will be randomized to the 
order of doses of CVL-562 (1 mg, 4 mg, 15 mg, or 25 mg, immediate release 
formulation) or placebo for the next 5 visits. The randomization will assign 75% of 
patients to the highest dose on the last visit and 25% will receive the highest 
dose on one of the other four visits. Only the highest dose will be subject to this 
pseudo-randomization strategy. This is intended to minimize the impact on study 
completion of the association of the 25 mg dose with nausea in approximately 
30% of subjects, which might unblind subjects and lead to study discontinuation. 
All other dosing will be randomly distributed. All female participants will be 
required to be on birth control (or abstinence) and will receive pregnancy tests at 
the start of each study visit. Information on nicotine use, the amount and duration 
of use will be collected at the start of the study using the Fagerstrom Test for 
Nicotine Dependence Questionnaire. All subjects will be tested for COVID-19 as 
part of Visit 1. COVID-19 testing may be repeated after Visit 1 based on 
symptoms. 
 
Each treatment visit will begin with clinical assessments required to continue on 
this study. These assessments include urine sample for toxicology/pregnancy 
exam, Positive and Negative Syndrome Scale (PANSS), Columbia-Suicide 
Severity Rating Scale—since last visit (C-SSRS, since last visit), MRI safety 
assessment, and vital signs. A lifestyle questionnaire will be administered to 
understand basic events that occurred in the hours before the scan, including how 
much caffeine was used, how much food was eaten, pain levels and whether 
nicotine was used.  If participants have not had a meal within two hours prior to the 
start of the study visit, they will be offered a small meal to induce a fed state, as 
the timing of the study drug’s effects have a different timeline during a fed vs. 
fasting state. A brief refresher session on the spatial working memory task will be 
presented to the participants to remind them of the task instructions, at this point 
or after drug administration prior to the start of scanning. Following this, the 
treatment visit medication will be administered and the subject will enter the fMRI 
scanner to perform the spatial working memory task. Vital signs will be taken 
before drug administration and prior to and after scanning. Scanning will be timed 
to have imaging coincide with peak CVL-562 plasma levels, i.e., it will begin 
approximately 75 minutes following medication administration and last for 
approximately 90 minutes (up to 2 hours). Plasma levels of CVL-562 will be 
obtained prior to and following imaging with a blood draw from either venipuncture 
or an IV continued with a slow rate of normal saline infused during the scan (20 
mL/hour) to minimize needlesticks. The slow rate of normal saline is used to keep 
the IV open during the scan, and prevent clotting in the IV. The use of either two 

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venipunctures (one prior to imaging and one following imaging) or a continuous IV 
will be made after assessing patient preference, and procedure feasibility. Vital 
signs, PANSS, C-SSRS—since last visit, and PennCNB will be administered 
immediately following removal from the scanner. All subjects will be observed for 
at least 2 hours following dosing, and provided follow-up (see below, Protection 
Against CVL-562 Risks). 
 
After completion of the 5 treatment visits, participants will be scheduled for a follow-
up visit to conduct an exit interview, with debriefing of the study. 
 
 
Figure 1. Overview of Study Design. 
 
4.1.1 4.1.1. Protection Against CVL-562 Risks.  
 
The subject recruitment process entails an effective and rigorous screening, which 
will exclude any subjects who could be at greater risk for complications because 
of medical, neurological or psychiatric illnesses.      We have successfully employed 
these stringent screening procedures in all our protocols and have had great 
success in recruiting subjects who are at low risk for receiving experimental 
pharmacology (ex: ketamine (55), delta9-tetrahydrocannabinol (43, 56), etc.) and 
who are likely to tolerate the procedure well. Subjects will be monitored during drug 
administration by an experienced member of the research team (nurse, 
coordinator and/or psychiatrist). These team members have experience with 
pharmacologic imaging, and will provide ongoing support and alleviate concerns 
for those subjects experiencing side-effects. Furthermore, ondansetron will be 
available for intravenous or sublingual administration to rapidly control nausea 
and/or vomiting during scanning if needed. Subjects will be observed for at least 2 
hours after dosing. If intolerable physical or behavioral symptoms persist, subjects 
will be assessed in the emergency room and/or on an inpatient unit depending on 
the level of severity of symptoms for further observation and overnight, if 
necessary. Vitals will be assessed prior to drug administration on each test visit, 
just prior to beginning fMRI scan, and after fMRI scanning finishes. We will also 
administer the Columbia-Suicide Severity Rating Scale—since last visit (C-SSRS, 
since last visit) prior to drug administration and after fMRI scanning, though it is 
important to note that CVL-562 has no known effect on suicidality. Subjects will be 

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advised NOT to drive to and from the testing sessions, and instead we will arrange 
alternative means of transportation for all subjects (e.g. taxi). A physician 
investigator (MD) will approve the discharge of subjects following the completion 
of each treatment visit. Following discharge from each treatment visit, subjects will 
be provided a number to call to reach an on-call psychiatrist (24 hours/day) should 
delayed unpleasant effects occur. Subjects who experience any intolerable effects 
at any point will not be permitted to continue participation. Please see Section 9.4 
for further details on criteria for stopping participation. Post-testing: Contact with 
participants will be maintained during the study and following its completion. We 
will contact all subjects approximately 24 hours after drug administration to check 
for side effects. A final, in-person follow-up visit will occur after the last treatment 
visit to assess side effects and complete final bloodwork.  Furthermore, we will 
conduct a follow-up call approximately 1 month after study completion (i.e., after 
the final in-person visit) to assess for late or ongoing adverse effects. Any subjects 
that experience lingering side effects will be followed by the study team until 
resolved or stabilized, and then will be directed to follow-up with their primary 
health care provider. All imaging will occur at sites specifically designed, equipped, 
and functioning in support of these types of studies, and includes the onsite 
presence of medical supervision with experienced medical, nursing, research 
and/or technical staff. Although we do not expect significant problems to occur, if 
any adverse effects occur during the fMRI session, appropriate treatment will be 
instituted for symptomatic relief. All sites will implement clear protocols for 
addressing medical urgencies and emergencies, including, but not limited to, 
emergent assessment, use of a crash cart, and transportation to the emergency 
room. 
 
4.2 
Treatment Regimen 
 
The clinical trial is designed as a multi-center, single, randomized dosing, double-
blind study with 5 treatment visits, each visit start time separated by at least 48 
hours (6 half-lives of CVL-562). We aim to complete all in-person visits for each 
participant over approximately a 1-2 month period, with likely variation given 
patient availability and schedule. Below is a more detailed description of 
procedures. 
 
4.2.1 Clinical Protocol Schedule of Events Completed by an Individual 
 
● Pre-screening - Potential participants will be contacted by phone by a research 
staff member to determine whether a participant is eligible to participate in an 
in-person screening visit (baseline visit). The data indicating that a participant 
is found to be eligible for Visit 1 will be entered directly into a REDCap 
database. Those who fail to meet eligibility criteria on the phone screen will not 
be invited to the in-person screening/baseline visit and will not participate in 
any additional research procedures. Potential participants will then be invited 
for the baseline visit (in-person assessment) with a doctoral-level clinician or 
an appropriately trained senior research assistant. Given the longitudinal 

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nature of the study, as well as planning for attrition, we aim to recruit a total of 
120 participants who would be eligible to receive CVL-562 based on medical 
and psychiatric assessments. Of those, we aim to have 100 participants 
complete full procedures (we have estimated attrition of 20 participants). The 
number of participants who are consented may exceed 120 subjects as we 
anticipate that some will be found ineligible on the first baseline visit due to 
medical or psychiatric or other reasons.  
 
● Visit 1 - This visit will serve as a baseline pre-randomization visit (4-8 hours 
total, possibly spread across a few days). During this visit, we will obtain 
informed consent and ascertain full eligibility criteria. The baseline visit will 
involve a structured clinical interview (SCID-V), Penn Reading Assessment 
(PRA), Edinburgh Handedness Inventory, spatial working memory task, 
practice flashing checkerboard task, PANSS, PennCNB letter n-back task, 
Calgary Depression Scale for Schizophrenia, Beck Anxiety Inventory, 
Columbia-Suicide Severity Rating Scale—baseline/screening (C-SSRS, 
baseline/screening), 
urine 
toxicology/pregnancy, 
baseline 
bloodwork 
(complete blood count with differential, comprehensive metabolic panel, 
Hepatitis B, Hepatitis C, HIV; optional genetics), EKG, vital signs, health 
history, physical exam, MRI eligibility, and an optional mock scanner 
experience. Pre-existing health information may be used to determine eligibility 
if it was obtained within 3 weeks prior to the date of consent. All subjects will 
be tested for COVID-19 as part of Visit 1. COVID-19 testing may be repeated 
after Visit 1 based on symptoms. All participants will be consented to participate 
in these procedures, however, only those who are found eligible for test visits 
will continue with the study. Given the numerous assessments and the length 
of time to complete them, the practical difficulties in securing MRI scan time, 
patient availability, and the need to keep patients engaged during the study to 
minimize dropout, this first visit may be split into a few days within the window 
of consent and Visit 2 (8 weeks). Following the end of Visit 1, the clinical lead 
investigator at each site will assess and confirm eligibility for further study visits 
based on information gathered at that visit and inclusion/exclusion criteria. For 
those participants for whom eligibility is difficult to determine, they will be 
discussed with a larger group of investigators to reach consensus on eligibility. 
Following determination of eligibility for test visits, participants will be 
randomized to a dosing schedule as follows: placebo, 1 mg, 4 mg, 15 mg, or 
25 mg —75% of the patients will be randomized to get the highest dose on the 
last visit.  
 
