A Double-Blind Placebo-Controlled Trial of a Sulforaphane Nutraceutical to Reduce the Symptoms of Schizophrenia
Phase: PHASE2
Conditions: Schizophrenia, Schizoaffective Disorder
Sponsor: Sheppard Pratt Health System

 
A Double-Blind Placebo-Controlled Trial of a Sulforaphane Nutraceutical  
to Reduce the Symptoms of Schizophrenia 
 
NCT02810964 
 
April 17, 2019 

 
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PROTOCOL 
 
Title of Study:  
A Double-Blind Placebo-Controlled Trial of a Sulforaphane 
Nutraceutical to Reduce the Symptoms of Schizophrenia 
Funding Source: 
 
Stanley Medical Research Institute 
Principal Investigator:         Faith Dickerson, Ph.D., M.P.H., Sheppard Pratt Health System 
Co-Investigators:           
Sunil Khushalani, M.D., Sheppard Pratt Health System 
Jed W. Fahey, Sc.D., Johns Hopkins School of Medicine  
Robert Yolken, M.D., Johns Hopkins School of Medicine 
 
 
1. INTRODUCTION AND OVERVIEW 
 
 
We intend to explore the hypothesis that symptoms of schizophrenia may be reduced by the 
administration of a sulforaphane compound when used in addition to standard antipsychotic 
medications. Sulforaphane is a molecule that belongs to the isothiocyanate group of organosulfur 
compounds found in broccoli sprouts. Sulforaphane has potent anti-oxidant and anti-inflammatory 
activities (Juge, Mithen, & Traka 2007).  A recent trial in adolescent and young adult males with 
autism spectrum disorder found that sulforaphane treatment as an add-on medication was associated 
with improved psychiatric symptoms (Singh et al. 2014). To date, there have not been any 
controlled studies of sulforaphane in persons with schizophrenia. The proposed trial is justified on 
the grounds that: 1) oxidative stress is associated with the pathophysiology of schizophrenia and  
sulforaphane has anti-oxidant and anti-inflammatory properties; 2) positive effects of sulforaphane 
have been found in autism, a disorder with some similarities to schizophrenia; and 3) the compound 
has relatively low toxicity and a low side effect profile.  If this sulforaphane compound is found to 
be beneficial, it would provide a safe, inexpensive, and widely-available new modality for the 
adjunctive treatment of schizophrenia.        
 
 
We will randomize N=64 participants with schizophrenia or schizoaffective disorder who 
have residual psychotic symptoms which are of at least moderate severity. The participants will 
receive the sulforaphane compound 6 tablets once per day (equivalent to ~ 100 micromoles 
(µmol) of sulforaphane) or placebo 6 tablets once per day, over the 18 weeks of the trial. We 
have selected the 18 week duration of the trial to maximize both the likelihood of obtaining a 
therapeutic effect and of retaining participants in the study. This is also similar to the duration of 
the active phase in the published autism trial (Singh et al. 2014).  
 
 
The principal investigator and her research group are highly experienced in carrying out clinical 
trials of adjunctive treatments in persons with schizophrenia with 7 successfully-completed trials 
that have been published (Dickerson, Boronow, Stallings, Origoni, & Yolken 2003; Dickerson, 
Stallings, Boronow, Origoni, Sullens & Yolken 2009; Dickerson et al. 2009; Dickerson et al. 2014; 
Dickerson et al. 2009; Dickerson et al. 2011; Fenton, Dickerson, Boronow, Hibbeln & Knable 
2001).  The Investigational New Drug Application (IND 130136) was recently reviewed by the 
Food and Drug Administration and the investigator received a “may proceed” letter on April 20, 
2016.  
 

 
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2. SCIENTIFIC BACKGROUND AND RATIONALE 
 
Schizophrenia and Oxidative Stress 
 
Schizophrenia is a pervasive human disease of unknown etiology. In recent years, evidence 
has accumulated indicating that some cases of schizophrenia are associated with oxidative stress 
(Boskovic, Vovk, Kores Plesnicar, & Grabnar 2011; Do, Conus, & Cuenod 2010; Saruwatari et 
al. 2013). Oxidative stress reflects an imbalance between the systemic manifestation of reactive 
oxygen species and a biological system's ability to readily detoxify the reactive intermediates or 
to repair the resulting damage. Diminished anti-oxidants and/or increased production of reactive 
species will result in oxidative damage of cell lipids, proteins, enzymes, carbohydrates, and DNA 
(Boskovic et al. 2011). In schizophrenia, oxidative stress is also associated with immune 
activation (Pedrini et al. 2012). Oxidative damage has been suggested to be a common 
pathogenic process in this disorder which contributes to ongoing psychiatric symptoms and poor 
outcomes.    
 
