Clinical trial NCT03617783
Conditions: Schizophrenia Schizoaffective Disorder
Sponsor: University of Maryland, Baltimore
Start date: 2019-07-18; Completion date: 2022-04-05
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine changes in serum butyrate levels with the prebiotic: Prebiotin (12g/day), an oligofructose-enriched inulin (OEI); the effect of OEI on the composition of the gastrointestinal microbiota in people with schizophrenia; and the relationship of the composition of the gut microbiota to various clinical, cognitive, and neuroimaging variables.

Detailed description:
Over the past 10 years, considerable evidence has emerged from animal studies to suggest that the gut microbiome has significant effects on brain development and behavior, with bidirectional communication between the enteric nervous system, gut and the central nervous system (CNS) (Diaz Heijtz et al, 2011; Douglas-Escobar et al, 2013; Dinan et al, 2014). The gut microbiota have been shown to: a) produce multiple neurotransmitters, including gamma-aminobutyric acid (GABA), dopamine, norepinepherine, and serotonin, and may regulate CNS levels of these neurotransmitters; b) modulate brain development through the regulation of synaptogenesis; and c) modulate the levels of stress hormones during brain development, which may affect stress response and anxiety behavior (Diaz Heijtz et al, 2011; Dinan et al, 2014; Sudo et al, 2004; O'Mahony et al, 2015). Moreover, the gut microbiota effects the production of neurotrophins, including brain-derived neurotrophic factor (BDNF), which plays a significant role in neurogenesis and synaptic plasticity (Sudo et al, 2004; Nemani et al, 2015).

The gut microbiome may also affect brain development and function through its regulation of immune system function, which is mediated, in part, through the production of short-chain fatty acids (SCFA). There are three major SCFAs: butyrate, propionate, and acetate. Butyrate is of particular interest, since it plays a key role in maintaining gut homeostasis and epithelial integrity: butyrate is the primary energy source for intestinal colonocytes; and, of the three SCFAs, butyrate appears to have the most pronounced effects on immune system function and may exert its effects directly through immune pathways and indirectly through the maintenance of the integrity of the intestinal-blood barrier (Hamer et al, 2008; Louis et al, 2010; Brahe et al, 2013; Vital et al, 2014). The intestinal-blood barrier restricts the entrance of toxins, pathogens and antigens into the blood circulation; thus, increased permeability could lead to the entrance of substances and subsequent immune response.

The multiple effects of the gut microbiome on brain development and behavior, suggest that alterations in the gut microbiome may occur in schizophrenia and play a part in the pathophysiology of the disorder. The increased prevalence of gastrointestinal disorders in schizophrenia; the association of infections, including infections with Toxoplasma gondii, which can induce intestinal inflammation, with the risk for the development of schizophrenia; and evidence of increased gut permeability provide further indirect evidence for disruption of the gut microbiome in this disorder (Dinan et al, 2014; Nemani et al, 2015; Severance et al, 2012; Severance et al, 2014). Although a number of studies have been conducted in other neuropsychiatric disorders, including autism (Parracho et al, 2005; Tomova et al, 2015), which demonstrate altered bacterial composition of the gut microbiome, there is only one published study of the microbiome in schizophrenia. Yolken and colleagues examined the oropharyngeal microbiome in people with schizophrenia, and found that there were increased levels of the bacteriophage, Lactobacillus phage phiadh, genome in the schizophrenia group, which were correlated with co-occurring immunological disorders (Yolken et al, 2015). There is one published study of gut microbiota in schizophrenia. Shen and colleagues found a significant reduction in butyrate producers in people with schizophrenia compared to healthy controls (Shen et al. Schiz Res, https://doi.org/10.1016/j.schres.2018.01.002).

The purpose of this study is to examine changes in serum butyrate levels with the prebiotic: Prebiotin (12g/day), an oligofructose-enriched inulin (OEI); the effect of OEI on the composition of the gastrointestinal microbiota in people with schizophrenia; and the relationship of the composition of the gut microbiota to various clinical, cognitive, and neuroimaging variables.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Prebiotin intervention 2: Placebo
Intervention descriptions: intervention 1: Prebiotin (12g/day), an oligofructose-enriched inulin (OEI) intervention 2: placebo-OEI

Protocol documents:
Prot_SAP_001.pdf: 
Study Product Guidelines and Considerations 
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Version 6 
 
 
13Sept2022 
Full Protocol Title 
Prebiotic Treatment in People with Schizophrenia 
 
 
Principal Investigator: 
Robert W. Buchanan, M.D. 
Director 
Maryland Psychiatric Research Center 
 
 
Supported by:  
The National Center for Complementary and Integrative Health 
1 R61 AT009990-01 
 
Study Intervention Provided by: 
Jackson GI Medical  


Study Product Guidelines and Considerations 
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Version 5 
 
 
26Jan2021 
Tool Revision History 
Version Number: 1.1 
Version Date: 2/5/2019 
Summary of Revisions Made: See attached “Summary of Review Responses” document. 
Version Number: 1.2 
Version Date: 3/26/2019 
Summary of Revisions Made: See attached “Summary of Review Responses” document. 
Version Number: 1.3 
Version Date: 4/8/2019 
Summary of Revisions Made: See attached “Summary of Review Responses” document. 
Version Number: 1.4 
Version Date: 6/13/2019 
Summary of Revisions Made: See attached “Summary of Review Responses” document. 
 