● Visit 2 - Test visit (4-6 hours): Initial clinical assessments including urine 
sample for toxicology/pregnancy exam, PANSS, vital signs, Columbia-Suicide 
Severity Rating Scale—since last visit (C-SSRS, since last visit), MRI safety 
assessment. A lifestyle questionnaire will be administered to understand 
basic events that occurred in the hours before the scan, including how much 
caffeine was used, how much food was eaten, pain levels and whether 
nicotine was used.  If participants have not had a meal within 2 hours prior to 

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the start of the study visit, they will be offered a small meal to induce a fed 
state, as the effects of the study drug have a different timing during a fed vs. 
fasting state. A brief refresher session on the spatial working memory task 
and the flashing checkerboard task will be presented to the participants to 
remind them of the task instructions, at this point or after drug administration 
prior to the start of scanning. Following this, the treatment visit medication will 
be administered. Then, the subject will have vital signs re-checked after 
medication administration, and enter the fMRI scanner to complete 
approximately 90 minutes (up to 2 hours) of data collection. Data collected in 
the scanner includes both high-resolution T1-weighted and T2-weighted 
structural images (approximately 20 minutes), 4 multi-band functional BOLD 
runs that involve trials of spatial working memory, trials of motor control, and 
trials of spatial working memory with distraction (approximately 40 minutes 
total), resting state scan (approximately 10 minutes), a resting state arterial 
spin labeling (ASL) scan to assess for changes in cerebral blood flow 
(approximately 10 minutes), and brief visual checkboard stimuli (to explore 
neurovascular coupling effects of CVL-562; approximately 5 min). The first 
test visit will also include a diffusion-weighted image (DWI) (approximately 20 
minutes). If the DWI is not collected at the first test visit it will be collected on 
one of the subsequent test visits.  Plasma levels of CVL-562 will be obtained 
prior to and following imaging with a blood draw from either venipuncture or 
an IV continued with a slow rate of normal saline infused during the scan (20 
mL/hour) to minimize needlesticks. The slow rate of normal saline is used to 
keep the IV open during the scan, and prevent clotting in the IV. The use of 
either two venipunctures (one prior to imaging and one following imaging) or a 
continuous IV will be made after assessing patient preference, and procedure 
feasibility. Vital signs, PANSS, Columbia-Suicide Severity Rating Scale—
since last visit (C-SSRS, since last visit), and PennCNB battery will be 
administered immediately after the completion of the scan. A study physician 
will be available for the entire test visit. Subjects will be observed for at least 2 
hours following dose administration, and provided follow-up. Visits 3, 4, 5, 6 
will be identical to Visit 2, with at least 48 hours of separation (six half-lives of 
CVL-562) between the start of each test visit day. All participants will be 
contacted by phone approximately 24 hours after the visit to briefly assess for 
any adverse effects. COVID-19 testing may be done if symptoms are 
suspected. 
 
● Visits 3, 4, 5, 6 - all identical to Visit 2.  
 
● Visit 7 - Follow up visit (approximately 2 hours): Individual follow up and de-
briefing. At this time female participants will receive a final urine pregnancy test. 
All participants will have a final blood draw for labwork for safety monitoring 
(complete blood count (CBC) with differential, and complete metabolic profile 
(CMP)). All participants will be called approximately 1 month after this follow up 
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4.3 
Special Procedures Related to COVID-19 
Given the ongoing pandemic, and the shifting waves of illness that have ensued 
since this protocol was approved, there will be additional precautions to ensure the 
safety of the participant and the staff during the course of the study and pandemic. 
All sites will follow their required site procedures for cleaning, distancing and 
testing. During Visit 1, all participants will receive COVID-19 testing. If a participant 
tests positive, they will be removed from study procedures and asked to follow 
current CDC guidelines for isolation and further testing. If, after the isolation period, 
they do not develop symptoms, they will be evaluated for continuation in the study. 
If they become symptomatic, the severity of their illness will be evaluated for 
potential exclusion from the study. As the exclusion criterion includes unstable 
medical illnesses, those participants who are COVID-19 positive and have 
significant symptoms may be excluded under this criterion. Should symptoms 
develop during the course of the study, participants will be tested for COVID-19. 
The severity of their symptoms, in conjunction with the outcome of testing, will be 
assessed for possible exclusion from the study, as determined by the clinical lead 
investigator at each site. Those who recover from their symptoms and are willing 
to resume study procedures must be free of significant symptoms at the time of 
restarting study procedures. Those who test positive for COVID-19 during this 
study will be designated as such for purposes of exploratory data analyses. 
 
 
Study procedures will generally continue to be on-site; however, to minimize 
contact, some assessments for Visit 1 may be conducted or monitored virtually, at 
the discretion of the site PI and research staff and based on the needs of the 
participant and local site. These assessments may include clinical interviews, 
scales, questionnaires, and the PRA. The sWM and Flashing Checkerboard task 
practices and medical assessments will continue to be done in-person. For the 
virtual components, study participants will be instructed to participate virtually in 
the same way they would while onsite (ex: alone in a room, no distractions, 
available for the designated amount of time). 
 
All virtual assessments will be conducted using secure, password-protected, 
HIPAA-compliant videoconferencing platform. Conducting these assessments 
virtually will allow research staff to continue research, maintain social distance, and 
also observe necessary components of affect (facial expression, vocal quality) that 
would be difficult to do behind masks. Finally, to ensure that assessment scoring 
can be reliable, we will record interviews, which may be an optional part of the 
study. Recording will allow investigators to ensure reliability and accuracy of data 
collection while conducting assessments virtually. Consenting for recording of 
assessments will be optional for participation in the study. All recordings will be 
stored centrally at Yale using a secure, password-protected HIPAA-compliant 
platform and each site will keep a copy of their recordings in a secure, password-
protected HIPAA-compliant platform. Only trained research staff members and 
investigators will have access to these videos for the purposes of assessing the 
reliability and accuracy of these assessments. Study processes may continue to 

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be modified in response to the COVID-19 pandemic, as medical and public health 
considerations evolve. 
 
4.4 
    Randomization  
 
Patients will each have 5 treatment visits, and the order of placebo, 1 mg, 4 mg, 
15 mg or 25 mg dosing will be randomized through the Investigational Drug 
Services at Yale New Haven Hospital. Drug dosing schedules will be balanced 
within and across sites. Each treatment visit start time would be separated by >=48 
hours (6 half-lives of CVL-562). The randomization will assign 75% of patients to 
the highest dose on the last visit and 25% will receive the highest dose on one of 
the other four visits. Only the highest dose will be subject to this pseudo-
randomization strategy, and all other doses will be randomly distributed. This 
randomization strategy is intended to minimize the impact on study completion of 
the association of the 25 mg dose with nausea in approximately 30% of subjects, 
which might unblind subjects and lead to study discontinuation.  Patients and 
investigators will be blind to the randomization. Cerevel will distribute the drug to 
the Yale Pharmacy directly. Yale Pharmacy will then distribute the drug in kits 
determined in the randomization protocol. 
 
4.5 
Side Effect Profiles from Prior Studies  
 
Prior studies have been conducted using maximum doses in excess of what is 
described here.  Overall, prior human studies find the study drug to be safe and 
well tolerated. The most common adverse events are nausea and headache, and 
these appear to be dose-dependent. In all studies, no deaths have occurred, and 
no significant changes in EKG, or bloodwork have occurred. See below (Table 1) 
for a description of prior studies conducted in human subjects. As we use a lower 
maximum dose than prior human studies and use four single doses separated by 
at least 48 hours rather than repeated daily doses for 15 days used in the prior 
schizophrenia study, we expect the frequency of side effects to be even lower in 
the proposed studies.   
 

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Table 1. Prior human studies using CVL-562. 
 
 
5. CONCOMITANT MEDICATIONS 
 
Participants may continue to be treated with psychiatric and medical medications 
as long as dosing has been stable for 3 weeks. As stated earlier, we limit 
antipsychotics allowed in the study to agents with low D1R affinity, thereby 
excluding olanzapine, clozapine, ziprasidone and asenapine.  
 
CVL-562, as well as some of the allowable antipsychotics in this study are 
metabolized by the P450 enzyme, CYP3A4. Therefore, both strong and moderate 
inducers (eg, carbamazepine) and inhibitors (eg, ketoconazole, valproate) of 
CYP3A4 are excluded during this study, as well as the 10 days prior to the initial 
visit. 
 