Sulforaphane  
 
It is widely recognized that high consumption of plant-based diets reduces the risk of cancer 
and many other chronic diseases (Hardman 2014; Vanamala 2015).  Evidence for the special 
protective role of cruciferous plants, such as broccoli, is very strong and has been ascribed 
largely to their high content of glucosinolates. Whereas glucosinolates are themselves not active 
protectors, they are converted to active compounds by both the coexisting plant enzyme, 
myrosinase, and by the microflora of the gastrointestinal (GI) tract to isothiocyanates which are 
extremely effective blockers of carcinogenesis (Shapiro et al. 2006).  A widely studied example 
is the presence in broccoli sprouts of the glucosinolate, glucoraphanin, which is converted by 
myrosinase to the isothiocyanate, sulforaphane (Fahey, Zhang, & Talalay 1997; Fahey, 
Zalcmann, & Talalay 2001).  Myrosinase is present in plant cells and is compartmentalized 
separately from the glucosinolates. Sulforaphane is metabolized rapidly by initial conjugation 
with glutathione, and successive steps of hydrolysis of the conjugates leading to ultimate 
formation of the N-acetyl-cysteine derivative. All these conjugates are dithiocarbamates and can 
be quantified by the cyclocondensation reaction developed in the Johns Hopkins laboratory of 
Dr. Jed Fahey, one of the study investigators (Ye et al. 2002). Sulforaphane crosses the blood 
brain barrier and has general but potent indirect anti-oxidant and anti-inflammatory activities 
which function systemically (Bahadoran, Mirmiran, & Azizi 2013; Dinkova-Kostova & Talalay 
2008; Fahey & Kensler 2007; Fahey & Talalay 1999; Koo, Park, Kim, & Lee 2013).   
 
 
The major mechanism by which sulforaphane protects cells was initially thought to be 
through Nrf2-mediated induction of phase 2 detoxification enzymes that elevate cell defense 
against oxidative damage and promote the removal of carcinogens. However, there may be 
additional mechanisms activated in response to sulforaphane including suppression of 
cytochrome P450 enzymes, induction of apoptotic pathways, suppression of cell cycle 
progression, inhibition of angiogenesis, and inhibition of inflammation (Fahey et al. 2015).  
 
 
The compound which we will use in this trial is a sulforaphane compound which was 
developed by Nutramax Laboratories and marketed commercially as Avmacol®. The compound 
contains a precursor of sulforaphane, glucoraphanin, formulated with an enzyme, myrosinase, 

 
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which results in the generation of sulforaphane in the gastrointestinal tract. This compound is the 
only one available on the consumer market which co-delivers glucoraphanin and the enzyme, 
myrosinase, needed to hydrolyze it to its active form, sulforaphane, and which is shelf-stable at 
room temperature. This same compound is also being used in two other trials with psychiatric 
populations (A 6-month Randomized, Placebo Controlled Study to Evaluate Sulforaphane Add-
on Effects In Treatment of First Onset and Early Stage Schizophrenia; Sulforaphane Treatment 
Of Children With Autism Spectrum Disorder).   
 
 
Until now, many clinical studies targeting sulforaphane have utilized a hydrolyzed broccoli 
sprout extract prepared and standardized by the Cullman Chemoprotection Center at Johns 
Hopkins University. The use of the hydrolyzed broccoli sprout extract is burdensome in clinical 
trials because the sulforaphane is only moderately stable over time and the product must be kept 
frozen to maintain bioavailability; in addition, the percent of the dose excreted in urine as 
sulforaphane is relatively low. The cost, convenience, reproducibility, and potential for post-
study continuance are all attractive features of a commercially available supplement compared to 
the made-for-clinical-trials-only broccoli sprout extract preparation.  
 
 
It is of note that although Dr. Fahey first described and developed broccoli sprouts as a 
source of glucoraphanin, neither he, nor the other researchers at Johns Hopkins or Sheppard Pratt 
involved in this study are connected with Nutramax, the company that produces the Avmacol® 
product, nor will they benefit from the sales of any Nutramax product. 
 
Previous Clinical Trials of Sulforaphane Supplementation in Neuropsychiatric Populations 
 
A randomized controlled trial of broccoli sprout extracts was performed by Singh et al. 
(2014) in N=44 adolescent and adult males with autism spectrum disorders. The effects on 
behavior of daily oral doses of sulforaphane (50-150 µmol) for 18 weeks followed by 4 weeks 
without the treatment were quantified by behavioral measures. After the treatment period, those 
randomized to sulforaphane showed substantial improvements in social interaction, abnormal 
behavior, and verbal communication, whereas those assigned to placebo showed minimal 
change. After discontinuation of the sulforaphane, the actively-treated group reverted to baseline 
levels on the behavioral measures (though 10 of 26 who received active compound were not seen 
for the follow-up). The number of adverse events did not differ between the groups; one 
participant receiving the active compound experienced a single seizure during the trial and one 
participant experienced a single seizure several weeks after discontinuing treatment; both had a 
history of seizure disorder which is common in people with autism. 
 
 
A second trial of broccoli sprout extracts in psychiatric patients was recently reported and 
was a small open-label trial of N=10 adult outpatients with schizophrenia, 7 of whom completed 
the trial (Shiina et al. 2015). Participants received a daily dose of 30 mg of the precursor, 
glucoraphanin (sulforaphane-glucosinolate), per day for 8 weeks. The primary outcome was a 
battery of computerized non-verbal tasks. Performance on one of the five cognitive tasks, the 
One Card Learning Task, improved in the trial but not the other tasks or ratings of psychiatric 
symptom severity. The sulforaphane compound was well tolerated. The very small sample size 
in this trial, the short treatment period, and the open-label design preclude any conclusions about 
the efficacy of the compound in schizophrenia. In addition, the study compound consisted of the 

 
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precursor, glucoraphanin, which was administered without the added enzyme, myrosinase, and 
likely had a conversion to sulforaphane which was 10% of that in the Singh et al. (2014) trial.  
 