Version Number: 2.1 
Version Date: 8/13/2019 
Summary of Revisions Made: Per OHRP requirement, the “Potential Benefits” section of the consent 
document was revised to include a more detailed list of potential benefits to the participant.  
 
Version Number 2.2 
Version Date: 12/16/19 
Summary of Revisions Made: Revised the BMI inclusion criterion to less than or equal to 40. Study 
medication name was changed from FOS to OEI due to manufacturer request; actual composition of 
the study medication was not changed.  
 
Version Number 2.3 
Version Date: 1/23/2020 
Summary of Revisions Made: Samantha Trikeriotis, Joel Palachuvattil, and Sharon Pugh were added 
as study team members.   
 
Version Number 2.4 
Version Date: 7/16/2020 
Summary of Revisions Made: Hanna Michel and Franklin Blatt were added, and Megan Powell 
removed from the study team roster.   
 
Version 3 
Version Date: 8/12/20 
Summary of Revisions Made: Gopal Vyas was added, and Anne Werkheiser removed, from the study 
team roster. The PIS and PPSS acronyms on the Schedule of Evaluations were expanded to clarify 
the assessment names.


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Version 4 
Version Date: 9/17/20 
Summary of Revisions Made: Heidi Wehring was removed from the study team roster; the Protocol 
Participation Status Sheet was removed from Days 1-9 on the Schedule of Evaluations; the adverse 
event section was revised to correct the inconsistencies in how we track and capture adverse events 
on the side effect checklist.   
 
Version 5 
Version Date: 1/26/21 
Summary of Revisions Made: Administrative change - Clarification of the intent of the exclusion of 
antibiotics for acute use and current infections and not medications for longer term use with 
antibiotic properties.  
 
Version 6 
Version Date: 9/13/2022 
Summary of Revisions Made: Administrative changes – Revisions to the study team roster: Added 
Colin Frazier; Removed Hanna Michel, Samantha Trikeriotis, and Samuel Kane-Gerard. 


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TABLE OF CONTENTS 
                                                               
     Page 
Clinical Intervention Study Protocol Template ............................................................................ 1 
PREFACE ............................................................................................................................................... 2 
Full Protocol Title ................................................................................................................................. 3 
Jackson GI Medical .................................................................................................................. 3 
Tool Revision History................................................................................................................ 4 
TABLE OF CONTENTS ....................................................................................................................... 5 
STUDY TEAM ROSTER ........................................................................................................ 11 
PARTICIPATING STUDY SITES ......................................................................................... 11 
1. STUDY OBJECTIVES .................................................................................................................... 15 
1.1 
Primary Objective ......................................................................................................... 15 
1.2 
Secondary Objectives ................................................................................................. 15 
2. BACKGROUND AND RATIONALE ............................................................................................ 15 
2.1 
Background on Condition, Disease, or Other Primary Study Focus .................... 15 
People with schizophrenia have a broad range of neurocognitive impairments, including 
abnormalities in attention, executive function, verbal and visual learning and 
memory, working memory, processing speed, and social cognition (Nuechterlein et 
al, 2004). These impairments are major determinants of functional outcome in 
schizophrenia (Green, 1996; Green et al, 2004). Unfortunately, first and second 
generation antipsychotics have limited benefits for these impairments (Keefe et al, 
2007; Buchanan et al, 2007), which has led to the evaluation of add-on 
pharmacological agents for the treatment of cognitive impairments, but results, to 
date, have been largely disappointing (Choi et al, 2013; Buchanan et al, 2007; 
Freedman et al, 2008; Winterer et al, 2008; Lieberman et al, 2013; Umbricht  et al, 
2014). Cognitive remediation and other non-pharmacological strategies have shown 
some promise, but the observed beneficial effects rarely generalize beyond the 
measures included in the training exercises (Dixon et al, 2010). In the absence of an 
effective treatment, cognitive impairments remain a critical unmet therapeutic need, 
and the development of a novel approach for the treatment of these impairments 
remains a central therapeutic challenge. ................................................................. 15 
2.2 
Study Rationale ............................................................................................................ 16 
Over the past 10 years, considerable evidence has emerged from animal studies to 
suggest that the gut microbiome has significant effects on brain development and 
behavior, with bidirectional communication between the enteric nervous system, gut 
and the central nervous system (CNS) (Diaz Heijtz et al, 2011; Douglas-Escobar et 