5.1 
Diet and Other Considerations 
 
As CVL-562 is metabolized by the P450 enzyme, CYP3A4 (Investigator Brochure), 
both strong and moderate inducers (carbamazepine) and inhibitors (ketoconazole, 
valproate, etc., as well as grapefruit juice (an inhibitor of CYP3A4) will be excluded 
during this study, as well as the 10 days prior to the initial visit. 
 
In relation to MRI scanning, information on participant caffeine use and nicotine 
use will be collected in order to assess possible confounds on the BOLD signal.  
 

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5.2 
Rescue Medication and Supportive Care 
 
There is no rescue medication that reverses the effects of CVL-562.  Intravenous 
or sublingual ondansetron will be available to treat acute nausea/vomiting that may 
occur on test days after the administration of CVL-562. For acute anxiety related 
to procedures in the scanner, participants will be removed from the scanner and 
assessed for continuation in the study. 
 
6. PATIENT POPULATION 
 
Patients with schizophrenia, schizoaffective or schizophreniform disorder 
participating in this study will be recruited primarily from specialized resources at 
each site dedicated to the early identification and treatment of patients with 
psychosis. The recruitment from these programs would be supplemented by 
referrals from established ambulatory clinics, intensive outpatient programs, 
inpatient units, and emergency room (ER) settings. In addition, clinically-based 
recruitment may occur through chart reviews and cold calling via telephone calls. 
Therefore, much of the communication strategies for identifying and soliciting 
referrals are related to communicating with specific relevant sources at each site. 
Nonetheless, we will use a variety of public sources (radio, newspaper, 
advertisement on public buses, Craigslist, etc.) to ensure a steady flow of patients 
at each site. In doing so, recruitment will employ an established pipeline that we 
and our colleagues across the Consortium sites have developed over the years. 
Subjects will be recruited through a combination of print, on-line, and traditional 
media advertising, posting of flyers in the local community, and outreach to 
community clinicians. All advertising materials will be approved in advance by the 
Institutional Review Board. Potential subjects will be instructed to contact the clinic 
coordinator(s) online or by phone to schedule a time to complete the initial phone 
screen (described earlier).  
 
6.1 
Inclusion Criteria 
 
- 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. 

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- 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) (1). 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. 
 
6.2 
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 judgment 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 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 

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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 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. 
- 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. 
- Daily use of the following medication within for at least 10 days prior to the 
initial visit study or during the study: Long-acting nighttime or daytime gamma 
aminobutyric acid-A (GABA-A) receptor facilitators; anticonvulsant medications 
used at high doses or for seizure control, or psychostimulants or medical 
cannabis. Participants can be re-assessed for eligibility once they have been 
free of daily use of these medications for >10 days. Participants may take non-
GABAergic sleep medications, short-acting GABA 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 re-assessed for eligibility once they 
have been on a stable dose of medication for >3 weeks. 
- CVL-562 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 within 10 days prior to or during study. 
Participants can be re-assessed for eligibility once they have been free of 
these medications/substances for >10 days.  
- Active attempts to discontinue smoking, vaping or other nicotine products 
within the 3 weeks prior to study or during the study. Participants can be re-

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assessed 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.                                                                                                                         
                     
7. DESCRIPTION OF PROCEDURES 
 
7.1 
Study Entry / Registration 
 
Eligibility will be determined locally by the site PI and/or research team using an 
eligibility checklist. The participant will be assigned a unique study ID generated 
by the NIMH Data Archive (NDA), pseudo-GUID (PGUID), after screening. A list 
of NIH PGUIDs will be provided to each site at start-up and assigned to each 
enrolled participant consecutively. The NIH PGUID will be used when the 
participant is registered into REDCap and will be used in related study 
documents and data collection. Because the NIH PGUIDs are lengthy but useful 
for public data upload through the National Institute of Mental Health Data 
Archive (NDA), a shorter, Simple ID will be used for the purposes of labeling the 
investigational drug packets and other data that require shorter identifiers. The 
corresponding Simple ID will be also entered into REDCap. Subjects will be 
entered into REDCap by research staff. Allocation of patients to treatment groups 
will be done using the randomization process outlined in section 4.3 
Randomization. De-identified data will be made publicly available through the 
NDA with data uploaded every 6 months. 
 
Participant re-screening may occur when a participant’s ability to meet inclusion 
or exclusion criteria has changed to suggest potential eligibility, when participants 
resume contact with the study team after being lost to follow-up, or when 
participants express renewed interest in participating after previously declining 
further participation. During re-screening, all study procedures should be 
repeated except for the SCID-V, the PRA and Edinburgh Handedness Inventory. 
 
7.2 
Safety and Data Capture of Laboratory Procedures and Assessments 
 
7.2.1 Psychological Assessments  
 
These are non-invasive assessments and have been used without difficulty or 
adverse events in previous studies with a similar population and design. Patients 
will be offered the opportunity to take frequent breaks to minimize fatigue. There 
are potential risks that subjects may become uncomfortable or distressed when 
discussing personal issues with study personnel or treatment providers. All 
participants are welcome to withdraw from the study at any time. Inter-rater 
reliability will be assessed. For all assessments with electronic source capture, a 

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paper source will be used as a backup option in the event of technical glitches or 
technical unavailability. The data from the paper source will then be manually 
entered by staff into REDCap and noted as coming from a paper source. The 
following assessments will be administered: 
 
- 
Structured Clinical Interview for DSM-V (SCID-V)(57)—this is a 
structured clinical interview that assesses psychiatric symptomatology 
and psychiatric diagnoses. All criteria are based on the DSM-V. 
Source data will be captured in electronic format through NetSCID’s 
via Telesage and exported and entered into REDCap. 
- 
Spatial working memory task(21)—this is a computerized fMRI task 
that tests participant’s working memory for spatial locations. 
Participants are asked to remember the location of a circle on each 
trial, and they use a high-precision joystick to indicate where they best 
remember the location to be. The control trials involve no working 
memory and involve moving the joystick to the location of the circle 
that is presented onscreen. On some trials, a second circle in a 
different location (noted as a distractor—placed either near to, or far 
from, the original circle) will be presented as a distractor to test the 
stability of the working memory. Participants will be trained on this task 
at the initial visit. At each subsequent test visit, they will perform this 
task in the fMRI scanner after receiving a dose of drug. Behavioral 
source data will be from E-Prime Eyelink SR Research software and 
Biopac or Siemens Physiological Measurement Unit  and analyzed in 
R. Imaging data will be collected at the scanner, and centrally stored 
using support from XNAT software maintained by investigators at Yale 
University. Behavioral and physiological data collected during the fMRI 
scan will be centrally stored at Yale University. Participants will also 
complete a version of this task at the baseline visit outside of the 
scanner in order to become familiar with this task and its instructions. 
- 
Flashing Checkerboard Task(58)—This is a computerized fMRI task 
used to measure neurovascular coupling.  Participants are asked to 
view a flashing checkerboard and press a button when the flashing 
stops. As with the spatial working memory task, the imaging data will 
be collected at the scanner and centrally stored using support from 
XNAT software maintained by investigators at Yale University.  
Behavioral data collected during the fMRI scan will be centrally stored 
at Yale University. Participants will also complete a practice session at 
Visit 1, and a few brief trials before the scan to become familiar with 
the instructions.    
- 
The Positive and Negative Syndrome Scale (PANSS)(59, 60)—this 
is a structured clinical interview that assesses symptoms of psychotic 
illnesses. Source data will be captured in electronic forms in REDCap. 
- 
Penn Computerized Neurocognitive Battery (PennCNB)(61)—this 
is a standardized battery of cognitive tests on the computer that 
assesses aspects of short-term memory, working memory, executive 

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function, etc. Data are captured and stored in a centralized database 
managed by the investigators at the University of Pennsylvania.           
The PennCNB n-back letter task, which assesses working memory 
and will be used in Visit 1, is part of the PennCNB. 
- 
Penn Reading Assessment (PRA)(1)—this is an assessment 
designed, validated and published by the investigators at the 
University of Pennsylvania to assess premorbid IQ. This is 
computerized and data are captured and stored in a centralized 
database managed by the investigators at the University of 
Pennsylvania. 
- 
Fagerstrom Test for Nicotine Dependence (FTND)(62)—this is a 
questionnaire administered by research staff to assess nicotine use. 
This scale has been made in the Redcap system and source data will 
be electronic in the REDCap system. 
- 
Calgary Depression Scale for Schizophrenia(63)—this is a rating 
scale administered by research staff to assess depression symptoms 
in patients with psychotic illnesses. This scale has been made in the 
REDCap system and source data will be electronic in the REDCap 
system. 
- 
Beck Anxiety Inventory(64)—this is a rating scale to assess 
symptoms of anxiety and is completed by the participant. This scale 
has been made in the Redcap system and source data will be 
electronic in the REDCap system. 
- 
Columbia-Suicide Severity Rating Scale—baseline/screening (C-
SSRS, baseline/screening)(65)—this is a structured interview 
administered by research staff to assess suicidality and related 
behaviors. This scale has been made in the REDCap system and 
source data will be electronic in the REDCap system. 
- 
Columbia-Suicide Severity Rating Scale—since last visit (C-
SSRS, since last visit)(65)—this is a structured interview 
administered by research staff to assess suicidality and related 
behaviors since the last time the scale was administered. This will help 
us track any changes to suicidality and related behaviors during the 
course of the study. This scale has been made in the Redcap system 
and source data will be electronic in the REDCap system. 
- 
Edinburgh Handedness Inventory(66)—this is a rating scale to 
assess hand dominance and completed by the participant. The scale 
has been made in the REDCap system, and source data will be 
electronic in the REDCap system. 
- 
Lifestyle Questionnaire—this is a structured interview to assess 
events that occur on the day of scanning prior to the fMRI scan being 
obtained. This covers information such as caffeine use, food intake 
and hydration. The source data is electronic and this information will 
be entered directly into REDCap. 
  