Preliminary Investigation to Determine Bioavailability of Study Compound 
 
This preliminary investigation is currently being carried out by Dr. Fahey of the Johns 
Hopkins School of Medicine. In brief, 20 healthy adult volunteers will be recruited from 
previous studies and advertisements. Participants will be screened after consent based on 
whether they are able to comply with the dietary restrictions and medication exclusions.  They 
will be asked to refrain from consuming cruciferous vegetables and condiments (e.g., mustard, 
horseradish, wasabi) that might contain glucosinolates or isothiocyanates for 3 days before and 
during the study. Participants will fast overnight and the following morning.  They will then take 
7 Avmacol® tablets orally; each tablet will contain 15 mg of glucoraphanin for an expected 
sulforaphane dose that should average 100-150 µmol. Participants will provide a pre-dosing 
urine sample, and the entire urine excreted during the first 8 hours and for the following 16 
hours, in segregated collections. Total dithiocarbamate excretion in each urine sample (three per 
participant) and urine creatinine concentrations will be determined.  Dithiocarbamates (DTC) are 
the ultimate metabolites of sulforaphane excreted in the urine, and are readily measured by 
techniques developed by the Cullman Chemoprotection Center (Ye et al. 2002).  It is expected 
that the conversion of the oral dose to the excreted DTC will be about 40%, but any mean 
conversion of >10% (the mean bioavailability without added myrosinase) will be considered 
acceptable. Preliminary results from this study are that conversion is at least 35% (personal 
communication, JW Fahey, March 9, 2016). 
 
Aims 
The primary aim of the study is: 
1. To evaluate the safety and efficacy of a sulforaphane compound for individuals with 
schizophrenia who have residual psychotic symptoms of at least moderate severity in a 
double blind trial. The primary outcome will be the severity of psychiatric symptoms as 
measured by the Positive and Negative Syndrome Scale (PANSS) (Kay, Fiszbein, & Opler 
1987).  We will also measure cognitive functioning with the MATRICS Consensus 
Cognitive Battery (MCCB) (Nuechterlein et al. 2008).  
 
Secondary aims of the study are: 
2. To study the effect of the sulforaphane compound in lowering several biomarkers of 
inflammation including C-Reactive Protein (CRP), heat shock protein 90, and other 
markers of inflammation and cell damage.  
3. To investigate the association between the efficacy of sulforaphane therapy and initial and 
follow-up levels of these markers.  
 
3. INFORMED CONSENT 
 
 
The informed consent form will contain a full explanation of the possible risks, alternative 
treatment options, and availability of treatment in the case of injury, in accordance with the 
Federal Regulations as described in 21CFR50.      
        

 
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The principal investigator is responsible for obtaining written informed consent from any 
potential participant before performing any study specific tests or assessments required by the 
protocol. It is the responsibility of the principal investigator to document each participant’s 
capacity to provide informed consent. The principal investigator may decide that an individual is 
not competent to give consent even though the treating source believes the participant to be 
competent, but not vice-versa. A copy of the signed document will be given to the participant 
(and providers as necessary); the original will be placed with the case report forms. 
 
4. PARTICIPANT INCLUSION AND EXCLUSION CRITERIA AND RECRUITMENT 
 
Participant Inclusion Criteria 
• Capacity for written informed consent 
• Age 18-65 years, inclusive 
• Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)  diagnosis of 
schizophrenia or schizoaffective disorder (APA 2013) as determined by the Structured 
Clinical Interview for DSM-5 Disorders (SCID-5) (First, Williams, Karg, & Spitzer 
2015)  
• Currently an outpatient at time of screening 
• Residual psychotic symptoms of at least moderate severity as evidenced by a Positive and 
Negative Syndrome Scale (PANSS) total score of 60 or higher AND one or more of the 
following:  one or more PANSS positive symptom scores of 4 or higher; OR containing 
at least three positive or negative items with scores of 3 or higher at the screening visit 
(Kay et al. 1987) 
• Receiving antipsychotic medication for at least 8 weeks prior to enrolling in the study 
with no antipsychotic medication changes within the previous 21 days from visit 2 (week 
0) 
• Conformance to PORT Treatment Recommendation about Maintenance Antipsychotic 
Medication Dose (Buchanan et al. 2010) 
• Proficient in the English language  
• Participated previously in one of our screening studies (A Study of Individuals with 
Psychiatric Illness to Determine the Presence Of Antibodies to Infectious Agents and 
Immune Markers; A Study of Individuals with Schizophrenia or Schizoaffective Disorder 
to Determine the Presence of Antibodies to Infectious Agents and to Establish Eligibility 
for Individuals' Participation in Future Studies; A Study to Determine Antibodies to 
Infectious Agents and Eligibility for Future Studies in Recent Onset Psychosis). Note: 
Participation in one of our screening studies may also take place during the same time 
period as the screening visit for this trial. 
 