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al, 2013; Dinan et al, 2014). The gut microbiota have been shown to: a) produce 
multiple neurotransmitters, including gamma-aminobutyric acid (GABA), dopamine, 
norepinepherine, and serotonin, and may regulate CNS levels of these 
neurotransmitters; b) modulate brain development through the regulation of 
synaptogenesis; and c) modulate the levels of stress hormones during brain 
development, which may affect stress response and anxiety behavior (Diaz Heijtz et 
al, 2011; Dinan et al, 2014; Sudo et al, 2004; O’Mahony et al, 2015). Moreover, the 
gut microbiota effects the production of neurotrophins, including brain-derived 
neurotrophic factor (BDNF), which plays a significant role in neurogenesis and 
synaptic plasticity (Sudo et al, 2004; Nemani et al, 2015). ................................... 16 
3. STUDY DESIGN .............................................................................................................................. 17 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ......................................................... 17 
4.1 
Inclusion Criteria........................................................................................................... 18 
4.2 
Exclusion Criteria ......................................................................................................... 18 
4.3 
Study Enrollment Procedures .................................................................................... 18 
5. STUDY INTERVENTIONS ............................................................................................................. 20 
5.1 
Interventions, Administration, and Duration ............................................................. 20 
5.2 
Handling of Study Interventions ................................................................................. 20 
5.3 
Concomitant Interventions .......................................................................................... 20 
5.3.1 Allowed Interventions ........................................................................................................ 20 
5.3.2 Required Interventions ........................................................................................................ 21 
5.3.3 Prohibited Interventions ...................................................................................................... 21 
5.4 
Adherence Assessment .............................................................................................. 21 
6. STUDY PROCEDURES ................................................................................................................. 21 
6.1 
Schedule of Evaluations ............................................................................................. 21 
6.2 
Description of Evaluations .......................................................................................... 23 
6.2.1 Screening Evaluation .......................................................................................................... 24 
6.2.2 Enrollment, Baseline, and/or Randomization ..................................................................... 26 
The study biostatistician will use a permuted block randomization system (block sizes 2 or 4), in 
which treatment assignment order is random within each block, with an equal number of 
participants assigned to each treatment, to generate a list of treatment assignments. Thus, it will be 
difficult to ascertain the next treatment assignment, even if a participant becomes unblinded, 
while any imbalance in the number of participants between the treatment groups will be kept 
within tight limits. ........................................................................................................................... 27 
6.2.3 Blinding .............................................................................................................................. 27 
6.2.4 Double-Blind Treatment Phase ........................................................................................... 28 
6.2.5 Completion/Final Evaluation .............................................................................................. 28 
7. SAFETY ASSESSMENTS ............................................................................................................. 29 


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7.1 
Specification of Safety Parameters ........................................................................... 29 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters
 ........................................................................................................................................ 29 
OEI is considered a food supplement and is being used for its indication to improve gut 
bacteria composition, thus it is not a drug product nor is it being used for any other 
indication. Participants randomized to OEI will receive 4 grams of OEI, mixed in 
water, three times a day for 10 days. We chose the 12 grams/day dose, because a 
previous study suggests that this dose is well tolerated and based on data from a 
pilot study conducted by our co-investigators. ........................................................ 29 
Participants randomized to placebo will receive maltodextrin (4 grams), mixed in water, 
three times a day for 10 days. Maltodextrin is a polysaccharide composed of glucose 
units, a mixture of chains that vary from 3 to 17 glucose units long; and is freely 
soluble or readily dispersible in water and is a quickly digested carbohydrate. 
Maltodextrin has previously been used in studies evaluating the effect of OEI 
prebiotics (Abrams et al, 2005; Casellas et al, 2007; Roller et al, 2007; De Peter et 
al, 2008; Dehghan et al, 2014), and produces minimal changes in inflammatory and 
metabolic measures (Casellas et al, 2007; Dehghan et al, 2014). ...................... 30 
7.3 
Adverse Events and Serious Adverse Events ......................................................... 30 
7.4 
Reporting Procedures ................................................................................................. 31 
7.5 
Follow-up for Adverse Events .................................................................................... 32 
7.6 
Safety Monitoring ......................................................................................................... 32 
8. INTERVENTION DISCONTINUATION ........................................................................................ 33 
9. STATISTICAL CONSIDERATIONS ............................................................................................. 33 
9.1 
General Design Issues ................................................................................................ 33 
9.2 
Sample Size and Randomization .............................................................................. 33 
Sample Size .................................................................................................................................... 33 
The proposed sample size is 20; the participants will be of either sex and any race, and between 
18-60 years old. They will meet Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 
criteria for schizophrenia or schizophreniform or schizoaffective disorder. .................................. 33 
Treatment Assignment Procedures ................................................................................................. 34 
9.3  
Definition of Populations ............................................................................................. 34 
9.4 
Interim Analyses and Stopping Rules ....................................................................... 34 
9.5 
Outcomes ...................................................................................................................... 34 
9.5.1 Primary Outcome ................................................................................................................ 34 
9.6 
Data Analyses............................................................................................................... 35 
10. DATA COLLECTION AND QUALITY ASSURANCE ............................................................. 36 
10.1 Data Collection Forms ................................................................................................. 36 