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7.2.2 Functional magnetic resonance imaging (fMRI).   
 
It is important to note that research has not found any adverse side-effects of MR 
imaging at field strengths used in the present protocol. fMRI scans will be gathered 
according to the United States Food and Drug Administration (FDA) guidelines for 
magnet strength and exposure to radio waves. Subjects will be monitored closely 
throughout the scan. Some subjects feel uncomfortable or anxious and on rare 
occasions, subjects experience upset stomach, have a metallic taste or feel 
tingling sensations or muscle twitches. There are some risks with an MRI scan for 
certain people, if subjects have a pacemaker or some metal object inside their 
body for example, however, we will take exceptional precautions through an 
extensive MR safety screen to exclude subjects with any contraindications during 
initial screening (MRI safety assessment—site specific). Furthermore, we will 
exclude any individuals who express concern about small spaces/claustrophobia 
during screening. For those subjects participating in the study we will offer the 
optional opportunity to undergo an adaptation session in a mock scanner to 
provide subjects an opportunity to be familiar with lying in the MRI scanner. If a 
participant becomes anxious during scanning, we will initially try to relax them by 
speaking to them over the intercom. In our experience, participants are the most 
uncomfortable when first entering the magnet, and the feelings dissipate as people 
adapt to the situation. If the discomfort persists, or if at any time a participant 
requests so, we will stop the imaging session immediately. Further continuation of 
this participant in the remainder of the study will be determined by the study 
investigators in collaboration with the participant.  
 
7.2.3 Urine drug screen 
 
The following drugs of abuse will be screened for: cannabinoids, cocaine, opiates, 
amphetamines, 
methamphetamines, 
benzodiazepines, 
barbiturates, 
and 
phencyclidine. If a participant tests positive for any drug of abuse except for 
marijuana or those prescribed for medical reasons on the urine drug test during 
Visits 1-6, they will not be allowed to continue further in the study, but will have the 
opportunity to continue once they abstain and the urine drug test is negative for 
those substances. Once the urine drug test is negative, the participant may be re-
evaluated to continue in the study. If the participant declines to abstain, they will 
be excluded from the study. 
If a participant tests positive for marijuana use at Visit 1, but their urine THC 
level is <150 ng/mL, they will be allowed to participate in the study. Marijuana use 
is very common in patients with schizophrenia, particularly those who are younger. 
This cutoff will allow us to recruit a wider group of early-episode patients with 
schizophrenia with presumed recreational marijuana use, but still exclude those 
with heavy use. Furthermore, we will continue to measure urine THC at Visits 2-6, 
and use the results as a covariate in analysis. The source data will be lab reports, 
and electronic capture into REDCap.  
 

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7.2.4 Physiological measures 
 
Physiological measures including blood pressure, respiratory rate and heart rate 
will be obtained at each visit. Vitals signs for Visit 1 may be considered relevant 
for up to 8 weeks after being measured. On test visits, this information will be 
obtained prior to drug administration, after drug administration but before fMRI 
scanning, and after completion of fMRI scanning. Prior to dosing the drug on Visits 
2-6, if vital signs are repeatedly out of range based on our designated 
inclusion/exclusion criteria, we will hold the study drug that day and, we will re-
check the vital signs at the subsequent visit. This information will be entered into 
REDCap. Continuous physiological (respiratory rate and heart rate) information 
will also be collected during the fMRI scan itself using MRI safe equipment from 
either the Siemens Physiological Measurement Unit or Biopac for potential 
exploratory regression analyses of the neuroimaging data. This information will be 
collected in electronic format by the respective equipment and stored centrally at 
Yale University.      
 
7.2.5 12-lead electrocardiogram 
 
A standard resting, 12-lead electrocardiogram (EKG) will be obtained, and be 
documented by recording date, time, normal/abnormal, abnormality (if any), and if 
clinically significant. A pre-existing EKG may be used to determine eligibility if it 
was obtained within 3 weeks prior to the date of consent. 
 
All EKGs will be evaluated by the investigators or a qualified cardiologist. If 
indicated, additional EKG assessments will be made at the discretion of the 
investigator. A cardiologist will rate the overall interpretation as normal or 
abnormal.  If abnormal, it will be decided as to whether or not the abnormality is 
clinically significant or not clinically significant. Those with prolonged QTc seen on 
EKG (>450 ms for males; >470 ms for females) will be excluded. EKG data will be 
uploaded into REDCap. The EKG may be considered relevant for up to 8 weeks 
after collected (11 weeks if obtained within the 3 weeks prior to the date of 
consent). 
 
7.2.6 Physical examination and health history 
 
The physical examination will include an assessment of the following: general 
appearance, skin, head and neck (including eyes, ears, and throat), lymph nodes, 
thyroid, musculoskeletal/extremities (including spine), cardiovascular, lungs, 
abdomen, and neurological systems. Health history assessment will include 
personal and family health history. All physical exam and health history 
documentation will be directly captured using REDCap. For participants who have 
lapses in study participation at Visit 1, the physical exam and health history may 
be considered relevant for up to 8 weeks after they were conducted. A pre-existing 
physical examination and health history may be used to determine eligibility if it 
was obtained within 3 weeks prior to the date of consent. 

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7.2.7 Laboratory assessments 
 
Blood samples for determination of clinical chemistry and hematology parameters 
will be taken at the time of the baseline visit and at the final visit (Table 2). For 
participants who have lapses in study participation at Visit 1, medical lab 
assessments may be considered relevant for up to 8 weeks from collection (up to 
11 weeks if it was obtained 3 weeks prior to the date of consent.). Pre-existing 
labwork may be used to determine eligibility if it was obtained within 3 weeks prior 
to the date of consent. Source data will be the lab reports, and the data will be 
entered into REDCap. Date and time of collection and results will be recorded. 
Collecting bloodwork for genetics will be optional on the part of the participant. The 
use of the genetic materials will be exploratory and used in relation to imaging and 
treatment findings. All blood collected for genetics analysis will be stored at Yale 
University, the site of the Principal Investigator. Any extracted genetic data will 
then be made available through the National Institutes of Health database of 
Genotypes and Phenotypes (daGaP). The following laboratory variables will be 
measured: 
 
Hematology 
Infectious Disease 
Clinical Chemistry 
Urine 
Complete Blood 
Count (CBC) with 
Differential 
Hepatitis B panel 
(Hep B surface 
antigen, surface 
antibody and core 
antibody) 
 
Comprehensive 
Metabolic Profile 
(CMP)  
Toxicology 
 
 
Hepatitis C 
(antibody) 
 
Pregnancy 
(hcG) 
 
HIV 
 
 
Table 3. Laboratory Assessments. Positive results for reportable communicable diseases will be 
reported to the public health authority as required by state law. The reportable diseases include 
HIV, Hepatitis B and Hepatitis C.  Subjects will be informed about this requirement in the consent 
form.    
 
7.3 
Special Safety Considerations 
 
7.3.1 MRI-related Risk Minimization 
 
Participants will be appropriately screened for metals as will all personnel who 
enter the room that contains the MRI scanner. This screening will involve a self-
reported MRI safety assessment as per local site policy, and assessment with a 
ferromagnetic metal detector. All females will have a pregnancy test prior to each 
MRI scan to ensure that they are not pregnant before being scanned.  The 
following are common sources of risk: 
 
MR sounds.  

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The MR scanner produces tapping sounds during operation, which may reach very 
loud levels. To minimize any discomfort from this noise, the participant will be 
provided with disposable earplugs that suppress external noise levels but do not 
eliminate voice communication with the scanner operator. The participant will have 
earplugs, which allow for blockage of environmental noise while maintaining 
communication and audibility of stimuli. If the participant finds the noise from the 
scanner objectionable, he/she may stop the study at any time.  
 
Claustrophobia. Some people feel claustrophobic in the MR scanner. If this 
happens the scan would be stopped immediately. Simulation with the mock 
scanner will be offered prior to actual scanning to familiarize participants, and 
minimize this risk. 
 