Participant Exclusion Criteria 
• Any clinically significant or unstable medical disorder as determined by the principal 
investigator and/or the study physician (e.g., HIV infection or other immunodeficiency 
condition (such as receiving chemotherapy), uncontrolled diabetes, congestive heart 
failure) 
• DSM-5 diagnosis of intellectual disability or comparable diagnoses determined by 
previous versions of the DSM 

 
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• DSM-5 diagnosis of a moderate or severe substance use disorder, except for caffeine or 
tobacco, within the last three months prior to the screening visit.  If the patient has a 
positive drug toxicity screen at the time of visit 1 (screening) further evaluation by the 
investigator will be done of the substance use to determine eligibility. 
• Any current use of a broccoli supplement (e.g., Avmacol® or other health food broccoli 
supplement) 
• Participated in any investigational drug trial in the past 30 days prior to the screening 
visit 
• Pregnant, planning to become pregnant, or breastfeeding during the study period 
 
 
Participants will be recruited from clinical programs at Sheppard Pratt and affiliated 
agencies. Participants may be drawn from individuals who participated in previous studies 
performed by our research group and who provided written permission to be re-contacted about 
future studies. Participants may also be recruited from other rehabilitation and treatment 
programs in central Maryland. Additionally, participants may be recruited from self-referrals 
through advertisements and/or word-of-mouth. All participants will provide written informed 
consent after the study procedures are explained to them. 
 
5. STUDY DESIGN AND PROCEDURES 
 
Study Overview 
 
Over a two year period, we will randomize N=64 participants who have residual psychotic 
symptoms which are of at least moderate severity. Based on our experience performing similar 
clinical trials, we anticipate that we will evaluate up to 100 participants in order to randomize 64.  
We expect a drop-out rate of 15% after randomization. The trial will begin with a 2 week single-
blind placebo run-in phase followed by a 16 week double-blind phase. During the placebo run-in 
phase, participants will receive placebo 6 tablets once per day. During the double-blind phase, 
participants will receive either the sulforaphane tablet 6 tablets once per day (equivalent to ~100 
µmol of sulforaphane) or the placebo 6 tablets once per day. The primary outcome that will be 
assessed is the severity of psychiatric symptoms as measured by the Positive and Negative 
Syndrome Scale (PANSS) (Kay et al. 1987). We will also measure cognitive functioning with 
the MATRICS Consensus Cognitive Battery (MCCB) (Nuechterlein et al. 2008). In addition, we 
will study the effect of the sulforaphane compound in lowering several biomarkers of 
inflammation including C-Reactive Protein (CRP), heat shock protein 90, and other markers of 
inflammation and cell damage. We will also investigate the association between the efficacy of 
sulforaphane therapy and initial and follow-up levels of these markers. For a detailed list of 
procedures and assessments at each study visit, see the Schedule of Assessments. 
 
Study Compound 
 
The active study compound and identical-appearing placebo will be prepared and provided 
by Nutramax Laboratories, Edgewood, MD, USA, the company that makes Avmacol®, a 
commercially-available over-the-counter compound (http://www.nutramaxstore.com/avmacolreg-
60-tablets-p430.aspx).  The active ingredient in Avmacol® is produced naturally by extracting the 
biologically inactive glucosinolate, glucoraphanin, from broccoli seeds, and compressing it in 
tablets with active myrosinase from broccoli sprouts. The ingestion of this compound leads to the 

 
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hydrolysis of glucoraphanin and the generation of sulforaphane within the gastrointestinal (GI) 
tract and the subsequent systemic absorption of the sulforaphane. 
 
 
The dose per tablet is 16 mg of glucoraphanin or 37 µmol; 6 tablets per day should yield 
about 100 µmol of sulforaphane (Fahey et al. 2015). The study compound will be provided as a 
.375 punch size, round concave tablet, about the size of a regular (325 mg) enteric-coated 
aspirin. The compound will be taken orally, once per day. Once per day dosing is selected in 
order to optimize compliance.  
 
  
The study compound will be stored in a freezer until time of dispensing for maximum 
assurance of potency even though Nutramax certifies it for 2 years shelf life at room temperature.  
At each visit during the treatment phase, the participant will receive a two week supply of the 
study compound that can then be stored at room temperature.  Participants will be asked to take 
the study compound at the same time each day. Participants will not be instructed to alter their 
diet or to reduce their intake of vegetables as the amount of sulforaphane that is obtained from 
ingested vegetables is low and not expected to change the results of the study. Any participant 
who is taking a broccoli neutraceutical supplement will be excluded.  
 
Concomitant Medications Allowed 
 
Participants will continue taking previous psychotropic medications that they are prescribed. 
However, we will request, insofar as possible, that no changes take place in the type or dose of 
their psychotropic medications for the duration of the study. At each study visit, we will record 
all medications and doses that the participant is receiving, noting any changes. There are no 
medications that are disallowed in this trial. 
 