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10.2 Data Management ....................................................................................................... 36 
10.3 Quality Assurance ........................................................................................................ 36 
10.3.1 
Training ........................................................................................................................... 36 
10.3.2 
Quality Control Committee ............................................................................................ 36 
10.3.3 
Metrics ............................................................................................................................ 37 
We will strive to ensure that all participants receive ≥ 90% of their assigned medication. The 90% 
criterion increases the likelihood that participants will receive adequate treatment to evaluate the 
effect of OEI on the biological signature. In order to monitor adherence, participants will be 
observed by research staff while they ingest the study medication. Since all participants will be 
inpatients, we do not expect problems with adherence, but we will carefully monitor adherence 
patterns, which will be described within each treatment group as part of any presentation of study 
results. ............................................................................................................................................. 37 
10.3.4 
Protocol Deviations ........................................................................................................ 37 
10.3.5 
Monitoring ...................................................................................................................... 37 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................................ 37 
11.1 Institutional Review Board (IRB) Review ................................................................. 37 
11.2 Informed Consent Forms ............................................................................................ 38 
11.3 Participant Confidentiality ........................................................................................... 38 
11.4 Study Discontinuation .................................................................................................. 38 
12. COMMITTEES ............................................................................................................................... 38 
13. PUBLICATION OF RESEARCH FINDINGS ............................................................................ 38 
14. REFERENCES .............................................................................................................................. 38 
15. SUPPLEMENTS/APPENDICES................................................................................................. 45 
WHAT ARE MY RESPONSIBILITIES IF I TAKE PART IN THIS RESEARCH? .............. 48 
POTENTIAL RISKS/DISCOMFORTS:............................................................................................ 48 
POTENTIAL BENEFITS .................................................................................................................... 48 
COSTS TO PARTICIPANTS ............................................................................................................. 49 
PAYMENT TO PARTICIPANTS ...................................................................................................... 50 
You will be paid by cash or check.  If paid by cash, then you will be paid at the end of each visit.  
If paid by check, then it may take up to 4-6 weeks to receive payment. .......................................... 50 
CONFIDENTIALITY AND ACCESS TO RECORDS .................................................................... 50 
RIGHT TO WITHDRAW ................................................................................................................... 50 
CAN I BE REMOVED FROM THE RESEARCH? ................................................................. 51 


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UNIVERSITY STATEMENT CONCERNING RESEARCH RISKS ............................................ 51 
I. Procedures Schedule 
II. Informed Consent Form Template 
III. DSMB Roster 


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STUDY TEAM ROSTER  
Robert W. Buchanan, M.D.  
55 Wade Avenue  
Catonsville, MD 21228 
410-402-7876 (p) 
410-402-7198 (f) 
rbuchanan@som.umaryland.edu 
M Patricia Ball   
55 Wade Avenue  
Catonsville, MD 21228 
410-402-6844 (p) 
410-402-7198 (f) 
pball@som.umaryland.edu 
 
Franklin Blatt 
55 Wade Avenue  
Catonsville, MD 21228 
410-402-7599 (p) 
410-402-7198 (f) 
fblatt@som.umaryland.edu 
 
Zeni Encomienda  
55 Wade Avenue  
Catonsville, MD 21228 
410-402-6844 (p) 
410-402-7198 (f) 
zencomienda@som.umaryland.
edu 
Colin Frazier 
55 Wade Avenue  
Catonsville, MD 21228 
410-402-6411 (p) 
410-402-7198 (f) 
cfrazier@som.umaryland.edu 
 
Matthew Glassman 
55 Wade Avenue  
Catonsville, MD 21228 
410-402-6411 (p) 
410-402-7198 (f) 
mglassman@som.umaryland.edu 
 
David Gorelick, M.D. 
55 Wade Avenue  
Catonsville, MD 21228 
410-402-6806 (p) 
410-402-7198 (f) 
dgorelick@som.umaryland.edu 
 
Ann Kearns  
55 Wade Avenue  
Catonsville, MD 21228 
410-402-6854 (p) 
410-402-7198 (f) 
akearns@som.umaryland.edu 
 
Deanna L. Kelly, Pharm.D. 
55 Wade Avenue  
Catonsville, MD 21228 
410-402-6861 (p) 
410-402-7198 (f) 
dlkelly@som.umaryland.edu 
 
Joel Palachuvattil 
55 Wade Avenue 
Catonsville, MD 21228 
410-402-6839 (p) 
410-402-7198 (f) 
jpalachu@som.umaryland.edu 
Sharon Pugh 
55 Wade Avenue 
Catonsville, MD 21228 
410-402-7113 (p) 
410-402-7198 (f) 
spugh@som.umaryland.edu 
Gopal Vyas, D.O. 
55 Wade Avenue  
Catonsville, MD 21228 
410-402-6865 (p) 
410-402-7198 (f) 
gopalvyas@som.umaryland.edu 
 
Jennifer Zaranski 
55 Wade Avenue  
Catonsville, MD 21228 
410-402-6060 (p) 
410-402-7198 (f) 
jzaranski@som.umaryland.edu 
 
 
 