Neurostimulation. In some cases it is possible that subjects might experience 
neurostimulation effects, such as muscle twitches and tingling sensations, due to 
the rapid switching of magnetic field gradients used in these examinations. There 
are no known risks associated with these effects. Stimulation of the muscles of the 
heart, causing an abnormal heart rhythm is much less likely to occur. The devices 
used in this research create magnetic field gradients within the limits specified by 
the FDA. 
 
Change in Body Temperature. A slight increase in body temperature may occur in 
the presence of radio frequency waves. A significant, deleterious increase in 
temperature is very unlikely at the settings employed in this study, which are within 
FDA guidelines. 
 
RF Antenna Effects. If metal wires or electrodes are attached to a person being 
imaged, radio frequency signals from the MR scanner may induce sufficient 
electrical currents in the wires to cause burns where the wires or electrodes contact 
the skin. If wires or electrodes are present, the scanner operator will inspect and 
arrange them to minimize the risk of induced currents. 
 
Quench Hazard. The MR scanner uses liquid nitrogen and liquid helium. It is 
remotely possible that the liquid nitrogen and helium could boil off rapidly and fill 
the magnet room with extremely cold dense gaseous nitrogen and helium, which 
can be dangerous if breathed for more than a few moments. When the scanner 
operator notices a quench, immediate assistance will be provided to anyone inside 
the magnet room. 
 
Pregnancy. Although there is no known risk to a pregnant woman or her fetus from 
a MRI scan, women of child-bearing age will be asked to take a urine pregnancy 
test. If they decline to take the test, they will not be eligible for participation. If the 
test is positive, they will not be able to participate. There were no adverse effects 
on embryo-fetal viability, intrauterine growth, or morphological development seen 
in pivotal reproductive toxicity studies conducted in rats and rabbits (see 

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Investigator’s Brochure). Those who become pregnant during the study will be 
excluded, and will have appropriate medical care and follow-up arranged. 
 
7.3.2       Data Protection 
 
All subject information will be kept confidential, and only members of the 
investigative team with appropriate Protection of Human Subjects and HIPAA 
training will have access to the data. Data will be maintained and secured in locked 
file cabinets or password-protected electronic media stored on devices approved 
and maintained for this purpose by Yale University (data coordinating site) in 
compliance with relevant regulations. Each site will keep a copy of the 
neuroimaging, behavioral and physiological data at their site. At all sites, digital 
media and filing cabinets are located in locked offices. A numbering code will be 
used to assign a unique identifier to each subject. The identification key will be 
digitally stored separately from all other data, using an encrypted, password 
protected database. All of the information obtained from subjects is referred to by 
code number, and kept locked in confidential files. This information is only 
available to study investigators and to relevant regulatory authorities upon request. 
As per agreement with the National Institute of Mental Health (NIMH), de-identified 
data will be shared publicly on the NIMH Data Archive (NDA https://nda.nih.gov/).  
  
7.3.3 Vulnerable subjects 
 
Schizophrenia is a debilitating and burdensome psychiatric illness with prominent 
cognitive deficits, and no targeted treatments for cognitive deficits. This clinical trial 
would be a first towards understanding specific neural mechanisms that can be 
targeted to improve cognition in patients with schizophrenia. 
 
7.3.4 Phlebotomy and IV placement 
 
Bruising, infection and thrombosis can occur with placement of the intravenous 
line. Having these procedures performed by experienced personnel using good 
clinical technique minimizes these risks. An experienced physician or nursing staff, 
as done in our previously completed studies, will perform this aspect of the 
protocol. Blood volume collection: The total amount of blood donated as part of 
this study is approximately 70 ml based on approximately 27 ml obtained for 
baseline laboratory tests, and approximately 40 ml (4 ml per blood levels sample, 
two samples per test visits, and 5 test visits). For the optional blood draw for 
genetics, an additional approximately 20 ml of blood will be drawn. 
For those patients receiving IV placement, normal saline will be infused at 20 
mL/hour. This is considered a slow infusion rate and will be done in order to keep 
the IV open and avoid clotting. 
  
7.3.5 Blood sampling for pharmacokinetics, preparation, and storage  
 

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All efforts will be made to obtain the pharmacokinetic samples at the exact nominal 
time relative to dosing.  However, pharmacokinetics samples obtained within 
approximately 15% of the nominal time (e.g., within 9 minutes of a 60 minute 
sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document. Sites will be 
provided materials and training for collecting these samples. Following collection, 
all samples will be spun, aliquoted and stored at each site, and then sent in batch 
to a collaborating site, Columbia University, for further storage at -80º Celsius. All 
processing of samples will be done at Columbia University by the Irving Institute 
for Clinical and Translational Research. To protect subjects’ confidentiality, the 
banked biospecimens and data generated from them will be coded with the 
subject’s study ID number. Samples will be kept in a locked, limited-access 
facility.  Data will be stored on password-protected computer systems. The key 
between the code and the subject’s personal identifiers will be held at the study 
site; the researchers using the biospecimens and data generated from them will 
not have access to the key nor any personally identifying information. 
Biospecimens will only be used for the purposes described here and in the 
informed consent document/patient information sheet.  Subjects can withdraw 
their consent for the use of their biospecimens at any time by making a request to 
the investigator, in which event any remaining biospecimen will be destroyed; data 
already generated from the biospecimens will continue to be stored to protect the 
integrity of existing analyses.  Results will not be provided to family members or 
other physicians; nor will they be recorded in the subject’s medical record.   
 
7.3.6 Minimizing risk associated with genetic testing. 
 
Genetic samples will be identified with a code number; a password-protected 
computer file will link subject information to this code. Materials for collecting 
genetic samples will be provided to each site, and the collected samples will be 
sent to Yale University for storage. Samples will be stored in a locked -80° C 
freezer. Any samples shared with other investigators as part of future research 
protocols utilizing this repository will be identified only by code number; no 
personal identifying information will ever accompany these samples. Any extracted 
genetic data will then be made available through the National Institutes of Health 
database of Genotypes and Phenotypes (daGaP). 
 
7.3.7 Minimizing risk associated with confidentiality.  
 
Patient’s charts and written research records will be stored in a locked file cabinet 
in a secure office, accessible only to the principal investigator and other study 
personnel. Electronic records of clinical and research data will be stored on a 
password-protected personal computer.  Participants will complete electronic 
questionnaires in the lab that are on REDCap, which is HIPAA compliant. REDCap 
is password protected, and will enable de-identified completion of all online 
questionnaires.  We have obtained a Certificate of Confidentiality from the National 
Institutes of Health to provide maximum protection for the confidentiality of 

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subjects’ clinical and research data.  
 
7.3.8 Minimizing risks associated with neuropsychiatric testing and evaluation. 
 
Some of the questions in the psychiatric interviews may be uncomfortable for the 
subject to answer.  Potential participants may refuse to answer any specific 
questions or discontinue the interview at any time. The tasks and structured 
interviews may be tiring, but every effort will be made to avoid making subjects 
tired.  Breaks will be offered frequently and subjects can quit at any time.  During 
the evaluation, unanticipated psychiatric and medical information may be 
uncovered.  In that case, findings will be discussed with the subject and 
appropriate follow-up will be advised.  
 
7.3.9 Benefits to the participant. 
 
As detailed in the consent form, there may be some benefit as a result of study 
participation, but no guarantee that individual benefit will be gained from 
participation in this study.  
 
7.3.10 Alternatives to participation. 
 
Participants are welcome to withdraw at any time, and to refuse participation in 
the study. The only alternative is to not participate in this study.  Refusal to 
participate will involve no penalty or loss of benefits to which the subject is 
otherwise entitled. 
 
 
8. SCHEDULE OF ASSESSMENTS 
 
 
Visit 1 Visit 2 
Visit 3 Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit Windows 
 
Up to 8 
weeks 
from last 
visit 
Between 
48 
hours-2 
weeks of 
last visit 
Between 
48 
hours-2 
weeks of 
last visit 
Between 
48 
hours-2 
weeks of 
last visit 
Between 
48 
hours-2 
weeks of 
last visit 
Up to 1 
week 
from last 
visit 
Informed Consent 
X 
 
 
 
 
 
 
Baseline bloodwork 
(CBC, CMP, Hepatitis 
B and C, HIV, 
optional genetics) 
EKG, health history, 
physical exam 
X 
 
 
 
 
 
 
SCID-V 
X 
 
 
 
 
 
 
Fagerstrom Test for 
Nicotine Dependence 
X 
 
 
 
 
 
 
Calgary Depression 
Scale for 
X 
 
 
 
 
 
 

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Schizophrenia 
Beck Anxiety 
Inventory 
X 
 
 
 
 
 
 
Columbia-Suicide 
Severity Rating 
Scale, baseline 
X 
 
 
 
 
 
 
PRA 
X 
 
 
 
 
 
 
Edinburgh 
Handedness 
Inventory 
X 
      
 
 
 
 
 
Penn CNB n-back 
letter task only 
X 
 
 
 
      
 
      
Spatial Working 
Memory task 
(training) 
X 
 
 
 
 
 