Screening for Eligibility 
 
Potential participants will be screened for eligibility based on a review of the psychiatric 
diagnosis or diagnoses, substance use history, medical history, and other criteria as listed in the 
study inclusion and exclusion criteria list. Information needed to determine eligibility will be 
obtained through careful review of the participant’s medical record, previous study documents, 
discussion with the treatment team, and/or participant interview. After likely eligibility is 
established, the participant will be seen for the screening visit. 
 
Screening Visit 
 
The screening visit assessments will be completed within 1 to 14 days of the research staff 
obtaining the signed consent or until sufficient evidence exists to fully assess inclusion and 
exclusion criteria. The screening assessments include obtaining informed consent, symptom and 
SCID-5 (First et al. 2015) interviews, a detailed psychiatric history (obtained from available 
medical records, previous study documents, and participant self-report), a physical examination 
and medical history, and clinical laboratory tests as described in more detail below. 
 
 
The clinical laboratory tests collected at the screening visit will include a complete blood 
count (CBC), complete metabolic panel (CMP), thyroid stimulating hormone (TSH), urinalysis, 
urine drug screen, and urine pregnancy test (if female and of child-bearing potential). Subsequent 
drug screening may be done at any time throughout the study at the discretion of the principal 
investigator.  A complete blood count (CBC), complete metabolic panel (CMP), and urinalysis 
will be repeated at visit 11 (week 18). 

 
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Vital signs, including blood pressure, temperature, pulse, height, and weight will be collected 
at the screening visit and repeated at visit 7 (week 10) and visit 11 (week 18). 
 
 
The following will be obtained, collected, and/or verified during the screening visit: 
 
Diagnostic and Background Information: 
• Primary DSM-5 Axis I diagnosis of schizophrenia or schizoaffective disorder (APA 
2013) as determined by the SCID-5 (First et al. 2015)  
• Background information including age, race, gender, participant and participant’s 
parents’ educational attainment, and psychiatric and medical history 
• Assessment of past and recent suicidal behavior evaluated with a suicide screening 
assessment that is based on the Columbia-Suicide Severity Rating Scale (Posner et al. 
2011) 
• List of current medications (may be obtained from the participant’s medical records) 
• Co-occurring medical conditions (obtained through a brief review of systems and/or 
medical records), and vital signs 
• Physical examination (unless one has been completed within the past 30 days and 
documented in medical records accessible to the research staff) 
• Blood and urine samples for clinical laboratory tests as described above   
• Written consent to contact outpatient treatment providers to inform them of the study and 
establish communication with them  
 
Clinical Instrument: 
• Positive and Negative Syndrome Scale (PANSS) (Kay et al. 1987), a rater-based scale 
used to assess and measure the severity of psychiatric symptoms over the past one week 
(unless previously obtained within the last one week) 
 
 
The screening visit will take approximately two hours to complete and may be divided into 
separate sessions to minimize participant fatigue.   
 
Research Laboratory Measures   
Samples for these measures will be obtained at visit 2 (week 0), the start of the placebo run-in 
phase, and other time points as noted below. 
• Blood sample (approximately 20 ml)  to measure levels of immune markers and antibodies 
to infectious agents including high sensitivity CRP, TNF alpha, antibodies to food antigens 
such as casein and gliadin (Severance et al. 2012),  and antibodies to NR2 (Dickerson, 
Stallings, Vaughan, Origoni, Khushalani, and Yolken 2012). Of note, CRP is a non-specific 
marker of inflammation which is elevated in many individuals with schizophrenia and has 
been found to be reduced by the administration of a sulforaphane nutraceutical (Bahadoran 
et al. 2013). These measures will also be performed at visit 7 (week 10) and visit 11 (week 
18). 
• Blood sample (approximately 8 ml) used to measure levels of biomarkers of inflammation 
including Keap1/Nrf2-induced markers of cytoprotection and of the heat shock response (in 
peripheral blood mononuclear cells), using real time PCR and protein gels (Western 
blots).  These samples will be analyzed in the Johns Hopkins Cullman Chemoprotection 

 
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Center of Dr. Fahey.  These measures will also be performed at visit 7 (week 10) and visit 
11 (week 18). 
• Blood sample (4-6 ml) for the measurement of the blood level of the antipsychotic 
medication. . These measures will be performed also at visit 11 (week 18). 
• Throat swab samples for study of the oropharyngeal microbiome.  These measures will be 
performed at visit 2 (week 0), visit 7 (week 10), and visit 11 (week 18) 
• Urine sample for compliance and dose potency testing. Sulforaphane-glutathione 
dithiocarbamate (DTC) metabolites will be measured from urine provided by participants as 
biomarkers of compliance. These tests will also be performed at the Johns Hopkins Cullman 
Chemoprotection Center. These measures will also be performed at visit 7 (week 10) and 
visit 11 (week 18). 
 
 
These blood, throat swab,  and urine samples will be identified by participant number only when 
they are sent to the research laboratories at Johns Hopkins for analysis. The clinical investigators 
will be blind to these results of the participant’s research laboratory tests during the course of the 
trial. The laboratory scientists will be blind to the participant’s treatment assignment during the 
course of the trial.  
 
Placebo Lead-In Phase 
 
Participants will begin a 2 week single-blind placebo phase at visit 2 (week 0), within 7 to 30 
days of completion of the screening visit. Visit 2 (week 0) will take approximately two to three 
hours to complete. Participants who complete the two week placebo run-in phase and continue to 
meet eligibility criteria will be randomized to a treatment arm at visit 3 (week 2).  
 