 
PARTICIPATING STUDY SITES 
Maryland Psychiatric Research Center site investigators: 
Robert W. Buchanan, M.D.   
55 Wade Avenue  
Catonsville, MD 21228 
410-402-7876 (p) 
410-402-7198 (f) 
rbuchanan@som.umaryland.edu 
 
Deanna L. Kelly, Pharm.D., BCPP  
55 Wade Avenue  


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Catonsville, MD 21228 
410-402-6861 (p) 
410-402-7198 (f) 
dlkelly@som.umaryland.edu 
 
 
PRÉCIS  
Study Title  
Prebiotic Treatment in People with Schizophrenia  
Objectives  
The primary objective of the study is to examine the effect of a 10-day course of 
the prebiotic: Prebiotin, an oligofructose-enriched inulin (OEI), on serum butyrate 
levels. We hypothesize that OEI, compared to placebo, will produce a greater 
increase in serum butyrate levels secondary to the stimulatory effects of OEI on the 
activity of known butyrate-producing bacteria.  
 
Design and Outcomes   
We will conduct a 10-day, double-blind, placebo-controlled, randomized clinical trial 
to examine the effect of OEI on serum butyrate levels. There will be two study 
phases: 1) a 2-week Evaluation Phase, during which potential participants will 
undergo baseline medical, vital sign, and symptom assessments to determine 
whether they meet inclusion criteria; and 2) a 10-day Double-blind Treatment 
Phase.  
 
Participants who complete the 2-week Evaluation Phase and continue to fulfill 
inclusion criteria will be entered into the 10-day double-blind treatment phase. 
Participants will be randomly assigned to OEI or placebo-OEI, with approximately 
10 participants in each group. Participants randomized to OEI will receive 4 grams 
of OEI, mixed in water, three times a day for 10 days, for a total dose of 12 grams. 
Participants randomized to placebo-OEI will receive 4 grams of maltodextrin, mixed 
in water, three times a day for 10 days.  A non-blind pharmacist will dispense all 
study medications. The blind will be broken only if a medical emergency requires 
this information.  
 
We will consent and evaluate up to 30 participants to reach the goal of 
approximately 24 participants randomized and 20 study completers.  We will plan 
to randomize approximately 24 participants, because we anticipate a 10-20% 
attrition rate.  We will consent and evaluate up to 30 participants, because we 
anticipate that some participants, who provide informed consent, may not meet 
eligibility criteria. However, we do not expect to need to consent 30 participants, 
because potential participants will be prescreened, through our partial HIPPA 
waiver, and those with obvious exclusion criteria (e.g. do not meet the age range 
criterion) will not undergo the informed consent process. 
 


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If a participant is unable to tolerate the study medication, then they will be 
withdrawn from study treatment, but we will continue to make every effort to collect 
scheduled study assessments. 
 
All participants will receive the identical, standardized diet, provided by a registered 
dietician, which will consist of 3 meals and one snack. The daily diet breakdown is 
approximately 2700 calories with the following composition: 100 g protein, 400 g 
carbohydrates, 28 g fiber, 6.7% saturated fat, 28% total fat, 240 mg cholesterol and 
4.4 g sodium. 
 
Interventions and Duration  
We are using a prebiotic, natural product: Orafti® Synergy1, sold in the US under 
the brand name Prebiotin®, for the study. Prebiotin® is an oligofructose-enriched 
inulin (OEI). Prebiotin® will be provided by Jackson GI Medical. Prebiotin® is 
considered a food powder, not a bacterial strain. Prebiotin® is a combination of 
chicory inulin fractions with selected chain lengths; the shorter chain inulin 
(oligofructose) is combined with longer chain inulin in essentially equal amounts. 
Inulins are indigestible polysaccharides and have been generally recognized as 
safe by the US Food and Drug Administration. Inulin consists of oligo- and 
polysaccharides composed of fructose units linked together by ß-(2, 1)-linkages. 
Almost every fructose chain is terminated by a glucose unit. The number of 
fructose and glucose units in inulin (Degree of Polymerization; DP) ranges between 
2 and 60. Shorter chain inulin (oligofructose) consists of oligosaccharides obtained 
by partial enzymatic hydrolysis from inulin. Part of shorter chain inulin is terminated 
by a glucose unit. The degree of polymerization is less than 10. Longer chain inulin 
consists of inulin of which shorter fractions were removed. Almost every molecule 
is terminated by a glucose unit and has a DP of 10 or higher. 
 
Prebiotin® is a fine, white to slightly yellow powder, which is hygroscopic and 
slightly sweet. The product is produced by Beneo-Orafti SA and distributed in the 
US by Jackson GI Medical.  
 
Prebiotin® meets full GMP requirements of characterization and standardization 
and full requirements contained in the NCCIH policy for Natural Product Ingredients 
(see https://nccih.nih.gov/research/policies/naturalproduct.htm#ctconsiderations).  
The product specification sheet includes the taxonomic nomenclature and the 
analysis of the product for contaminants/impurities, including microorganisms. This 
specification sheet also contains solubility information and minimum 
durability/stability information. Each parameter contains the limit, the units, the 
reference method and the frequency of continued testing. In addition, the 
information for nutritional declaration in the US by 21 CFR 101.9 is included in the 
specification sheet.    
 