 
Flashing 
Checkerboard task 
(practice) 
X 
 
 
 
 
 
 
Randomization for 
dose of CVL-562 
X 
 
 
 
 
 
 
Mock scanner 
experience (optional) 
X 
 
 
 
 
 
 
COVID-19 testing 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
MRI Safety 
Assessment 
X 
X 
X 
X 
X 
X 
 
Urine toxicology 
X 
X 
X 
X 
X 
X 
 
Urine pregnancy test 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
 
PANNS, pre-dose 
X 
X 
X 
X 
X 
X 
 
Spatial Working 
memory task and 
Flashing 
Checkerboard Task 
(refresher) 
 
X 
X 
X 
X 
X 
 
Dose of CVL-562 
 
X 
X 
X 
X 
X 
 
Lifestyle 
Questionnaire, pre     
-dose 
 
X 
X 
X 
X 
X 
 
Neuroimaging 
session, including 
structural MRIs, 
Spatial Working 
Memory Task--fMRI, 
 
X 
X 
X 
X 
X 
 

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resting-state fMRI, 
ASL, flashing 
checkerboard stimuli, 
and DWI (for first visit 
only), post-dose 
Blood draw for CVL-
562 levels, post-dose 
(pre-scan and post-
scan) 
 
X 
X 
X 
X 
X 
 
Columbia-Suicide 
Severity Rating 
Scale, since last visit; 
pre-dose and post-
dose 
 
X 
X 
X 
X 
X 
 
PANNS, post-dose 
 
X 
X 
X 
X 
X 
 
PennCNB battery, 
post-dose 
 
X 
X 
X 
X 
X 
 
Adverse events             
X 
X 
X 
X 
X 
X 
X 
Follow-up/Debriefing 
 
 
 
 
 
 
X 
Final labwork (CBC, 
CMP) 
 
 
 
 
 
 
X  
Table 4. Schedule of Assessments. Visit 2 will occur 8 weeks after consent. All participants will 
be called approximately 24 hours after each treatment visit (Visits 2-6) to assess for adverse 
effects. All participants will be called 1 month after the final visit (Visit 7) to assess for lingering 
adverse effects. For those participants that need to be re-screened, all screening measures will 
be repeated except the SCID-V, the PRA and the Edinburgh Handedness Inventory. 
 
9. ASSESSING AND REPORTING ADVERSE EVENTS 
 
9.1 
Definition 
 
Adverse Event. An adverse event (AE) is defined as any untoward medical 
occurrence in a study participant taking the study drug(s) which does not 
necessarily have a causal relationship with the study drug(s). An adverse event 
can be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the study 
drug(s) or protocol-specified procedure, whether or not considered related to the 
study drug(s) or protocol-specified procedure. Any worsening (i.e., any clinically 
significant adverse change in frequency and/or severity) of a pre-existing 
condition that is temporally associated with the use of the study drug(s), is also 
an adverse event. 
  
Serious adverse event. A serious adverse event (SAE) is an AE that fulfills one 
or more of the following criteria: 
1. Results in death 
2. Is immediately life-threatening 
3. Requires in-patient hospitalization or prolongation of existing hospitalization 

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4. Results in persistent or significant disability or incapacity 
5. Results in a congenital abnormality or birth defect 
6. Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above 
                                                                                                                                   
 
9.2 
Evaluating Adverse Events Including Serious Adverse Events 
 
AE Severity  
An investigator who is a qualified physician will evaluate all adverse events for 
severity according to the following criteria: 
  
·      Mild (Grade 1) corresponds to an event not resulting in disability or 
incapacity and which resolves without intervention 
·      Moderate (Grade 2) corresponds to an event not resulting in disability 
or incapacity but which requires intervention 
·      Severe (Grade 3) corresponds to an event resulting in temporary 
disability or incapacity and which requires intervention 
·      Life-threatening (Grade 4) corresponds to an event in which the study 
participant was at risk of death at the time of the event 
·      Fatal (Grade 5) corresponds to an event that results in the death of the 
study participant 
  
AE Expectedness 
An investigator who is a qualified physician will evaluate AEs for expectedness. 
AEs can be ‘Unexpected’ or ‘Expected’. Most common Expected AEs include 
headaches, nausea, fatigue and vomiting. Please refer to the investigative 
brochure (IB) for additional information. 
  
Unexpected AEs are those AEs in which the nature, severity, or frequency is not 
consistent with either: 
  
1) 
The known or foreseeable risk of AEs associated with the procedures 
involved in the research that are described in (a) the protocol-related 
document, such as the IRB-approved research protocol, any applicable 
investigator’s brochure, and the current IRB-approved informed consent 
document, or (b) other relevant sources of information, such as product 
labeling and package inserts; or 
  
2) 
The expected natural progression of any underlying disease, 
disorder, or condition of the study participant(s) experiencing the AE and 
the study participant’s predisposing risk factor profile for the AE. 
  
AE Attribution 
An investigator who is a qualified physician will evaluate AEs for attribution. The 
investigator must attempt to determine if an AE is in some way related to the use 

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of the study drug and define an attribution category. This relationship should be 
described as follows: 
  
·      Definite – The AE is clearly related to the study drug. 
The event follows a reasonable temporal sequence from administration of 
the study drug, the event follows a known response pattern to the study 
drug and based on the known pharmacology of the study drug, the event is 
clearly related to the effect of the study drug. The AE improves upon 
discontinuation of the study drug and reappears upon repeat exposure. 
  
·      Probable – The AE is likely related to the study drug. 
The event follows a reasonable temporal sequence from administration of 
the study drug, the event follows a known response pattern to the study 
drug AND the event cannot have been reasonably explained by an 
intercurrent medical condition OR the event cannot be the effect of a 
concomitant medication. 
  
·      Possible – The AE may be related to the study drug. 
The event follows a reasonable temporal sequence from administration of 
the study drug and the event follows a known response pattern to the study 
drug BUT the event could have been produced by an intercurrent medical 
condition which, based on the pathophysiology of the condition, and the 
pharmacology of the study drug, would be unlikely related to the use of the 
study drug OR the event could be the effect of a concomitant medication. 
  
·      Unlikely – The AE is doubtfully related to the study drug. 
AE does not have temporal relationship to intervention, could readily have 
been produced by the study participant’s clinical state, could have been due 
to environmental or other interventions, does not follow known pattern of 
response to intervention, does not reappear or worsen with reintroduction 
of intervention. 
  
·      Unrelated – The AE is clearly NOT related to the study drug. 
The event is clearly due to causes distinct from the use of the study drug, 
such as a documented preexisting condition, the effect of a concomitant 
medication, or a new condition, which, based on the pathophysiology of the 
condition, and the pharmacology of the study drug, would be unrelated to 
the use of the study.  
 
All SAEs will be reported to the project manager within 24 hours of the site 
becoming aware of the event. 
 
                
 
9.3 
Procedures 
 

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● AEs will be recorded from the time the consent form is signed through 
30 days after the last visit (i.e., at the one month follow-up from Visit 7).  
In addition, SAEs will be reported to the appropriate regulatory 
authorities, the IRB of Record, and investigators in accordance with all 
applicable laws and regulations. 
  
● AE reporting must also be carried out by each participating site 
investigator, according to their local policies and procedures, to the IRB 
responsible for oversight of their subjects. A copy of the IRB’s 
acknowledgement will be forwarded to the study project manager.  In 
addition, all AEs will be recorded on an Adverse Event Log at each site 
and entered in REDCap within 72 hours of the site staff becoming aware 
of the event.  All AEs must be followed until resolution or stabilization.  
 
● Unanticipated and unexpected problems involving risk to the subject 
and/or others, whether related or unrelated to participation in the study, 
must be reported within 24 hours of the site staff becoming aware of the 
event to the study project manager.  The project manager shall report 
all SAEs to the Sponsor Principal Investigator, who shall review and 
evaluate the evidence, and collaborate with the site PI on the final 
determination regarding attribution for reporting purposes to the 
following: FDA, Data Safety Monitoring Board (DSMB), Advarra, and/ or 
Cerevel.  
 
● SAEs which occur any time after the study participant has consented 
until one month (defined as 30 days) after Visit 7 (i.e., at the final follow-
up phone call) which are unexpected and possibly, probably, or definitely 
related to the research must be reported by the participating site to the 
study project manager within 24 hours of the site staff becoming aware 
of the event.  
  
● FDA and Cerevel Reporting 
● The Sponsor Principal Investigator’s Investigational New Drug (IND) 
office will report SAEs to the FDA (if required) via an IND Safety Report 
on 3500A MedWatch form according to FDA 21CFR312.32 within 15 
calendar days of the event occurring (within 7 days if the event is fatal 
or life-threatening). The Sponsor Principal Investigator’s project 
manager will also report to Cerevel within that same time period. 
 
● Advarra Reporting 
● Each site investigator and/or designee will promptly report unanticipated 
problems occurring at the site to Advarra as per their written policies and 
procedures.  SAEs that do not require prompt reporting will be reported 
at the time of continuing IRB review per their written policies and 
procedures via the Advarra CIRBI platform. 
 