Randomization and Double-Blind Treatment Phase 
 
Double-blind randomization will occur at visit 3 (week 2). Participants will be randomized to 
receive either the sulforaphane compound or placebo tablets which are indistinguishable from the 
sulforaphane tablets for the 16 weeks of the double-blind phase. Symptom evaluations will be 
completed at bi-weekly study visits at which time participants will also be evaluated for adverse 
events. Visits 3 to 10 (weeks 2 to 16) will take approximately one hour each to complete. Visit 
11 (week 18) will take approximately two to three hours to complete.  
 
 
Randomization will assure that out of N=64 total participants, approximately half are 
assigned to each treatment arm. In addition, block randomization, based on initial PANSS total 
scores, will be used to assign participants to the two treatment groups to avoid differences in 
initial PANSS scores between the groups. Only the study data manager and the study pharmacist 
will be aware of participant assignment during the trial.  
 
 
Treatment providers will be asked to maintain participants on the same psychotropic 
medication regime throughout the study. At each bi-weekly study visit, research staff will 
document any medication changes. Any medication changes that are made will be studied as a 
secondary outcome. 
 
 
The study compound will be taken once per day and the dose will not be adjusted throughout 
the trial. 
 

 
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Visit Windows 
 
Visit 2 (week 0) will take place 7 to 30 days after visit 1 (screening). Visits 3 to 11 (weeks 2 
to 18) will take place 12 to 16 days after the previous visit. Visits may be divided into separate 
sessions to minimize participant fatigue. 
 
Compliance 
 
Pill counts and/or participant reports of compliance will be obtained. If pill counts or 
participant reports indicate the participant has not taken all of the prescribed study compound, the 
participant will be counseled about the importance of following directions. If the participant has 
missed more than 32 daily doses cumulatively throughout the study (>25% of study drug), the 
participant will be terminated from the study. 
 
 
Compliance will also be confirmed with laboratory testing of urine samples provided by 
participants at 3 points during the trial (visits 2, 7, and 11). Participants will be told that these 
samples will be collected at random. These urine samples will be used to measure sulforaphane-
glutathione metabolites in Dr. Fahey’s laboratory.  
    
Discontinuation  
A participant may be discontinued from the study for any of the following reasons: 
• If the participant fails to follow study directions (failure to keep appointments, follow 
directions or take the study compound as instructed) 
• If the participant does not attend study visits, or is not in contact with research staff for 3 
bi-weekly consecutive study visits 
• If the participant has a positive drug screen, research staff will inform the participant that 
a repeat test will be done at the next visit; if the next test is positive then she/he will be 
removed from the study 
• If it is the judgment of the study physician, in an effort to improve the participant’s 
medical care, or if the participant develops a serious medical illness, becomes pregnant, 
or begins breast feeding 
• If the participant has unexpected or serious side effects or serious medical complications 
 
 
If a participant discontinues from the study, discontinuation assessments will be done at the 
discretion of the principal investigator.  
 
 
A participant may withdraw from the study at any time at his/her own request. 
 
Clinical Outcome Measures 
• The primary outcome measurement will be the change in scores on the Positive and 
Negative Syndrome Scale (PANSS) (Kay et al. 1987) from the beginning to the end of the 
double-blind treatment phase, visits 3 to 11 (weeks 2 to 18).  The PANSS contains 30 items 
that assess symptoms of schizophrenia including positive, negative and general symptom 
psychopathology. The PANSS was chosen because of its widespread use in clinical studies 
of psychosis and its demonstrated reliability in assessing psychopathology across diverse 
patient populations. 
 

 
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• Secondary outcomes will be changes in scores on the MATRICS Consensus Cognitive 
Battery (MCCB) (Neuchterlein et al. 2008). The MCCB is comprised of  7 cognitive 
domains and 10 related tests (Trail Making Test: Part A; Brief Assessment in Cognition in 
Schizophrenia: Symbol Coding; Hopkins Verbal Learning Test-Revised; Wechsler Memory 
Scale-Third Ed: Spatial Span; Letter-Number Sequencing; Neuropsychological Assessment 
Battery: Mazes; Brief Visuospatial Memory Test-Revised; Category Fluency: Animal 
Naming; Mayer-Salovey-Caruso Emotional Intelligence Test: Managing Emotions; and 
Continuous Performance Test-Identical Pairs). 
 
6. SAFETY 
 
Data Safety Monitoring Board 
 
This committee will be composed of a group of three scientists who are not directly involved 
with the study and are qualified to serve in an advisory capacity in order to evaluate safety and 
efficacy of the trial. The safety monitoring board will convene before the study begins and, after 
the trial is underway, at regular intervals that they determine to be appropriate or at other times at 
the request of the study investigators.   
 
Physical Examination and Clinical Laboratory Tests 
 
A physical examination will be performed at the screening visit (unless one has been 
completed within the past 30 days and documented in medical records accessible to the research 
staff). Clinical laboratory tests including CBC, CMP, thyroid stimulating hormone (TSH), and 
urinalysis will also be performed. The study physician will determine the participant’s medical 
eligibility for the study after reviewing the findings from the screening physical examination and 
laboratory tests.   
 