The total length of study participation for each individual participant will be 25 days. 
There will be 5 study visits: 2 visits during the 2-week Evaluation Phase and 3 visits 
during the Double-blind Treatment Phase.  


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The total time of study participation is 18-20 hours. The two Evaluation Phase visits 
will take a combined total of 3-5 hours to complete. The Day 0 and Day 11 visits 
will take approximately 7 hours each to complete; on these days participants will 
undergo the inulin (OEI) challenge to assess the extent to which OEI has modified 
the biological signature: serum butyrate levels. The extended length of the visit is 
due to the need to wait 6 hours for the peak in serum butyrate following the inulin 
administration. The Day 10 visit will take approximately 1 hour to complete. 
 
Sample Size and Population  
Participants (n=20) will be of either sex and any race, and between 18-60 years 
old. Participants will be recruited from the greater Baltimore metropolitan area. 
They will meet Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 
(APA, 2013) criteria for schizophrenia or schizophreniform or schizoaffective 
disorder. A best estimate diagnostic approach will be utilized in which information 
from the Structured Clinical Interview for DSM-5 (First et al, 2015) is supplemented 
by information from family informants, previous psychiatrists, and medical records 
to generate a diagnosis. Participants will be judged by their primary clinician to be 
clinically stable and will be prescribed the same antipsychotic and dose for at least 
14 days prior to study entry. In light of the potential impact of obesity on the gut 
microbiota (Brahe et al, 2013), participants will be required to have a body mass 
index (BMI) ≤ 40, i.e., we will restrict the population to those with normal or mild to 
moderate increased BMI and exclude potential participants who are morbidly 
obese. The proposed BMI criterion reflects the typical range of BMI values of 
people with schizophrenia who enter our treatment units and studies, and will serve 
to minimize the impact of morbid obesity on the study results. We will not restrict 
the type of antipsychotic, with which the participant is treated. 
 
Participants with inflammatory bowel diseases or other gastrointestinal disorders, 
whose pathology or treatment could significantly increase the risk associated with 
the proposed treatment; who have an organic brain disorder; who have an 
intellectual disability; who have been treated with an antibiotic or immune therapy 
within the last three months; who have been treated with a prebiotic or probiotic 
within the last three months; who are unable to understand English or cooperate 
with study procedures; or who meet DSM-5 criteria for alcohol or substance use 
disorders (except Tobacco Use Disorder) within the last 3 months will be excluded. 
Female participants who are pregnant or lactating will be excluded. Participants 
must be judged competent to participate in the informed consent process and 
provide voluntary informed consent. 
 
The use of the proposed inclusion/exclusion criteria will result in a study population, 
which is representative of hospitalized people with schizophrenia and related 
disorders; minimizes the effect of potential confounder variables; and maximizes 
the safety of the study protocol. 
 


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The study biostatistician will use a permuted block randomization system (block 
sizes 2 or 4), in which treatment assignment order is random within each block, 
with an equal number of participants assigned to each treatment, to generate a list 
of treatment assignments. Thus, it will be difficult to ascertain the next treatment 
assignment, even if a participant becomes unblinded, while any imbalance in the 
number of participants between the treatment groups will be kept within tight limits. 
All raters, investigators and other staff will be blind to treatment assignment except 
for the pharmacist. The pharmacist does not participate in assessing any of the 
primary symptom or side effect dependent variables and conveys no information 
about treatment assignment to participants or staff except in a medical emergency. 
1. STUDY OBJECTIVES 
1.1 
Primary Objective 
In the context of a 10-day, double-blind, placebo-controlled, randomized clinical 
trial (RCT), we will examine whether the prebiotic: Prebiotin (12g/day), an 
oligofructose-enriched inulin (OEI), increases serum butyrate levels. Participants 
with schizophrenia or a related disorder will be randomly assigned to OEI or 
placebo-OEI, with approximately 10 participants in each group. We hypothesize 
that OEI, compared to placebo, will produce a greater increase in serum butyrate 
levels secondary to the stimulatory effects of OEI on known butyrate-producing 
bacteria. 
1.2 
Secondary Objectives 
N/A 
2. BACKGROUND AND RATIONALE 
2.1 
Background on Condition, Disease, or Other Primary Study Focus 
People with schizophrenia have a broad range of neurocognitive impairments, 
including abnormalities in attention, executive function, verbal and visual learning 
and memory, working memory, processing speed, and social cognition 
(Nuechterlein et al, 2004). These impairments are major determinants of functional 
outcome in schizophrenia (Green, 1996; Green et al, 2004). Unfortunately, first and 
second generation antipsychotics have limited benefits for these impairments 
(Keefe et al, 2007; Buchanan et al, 2007), which has led to the evaluation of add-
on pharmacological agents for the treatment of cognitive impairments, but results, 
to date, have been largely disappointing (Choi et al, 2013; Buchanan et al, 2007; 
Freedman et al, 2008; Winterer et al, 2008; Lieberman et al, 2013; Umbricht  et al, 
2014). Cognitive remediation and other non-pharmacological strategies have 
shown some promise, but the observed beneficial effects rarely generalize beyond 
the measures included in the training exercises (Dixon et al, 2010). In the absence 
of an effective treatment, cognitive impairments remain a critical unmet therapeutic 