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● Reporting to DSMB and NIMH 
● Any actions taken by one entity in response to adverse event reports will 
be reported to the other entities. SAEs that are unexpected, and 
possibly, probably, or definitely related to the intervention will be 
reported to the DSMB by the study project manager in writing within 24 
hours of awareness of the event. All other SAEs, expected or non-
serious adverse events, will be reported to the DSMB in the DSMB data 
reports submitted every 6 months or at the time of continuing IRB review 
of the study, and to the FDA in the IND annual report.  DSMB 
recommendations/outcomes will be made available to the NIMH. 
 
● COVID-19-related AEs and SAEs 
● All AEs and SAEs that are confirmed, or suspected to be related to, 
COVID-19 will be tracked within the REDCap system. These AEs and 
SAEs will be evaluated and reported using the same criteria as other 
AEs and SAEs. 
 
 
9.4   Criteria for stopping study 
 
For individual subjects, the stopping criteria are: 
● Withdrawal of consent and/or patient decision; 
● Loss to follow up; 
● Changes to eligibility based on inclusion/exclusion criteria; 
● Clinical judgment of the investigator or at request of subject, sponsor, or 
regulatory authority; 
      
Criteria for Stopping or Suspending Enrollment: 
●       
● Assessment that risks outweigh benefits in the view of either the DSMB, the 
study investigators or study sponsors  
● Decision by sponsors to withdraw funding or cease pursuing completion of 
the study.      
 
10. STATISTICAL CONSIDERATIONS 
 
10.1 Statistical Design and Power 
 
10.1.1 Primary Endpoint 
 
To test if CVL-562 has dose-related effects in schizophrenia patients on neural 
biomarkers of D1R/D5R stimulation. The proposed research includes 120 female 
and male adults (18-45 years) who meet diagnostic criteria for schizophrenia, 
schizoaffective disorder, or schizophreniform disorder and who are presenting 
early in their psychosis course (i.e., <5 years of psychosis duration since first 
frank psychotic episode). We will make every attempt to balance our recruitment 

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efforts with regard to sex.  
 
All preprocessing of imaging data will follow Human Connectome Project (HCP) 
pipelines(67). For each CIFTI-based gray-ordinate, least-squares coefficients will 
be generated independently reflecting BOLD signal during task conditions. We 
will use a general linear model to fit the hemodynamic response function (HRF) 
using a finite impulse response function (FIR) for the timepoints covering the 
encoding (timepoints 1-2) and delay epochs (timepoints 3-14) and the natural 
decay in the HRF (timepoints 15-20). Assessing the HRF across these 20 
timepoints for each task condition (motor, spatial working memory, distraction-
near and distraction-far) will allow us to examine the effects of dose response 
across our epochs of interest. From these general linear models, we will form 
within-subject contrasts for second-level analyses. We will use non-parametric 
combination (NPC) to examine the multivariate effects of dose (5 levels) and task 
condition (motor, spatial working memory, distraction-near and distraction-far) at 
each timepoint within each voxel of an independently defined mask of spatial 
working memory regions from the prior work of Dr. Cho (co-investigator). When 
compared with an ANOVA or related MANOVA, NPC provides a more 
statistically efficient and robust approach for this primary endpoint, while still 
allowing for testing of dose-dependent effects of drug on the task BOLD signal at 
different timepoints(68). NPC has the additional advantage of accommodating 
the multivariate and potentially non-normally distributed nature of our endpoints. 
Furthermore, NPC maintains better power at fixed sample sizes than traditional 
multivariate tests, which have increasing power as the number of modalities 
increases, until an inflection point, after which traditional test power declines.  
Significant voxels will be determined using non-parametric statistics and 
corrections for multiple comparisons as appropriate. 
 
As this is a multi-site neuroimaging project, we will validate neuroimaging data 
acquisition, transfer and processing prior to clinical data collection. These will be 
tested using members of the research team who will undergo neuroimaging 
procedures at each site. Scanning the same persons at each site will allow the 
research team to compare the image acquisition, as well as the collection of 
behavioral and eye-tracking data, at each site. We have opted for this instead of 
the exclusive use of phantoms, as task-based images would not be possible to 
collect with phantoms. Furthermore, we have opted to use research personnel 
who travel to each site, rather than examining the first few patients recruited, as 
we would like to examine image acquisition within-subject, and fully compare 
sites. Use of our recruited patients would not allow for within-subject 
comparisons of sites as the clinical protocol is meant to be carried out at one site. 
Ongoing stability of MRI scanners will be checked using regular phantom 
scanning.  
 

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Figure 2. Power Calculation for the Primary Endpoint. 
 
Power: The Primary Endpoint is concerned with within-subject repeated 
measurement of the CVL-562 dose response on the neuroimaging index. 
Therefore, the key power consideration is for a group-level within-subject t-test 
for the combined partial t-tests (Cohen’s d). With anticipated attrition we 
anticipate a final sample of N=100 complete patient datasets across all sites. 
However, given that data quality and retention may lead to smaller eventual 
samples, we projected detectable effect sizes using a projected power of at least 
80%, and p<0.05. Given our study design, and the NPC approach, we will be 
able to detect small-to-medium effect sizes (0.18-0.37) for sample sizes ranging 
between 25-100 participants with full data. Here, we provide an illustration of the 
achieved effect sizes at 80% power across possible sample size ranges (Figure 
2). 
 
10.1.2 Secondary Endpoint 1  
 
The dose-response-based change in BOLD signal will be examined for each 
individual participant to see how many participants exhibit a change in BOLD 
signal. For each individual, a binary outcome will be calculated based on the 
dose x timepoint x task condition within subject analysis of BOLD signal. We will 
report the proportion of participants that exhibits a dose response and assess 
whether this is related to baseline working memory performance. 
 
10.1.3 Secondary Endpoint 2 
 
We will test if CVL-562 produces a dose-related modulation of sWM performance. 
We will leverage behavioral data generated during neuroimaging to quantify dose-
related CVL-562 effects on sWM performance and also on sWM performance with 
distraction. Here, the outcome measure will be the sWM performance measured 
as the angular difference between the target presentation and the participant’s 
response. We will conduct a 4 (task condition--motor, spatial working memory, 
near-distraction, far-distraction) x 5 (dose) repeated measures ANOVA. Post-hoc 
analyses will be conducted to demonstrate the directional effects of behavioral 
performance with respect to dosing. All statistics will be corrected for multiple 

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comparisons. 
 
10.1.4 Secondary Endpoint 3   
 
We will directly examine the association between sWM performance and task-
evoked BOLD signal. An analysis of variance of the dose-dependent effects of 
CVL-562 on the task-evoked BOLD signal will be conducted as described for the 
Primary Endpoint, but instead will use the trial-by-trial regressor of sWM 
performance as a covariate. sWM performance will be measured as described in 
Secondary Endpoint 2, and will be treated as a covariate of interest in the above-
specified general linear model. An effect of a 5 (drug dose) x 4 (task condition) 
interaction with the sWM precision covariate would indicate that the drug has an 
effect of BOLD signal change that is specifically associated with a change in trial-
by-trial sWM performance.  
 
10.1.5 Secondary Endpoint 4 
 
We will conduct an analysis of variance of the dose-dependent effects of CVL-
562 on the functional connectivity of brain regions during spatial working 
memory. In contrast to the task-evoked modeling, here we will use 'time point' 
selection methods to isolate specific time points during the delay period of each 
trial, which we will combine into a time series. This BOLD signal will be used to 
co-vary a given region of interest with the rest of the brain. Given prior work by 
our team we will focus on the fronto-parietal control network (FPCN) as a 'seed' 
region for this task-evoked FC analysis. Specifically, we will quantify covariation 
of the extracted FPCN signals with all other CIFTI greyordinates. This index of 
FPCN 'functional integrity' will be obtained across sWM conditions and CVL-562 
doses for each subject and will then be entered into 2nd-level random effect 
analyses. 
 
10.1.6 Secondary Endpoint 5 
 
We will conduct an analysis of variance of the dose-dependent effects of CVL-
562 on the resting state functional connectivity using a data-driven global brain 
connectivity (GBC) metric. Notably, GBC examines connectivity from a given 
voxel (or area) to all other voxels (or areas) simultaneously by computing 
average connectivity strength—thereby producing an unbiased approach as to 
the location of dysconnectivity. Also, unlike typical seed approaches, GBC 
involves one statistical test per voxel (or area) rather than one test per voxel-to-
voxel pairing, substantially reducing multiple comparisons. Per-subject GBC will 
be obtained for each CIFTI greyordinate at each CVL-562 dose for each subject 
and will then be entered into 2nd-level random effect analyses.  
10.1.7 Secondary Endpoint 6  
 
Resulting resting state GBC maps will be compared against transcriptomic maps 
of genes relevant to psychotic disease processes from the Allen Human Brain 

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Atlas (https://human.brain-map.org/) using correlation analyses. This will allow us 
to see whether spatial patterns of resting state GBC map onto regions enriched 
for gene expression relevant to schizophrenia and related illnesses. 
 