 
In the event that the study physician determines that a participant’s lab value is clinically 
significant, the participant will be made aware of the abnormal laboratory finding and will be 
referred for follow-up with his/her primary care physician or other appropriate medical care.  
Lab results may be sent to participant’s primary care physician or other treatment providers.  
Copies of lab-work will be made available to participants upon their request. Clinically 
significant abnormal laboratory findings may be repeated to determine the participant’s 
eligibility for the study. 
 
 
In the case of serious medical illness and/or abnormal laboratory findings that emerge in the 
course of the study, the study physician may determine that a participant should be terminated or 
excluded from the study. 
 
Pharmacy Oversight 
 
The study compound will be kept in a locked freezer which is monitored daily for 
temperature by a computerized monitoring system. Supplement storage and audits will be 
performed quarterly by the Sheppard Pratt study pharmacist, Dr. Joshana Goga.  
 
Minimizing Risk 
 
Participants will be maintained on their regular psychotropic medications, with the intent to 
avoid any changes in dose or medication. Each participant will be instructed and expected to 

 
12
continue treatment with his/her mental health providers and to remain on his/her prescribed 
psychotropic medications throughout the study. During the study, participants will be seen on a 
bi-weekly basis during scheduled visits and assessed for the presence of any adverse events.  
 
 
If a participant reports psychiatric symptoms that raise concern about safety such as 
imminent, potentially-dangerous behavior, research staff will consult with the principal 
investigator and/or study physician and may contact the participant’s current treatment providers. 
Permission to contact treatment providers will be obtained at the screening visit and updated as 
necessary throughout the study if providers change. Research staff will encourage participants to 
seek immediate help in these cases. Additionally, research staff may arrange for emergency 
assessment if a participant presents as a danger to self or others, in consultation with the 
principal investigator and/or the study physician. If safety cannot be assured, research staff will 
call 9-1-1.    
 
Privacy and Confidentiality 
 
Confidentiality will be protected by ensuring all research staff have been properly trained in 
confidentiality and human participant research procedures, coding all participant information 
when possible, and by securing participant files in locked filing cabinets or on secured databases 
with access available only to the research staff.  Furthermore, data entered into a computer 
database will be stored on secured computers that will be password-protected with access 
available only to the research staff. Any screening information obtained from potential research 
participants who subsequently do not participate in the research study will be destroyed.  
 
 
Data obtained in this study will be shared with the National Database for Clinical Research 
Related to Mental Illness (NDCT), which is required by the funding source. NDCT is a data 
repository run by the National Institute of Mental Health (NIMH) that allows researchers to 
collect and share de-identified data from studies related to mental illness. Other researchers may 
apply to obtain access to de-identified data from this study.  The NIMH carefully analyzes each 
request in order to minimize risks of privacy. The information provided to NDCT may help 
researchers around the world treat future children and adults with mental illnesses so that they 
have better health outcomes. Participants will not be contacted directly about the study data 
shared during and after their research participation, and no protected health information will be 
entered into the NDCT.    
 
Adverse Effects and Drug Interactions  
 
Broccoli sprouts have been widely marketed throughout the world as a food source. Oral 
broccoli sprout preparations have been used in a number of human studies as described above to 
investigate the pharmacologic properties, safety, and biological effects of sulforaphane 
glucosinolates. Avmacol® supplements have been available to the public since 2013.  The 
manufacturer reports that as of February 15, 2016, over 12,000 bottles have been distributed and 
there have been no reported adverse events from consumers in the general public.  
 
 
Potential adverse effects that might be expected include mild GI symptoms such as 
indigestion, belching, or loose stools. These are the only symptoms that have been reported in the 
many clinical trials of glucoraphanin-rich or sulforaphane-rich broccoli sprout extracts (Alumkal 
et al. 2015; Cornblatt et al. 2007; Egner et al. 2011; Egner et al. 2014; Fahey, Talalay, & Kensler 

 
13
2012; Heber et al. 2014; Kensler et al. 2012; Poulton et al. 2013; Riedl, Saxon, & Diaz-Sanchez 
2009; Shapiro et al. 2006; Shapiro, Fahey, Wade, Stephenson, & Talalay 1998; Shapiro, Fahey, 
Wade, Stephenson, & Talalay 2001; Singh et al. 2014; Ye et al. 2002). True allergic reactions to 
broccoli (as opposed to intolerance or taste aversion) have never been reported.  Sulforaphane 
might decrease how quickly the liver breaks down some medications because of the modulation 
of cytochrome enzymes such as P450; however, the extent of this effect is expected to be limited 
at the doses we are using. Moreover, the effects of sulforaphane on the modulation of drug 
metabolism/transport enzymes are varied and may serve to increase or to decrease the blood 
levels of medications that are metabolized by the liver (Fimognari, Lenzi, & Hrelia 2008).  We 
will measure blood levels of antipsychotic medications at the beginning and end of the trial with 
tests performed by a local clinical laboratory. 
 