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need, and the development of a novel approach for the treatment of these 
impairments remains a central therapeutic challenge.  
 2.2 
Study Rationale 
Over the past 10 years, considerable evidence has emerged from animal studies to 
suggest that the gut microbiome has significant effects on brain development and 
behavior, with bidirectional communication between the enteric nervous system, 
gut and the central nervous system (CNS) (Diaz Heijtz et al, 2011; Douglas-
Escobar et al, 2013; Dinan et al, 2014). The gut microbiota have been shown to: a) 
produce multiple neurotransmitters, including gamma-aminobutyric acid (GABA), 
dopamine, norepinepherine, and serotonin, and may regulate CNS levels of these 
neurotransmitters; b) modulate brain development through the regulation of 
synaptogenesis; and c) modulate the levels of stress hormones during brain 
development, which may affect stress response and anxiety behavior (Diaz Heijtz 
et al, 2011; Dinan et al, 2014; Sudo et al, 2004; O’Mahony et al, 2015). Moreover, 
the gut microbiota effects the production of neurotrophins, including brain-derived 
neurotrophic factor (BDNF), which plays a significant role in neurogenesis and 
synaptic plasticity (Sudo et al, 2004; Nemani et al, 2015). 
The gut microbiome may also affect brain development and function through its 
regulation of immune system function, which is mediated, in part, through the 
production of short-chain fatty acids (SCFA). There are three major SCFAs: 
butyrate, propionate, and acetate. Butyrate is of particular interest, since it plays a 
key role in maintaining gut homeostasis and epithelial integrity: butyrate is the 
primary energy source for intestinal colonocytes; and, of the three SCFAs, butyrate 
appears to have the most pronounced effects on immune system function and may 
exert its effects directly through immune pathways and indirectly through the 
maintenance of the integrity of the intestinal-blood barrier (Hamer et al, 2008; Louis 
et al, 2010; Brahe et al, 2013; Vital et al, 2014). The intestinal-blood barrier restricts 
the entrance of toxins, pathogens and antigens into the blood circulation; thus, 
increased permeability could lead to the entrance of substances and subsequent 
immune response. 
 
The multiple effects of the gut microbiome on brain development and behavior, 
suggest that alterations in the gut microbiome may occur in schizophrenia and play 
a part in the pathophysiology of the disorder. The increased prevalence of 
gastrointestinal disorders in schizophrenia; the association of infections, including 
infections with Toxoplasma gondii, which can induce intestinal inflammation, with 
the risk for the development of schizophrenia; and evidence of increased gut 
permeability provide further indirect evidence for disruption of the gut microbiome 
in this disorder (Dinan et al, 2014; Nemani et al, 2015; Severance et al, 2012; 
Severance et al, 2014). Although a number of studies have been conducted in 
other neuropsychiatric disorders, including autism (Parracho et al, 2005; Tomova et 
al, 2015), which demonstrate altered bacterial composition of the gut microbiome, 
there is only one published study of the microbiome in schizophrenia. Yolken and 
colleagues examined the oropharyngeal microbiome in people with schizophrenia, 


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and found that there were increased levels of the bacteriophage, Lactobacillus 
phage phiadh, genome in the schizophrenia group, which were correlated with co-
occurring immunological disorders (Yolken et al, 2015). There is one published 
study of gut microbiota in schizophrenia. Shen and colleagues found a significant 
reduction in butyrate producers in people with schizophrenia compared to healthy 
controls (Shen et al. Schiz Res, https://doi.org/10.1016/j.schres.2018.01.002). 
 