10.1.8 Exploratory Endpoint 1      
 
We will conduct exploratory analyses to test whether genetic variants are related 
to BOLD signal changes in response to CVL-562. Genetic variants examined 
may include, but are not limited to, those genes involved in CVL-562 metabolism, 
the dopamine 1 receptor, or schizophrenia illness development. 
 
 
11. ADMINISTRATIVE AND REGULATORY  
 
11.1 Multicenter Management and Coordination 
 
The Yale University Coordinating Site Project Management team will support the 
PI with the multi-site management aspects of this trial. This includes, but is not 
limited to, study start-up, regulatory assistance (IRB submissions, amendments, 
and renewals), provision of template study forms (tracking and eligibility 
checklists, etc.), site qualification and activation, training, and overall project 
management. The Coordinating Site Project Management team will provide tools 
to assist the study teams in conducting the trial appropriately and according to 
ICH Good Clinical Practice.  
 
The Coordinating Site Project Management team will ensure that all participating 
sites undergo training in which all key study personnel will be instructed study 
procedures, informed consent, source documentation requirements, safety and 
adverse event reporting, Good Clinical Practice guidelines and additional study 
related topics. This training will be conducted by the Yale Center for Clinical 
Investigation (YCCI) Study Monitor and/or Project Management staff and 
documentation of completion will be required for all personnel. The PI will be 
available to site investigators for questions and re-training (if necessary). 
 
After a site initiation visit, which includes Good Clinical Practice (GCP), 
participating sites will receive a regulatory start up packet from the Project 
Manager or designee prior to beginning study procedures.  The start up packet 
will contain all required regulatory documentation and procedures that will need 
to be completed prior to site activation.  Upon satisfaction of these requirements, 
each site will receive a site initiation letter from the Project Manager or designee 
indicating the site is fully activated and can begin enrollment and study 
procedures.  All regulatory documents will be maintained on site and accessible 
for monitoring visits. 
 
11.2 Data safety and monitoring plan (DSMP) 
 

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11.2.1 Safety Evaluations  
 
Review of safety data will be conducted on all participants who have signed 
informed consent. Any safety concern or new information that might affect either 
the safety or the ethical conduct of this trial will be immediately forwarded to the 
principal investigator. Any adverse events that occur during the study will be 
recorded on the adverse event case report form in the eCRFs in REDCap The site 
investigators will be responsible for informing the IRB per local policy.  
 
11.2.2 Safety Monitoring  
 
The principal investigators, in conjunction with Yale Center for Clinical 
Investigation (YCCI), will provide primary oversight data and safety monitoring. 
They will be responsible for reviewing and monitoring compliance and deviations 
of this study. The sponsor Principal Investigator, the Institutional Review Board 
(IRB), the FDA or the NIMH have the authority to stop or suspend the study or 
require modifications.  
 
The principal investigators will review the data from this protocol bi-annually, at a 
minimum. Information to be reviewed includes: a summary report generated from 
the study database (which includes participant accrual, adverse events (including 
SAEs), and deviations), as well as monitoring reports. Other information and/or 
data will be provided upon request. During the review process the principal 
investigator will evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment.  
 
Reportable Events (which are events that are serious or life-threatening and 
unanticipated (or anticipated but occurring with a greater frequency than 
expected) and possibly, probably, or definitely related) or Unanticipated 
Problems Involving Risks to Subjects or Others (UPIRSO) that may require a 
temporary or permanent interruption of study activities will be reported 
immediately (if possible), followed by a written report within 5 calendar days of 
the investigator becoming aware of the event to the IRB (using the appropriate 
forms from the website) and any appropriate funding and regulatory agencies. 
The Principal Investigator will apprise fellow investigators and study personnel of 
all UPIRSOs and adverse events that occur during the conduct of this research 
project through regular study meetings or via email as they are reviewed by the 
principal investigator. The protocol’s research monitor(s), study sponsors, 
funding and regulatory agencies, and regulatory and decision-making bodies will 
be informed of unanticipated, serious adverse events within 5 days of the event 
becoming known to the principal investigator. 
 
11.2.3 Data Safety Monitoring Board  
 
The Data Safety Monitoring Board (DSMB) will meet approximately annually (prior 
to first randomization, end of first year of randomization, and completion of last 
subject). Study progress summaries would be provided to the DSMB members 

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approximately three weeks prior to each meeting. The DSMB is entrusted to 
review serious adverse events (SAE)s within 7 days, review adverse events (AEs) 
on an annual basis, and to monitor recruitment progress in order to evaluate study 
feasibility. Recruitment reports would be provided to the DSMB every 6 months 
with an optional face-to-face meeting at that time.  
 
11.2.4 Study Site Monitoring  
 
The principal investigators and YCCI are responsible for monitoring the 
performance of all of participating sites. This will be performed by conducting a 
study site initiation visit, as well as regularly scheduled monitoring visits and/or 
remote monitoring throughout the life of the protocol. Should travel be deemed 
difficult due to the COVID-19 pandemic or other related reasons, monitoring, 
including the study site initiation visit, may be remotely conducted. At the end of 
the trial, the monitor will then perform a study site close-out visit at all participating 
sites.  
 
YCCI will utilize their standard initiation, monitoring and close-out visit reports. 
Following each site visit, a visit report will be generated containing information on 
site activities, and a summary of pertinent points and action items together with a 
copy of the follow-up letter will be sent to each investigative site.  
 
During monitoring visits, some of the items that will be reviewed are the following:  
● Training of the sites  
● Site personnel qualifications to participate in the trial  
● That study related documents are current  
● That regulatory compliance is accomplished  
● That each subject has signed the informed consent  
● That the current and approved protocol is complied with (including reporting 
and logging of all protocol deviations)  
● That all SAEs and AEs have been reported appropriately  
● That source documentation matches CRFs  
 
YCCI will document the required study monitoring activities in a detailed Clinical 
Monitoring Plan. 
 
11.3 Confidentiality & Security of Data 
 
11.3.1 Data Security and Storage  
 
Each site will collect data using HIPAA trained personnel, and all electronic 
source data and neuroimaging data will be centrally stored at Yale University or 
at the University of Pennsylvania (for relevant questionnaires). Each site will 
keep a copy of the neuroimaging, behavioral and physiological data they have 
collected. Any data with paper sources will be stored at the site that collected the 
data. Electronic data will be stored and analyzed as de-identified, and the only 

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database where identifying information can be linked to a de-identifier will be 
encrypted and password protected. This database will only be accessible by 
specific study personnel. All study personnel will receive HIPAA compliance 
training. All paper data and personal health information will be de-identified and 
kept in lockable cabinets and lockable offices. As per requirements from the 
National Institute of Mental Health (NIHMH), de-identified data will be shared and 
made publicly available on the NIMH Data Archive (NDA, https://nda.nih.gov/).   
 
11.3.2 Informatics Equipment and Tools  
 
XNAT and REDCap resources will be used for data-sharing, data storage and 
transfer. The clinical and neuroimaging data-sharing and organization will use a 
2-prong neuro-informatics strategy deployed at Yale: i) Clinical behavioral data 
will be stored and shared via the REDCap database; ii) The de-identified 
neuroimaging data and other multi-modal data sources will be stored and shared 
via the Extensible Neuroimaging Archive Toolkit (XNAT), which readily integrates 
with REDCap. REDCap is a free, secure, web-based application designed to 
support data capture for research studies (http://project-redcap.org). The system 
was developed by a multi-institutional consortium initiated at Vanderbilt 
University. The PI’s team at Yale will use a fully HIPAA-compliant REDCap 
database, which is optimized for capture of longitudinal assessments. 
Importantly, the REDCap database is fully compatible with the XNAT system, 
which is an informatics platform for managing, exploring, and sharing 
neuroimaging data (http://www.xnat.org), developed at Washington University in 
St. Louis. Specifically, XNAT is designed to facilitate quality control procedures 
and provides secure access to and storage of both clinical and neuroimaging 
data. XNAT follows a 3-tier architecture that includes a data archive, user 
interface, and middleware engine. Data can be entered into the archive as XML 
or through data entry forms. Newly added data are stored in a virtual quarantine 
until an authorized user has validated it. XNAT subsequently maintains a history 
profile to track all changes made to the managed data. User access to the 
archive is provided by a secure web application. The web application provides a 
number of quality control and productivity features, including data entry forms, 
data-type-specific searches, searches that combine across data types, detailed 
reports, and listings of experimental data, upload/download tools, access to 
standard laboratory workflows, and administration and security tools. The 
research team will upload de-identified DICOM and/or NIFTI images. These 
images will be maintained via the XNAT database on the Yale servers and 
storage systems. As noted, the clinical information captured in REDCap can be 
readily integrated into XNAT for joint analyses. Furthermore, the XNAT database 
is deployed as part of the Human Connectome Project, providing a well-tested 
and robust long-term strategy for data management and pipeline workflow as 
proposed here. 
 
 
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