 
It is of note that numerous other factors influence drug interactions in addition to P450 
isoenzymes including age, gender, smoking, and genetic factors. Also, 30 to 40% of the 
participants in the previous Singh et al. (2014) study in adult autism were receiving antipsychotic 
medications; per the principal investigator of this study, clinical worsening was observed in only 
one subject and he turned out to be on placebo (A. Zimmerman, personal communication, Sept 4, 
2015). 
 
Adverse Events and Reporting 
 
For the purposes of collecting and evaluating all information found during this trial, an 
adverse event is any undesirable or unexpected experience that occurs after informed consent has 
been obtained without regard to the possibility of a causal relationship, and without regard to 
treatment group assignment. A serious adverse event is any adverse event that: results in death; is 
life threatening; results in inpatient hospitalization or prolongation of existing hospitalization; 
results in a persistent or significant disability/incapacity; or results in congenital anomaly/birth 
defect. For all adverse events, research staff will question the participant regarding the 
occurrence and nature of the event and will document the information obtained. Adverse events 
shall be followed until they return to baseline or stabilize regardless of whether the participant 
has discontinued the study early or completed the final study visit, visit 11 (week 18); if 
occurring at the end of the study, the adverse events will be referred to the participant’s primary 
care physician and/or other treatment provider for continued treatment and/or follow-up.  All 
serious adverse events will be documented and reported to the Institutional Review Board (IRB) 
within the required time period. All adverse events will be summarized in a report at intervals 
requested by the IRB and the overseeing Data Safety Monitoring Board. 
 
7.  STATISTICAL ANALYSIS 
 
 
Power calculations indicate that a sample size of N=64 has 80% power to find an effect size 
of d = .76 with an alpha =.05 and a two-tailed test of change between groups from screening to 
end of study.   
 
 Aim 1:  Safety data will be analyzed using incidence density analysis, to compare rates of 
adverse events across groups, as well as survival analysis, to assess group differences in 
retention. PANSS total scores will be the primary efficacy endpoint.  Repeated-measures 
regression models will be used to assess the main effects of group and time, plus the time by 
group interaction. This method is able to utilize all available data from participants with 

 
14
incomplete follow-up, thus including participants who drop out of the study.  (Based on our 
experience in previous trials with this population, we anticipate attrition of about 15% over the 
course of the trial.) A similar analytical approach will be used for the PANSS subscales and the 
MCCB outcome measures. 
 
Aim 2: Repeated measures regression modeling will also be used to evaluate the effect of 
medication group, time, and their interaction on inflammatory biomarkers. 
 
Aim 3: Treatment groups will be compared with respect to initial and follow-up levels of 
inflammatory biomarkers using t-tests.  If groups are found to differ in this regard, the efficacy 
analyses will be repeated, adding the initial biomarker levels as covariates in the model. 
 
8. COMPENSATION 
 
 
Participants will receive $20 for completing visit 1 (screening) and $20 for completing visit 2 
(week 0).  For visits 3 to 10 (weeks 2 to 16), participants will receive $15 for each visit. At visit 
11 (week 18), the ending visit, participants will receive $20 for completing the visit and an 
additional $40 completion bonus (for a total of $60). The maximum compensation received by a 
participant who completes the entire trial will be $220. 

 
15
9. SCHEDULE OF ASSESSMENTS 
 
 
Screening 
1-14 days 
Week 
0 
Start Placebo 
Week 
2 
Start 
Randomized 
Phase 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Visit Window 
Interval 
 
1-14 Days  7 – 30 Days 
14 Days 
(+/- 2 days) 
14 Days 
(+/- 2 days) 
14 Days 
(+/- 2 days) 
14 Days 
(+/- 2 days) 
14 Days 
(+/- 2 days) 
14 Days 
(+/- 2 days) 
14 Days 
(+/- 2 days) 
14 Days 
(+/- 2 days) 
14 Days 
(+/- 2 days) 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
DSM-5 SCID 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
X 
 
 
 
X 
Psychiatric and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Substance Use 
History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
CBC, CMP and 
TSH* 
X 
 
 
 
 
 
 
 
 
 
X* 
Urinalysis including 
pregnancy*  and 
drug screening* 
X 
 
 
 
 
 
 
 
 
 
X* 
Immunological and 
infectious markers 
from blood samples 
 
X 
 
 
 
 
X 
 
 
 
X 
Throat swab samples 
 
X 
 
 
 
 
X 
 
 
 
X 
Markers of SUL 
metabolism from 
blood samples 
 
X 
 
 
 
 
X 
 
 
 
X 
Blood level of 
antipsychotic 
medication 
 
X 
 
 
 
 
 
 
 
 
 
X 
SUL metabolites 
from urine samples 
 
X 
 
 
 
 
X 
 
 
 
X 
Med List 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pill Report 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PANSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
 
 
 
 
 
 
 
 
 
 
MCCB 
 
X 
 
 
 
 
 
 
 
 
X 
Contact treatment 
providers 
X 
 
 
 
 
 
 
 
 
 
 
Payment 
$20 
$20 
$15 
$15 
$15 
$15 
$15 
$15 
$15 
$15 
$60 
*TSH, urine pregnancy, and urine drug screen only performed at Visit 1/Screening* 

 
16
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