The purpose of this study is to examine changes in serum butyrate levels with the 
prebiotic: Prebiotin (12g/day), an oligofructose-enriched inulin (OEI); the effect of 
OEI on the composition of the gastrointestinal microbiota in people with 
schizophrenia; and the relationship of the composition of the gut microbiota to 
various clinical, cognitive, and neuroimaging variables.  
3. STUDY DESIGN 
In a sample of inpatients  with a DSM-IV-TR/DSM-5 diagnosis of schizophrenia or 
schizoaffective disorder, we will conduct a 10-day, double-blind, placebo-controlled, 
randomized clinical trial to examine the effect of a prebiotic, oligofructose-enriched inulin 
(OEI) on serum butyrate levels; the relative preponderance of butyrate-producing bacteria 
in the gut microbiome; and the relationship of these measures to cytokine or gut 
permeability measures, signs and symptoms of schizophrenia, and/or metabolic measures. 
We will consent and evaluate up to 30 participants to reach the goal of approximately 24 
participants randomized and 20 study completers.  We will plan to randomize 
approximately 24 participants, because we anticipate a 10-20% attrition rate.  We will 
consent and evaluate up to 30 participants, because we anticipate that some participants, 
who provide informed consent, may not meet eligibility criteria. However, we do not expect 
to need to consent 30 participants, because potential participants will be prescreened, 
through our partial HIPPA waiver, and those with obvious exclusion criteria (e.g. do not 
meet the age range criterion) will not undergo the informed consent process. Participants 
will be randomized to either OEI, 12 g/day or matching placebo, with approximately 10 
participants in each group. We will use an inpatient sample in order to standardize meals, 
exercise and environmental mediators. We will recruit patients from the Treatment 
Research Program inpatient unit, Maryland Psychiatric Research Center, University of 
Maryland School of Medicine.  
 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
The overall goal of this project is to determine whether oligofructose-enriched inulin (OEI) 
is an effective treatment for schizophrenia. We will use an inpatient sample in order to 
standardize meals, exercise and environmental mediators. The population to be included 
will not include any people in prisons, but will include psychiatric inpatients who are court-
ordered for care. The research on understanding the gut microbiota, as well as 
understanding if over the counter prebiotics may change the gut microbiota, have minimal 
inherent risk regardless of the court-ordered status of the research participants. This 
research, however, can only take place in a controlled living environment with all people 
receiving standardized meals and similar environmental influences to have unflawed 


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results. Court-ordered patients comprise the majority of the inpatient psychiatric unit 
population. The environment at Spring Grove Hospital Center is identical for both court-
ordered and non-court-ordered patients on the Treatment Research Unit. 
4.1 
Inclusion Criteria 
Participants must meet all of the inclusion criteria to participate in this study: 
1) DSM-IV-TR /DSM-5 diagnosis of schizophrenia or schizoaffective 
disorder;  
2) Age 18-60 years;  
3) Considered clinically stable by the treating psychiatrist; 
4) Currently treated with an antipsychotic, with no dose changes in last 14 
days;  
5) Ability to participate in the informed consent process, as determined by a 
score of 10 or greater on the Evaluation to Sign Consent;  
6)  BMI ≤ 40 
4.2 
Exclusion Criteria 
All candidates meeting any of the exclusion criteria at baseline will be excluded 
from study participation: 
1) Gastrointestinal disorders, including, but not limited to Crohn’s Disease, 
Irritable Bowel Syndrome, Celiac Disease, whose pathology or treatment 
could alter the presentation or treatment of schizophrenia or significantly 
increase the risk associated with the proposed treatment protocol 
2) Organic brain disorder, including cerebrovascular accident; epilepsy; 
traumatic brain injury, Loss of consciousness (LOC) for more than 30 
minutes 
3) Intellectual disability 
4) Acute antibiotic use  
5) Immune therapy within the last three months 
6) Prebiotic or probiotic treatment within the last three months 
7) Inability to understand English 
8) Inability to cooperate with study procedures 
9) Pregnant or lactation secondary to pregnancy  
10) Meet DSM-5 criteria for alcohol or substance use disorders (except 
Tobacco Use Disorder) within last 3 months 
4.3 
Study Enrollment Procedures  
Potential participants will be recruited from the MPRC Treatment Research 
Program, and will consist of people who are currently hospitalized on the TRP or 
who are admitted to the TRP over the course of the study. We chose to limit the 
study population to inpatients, so we could standardize the diet across participants 
in this phase of the project. Reasons for ineligibility or non-participation of eligible 
candidates will be documented in the Enrollment Log.  
 


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The consent form will include an explanation of the risks and benefits of 
participation; assurances of confidentiality; and an explanation that participation is 
entirely voluntary, the decision to participate will in no way influence or restrict 
services at participating sites, and the participant is free to withdraw at any time 
without negative consequences. As some potential participants will have poor 
reading skills, the consent form will be read aloud to all participants in tandem with 
their own silent reading of the document. The individual securing consent will 
review any points about which the participant is unclear, and the participant will be 
invited to ask questions as needed. Our research staff is carefully trained in 
strategies for interacting with people with severe mental illness, including speaking 
slowly and clearly, stopping to summarize frequently, and providing time for 
questions. They are all supervised by senior staff members. All participants who 
express willingness to provide consent will be queried about the consent form in 
order to ensure that they have adequate understanding of the study requirements.  
This questioning is performed systematically, and research staff members 
document that this review has been completed. After reading the consent, and 
before obtaining a signature, a brief questionnaire is administered to verify that the 
participant is competent to provide consent and has demonstrated comprehension 
of the consent document. This questionnaire is attached to the informed consent 
form and is completed immediately after explaining the informed consent form and 
before obtaining the participant's signature on the form. If the participant does not 
understand the consent form, the recruiter will try to explain points of confusion, 
and administer the questionnaire again. Those failing to answer the questions 
adequately will not be recruited into the study. The recruiter will also make a clinical 
judgment and not recruit participants who appear unable to grasp key aspects of 
the procedure. This approach, which requires a proactive demonstration on the 
part of the participant that they understand what is being requested, has been used 
extensively by investigators at the MPRC. Included participants must also be 
judged competent to consent by the Evaluation to Sign Consent (ESC) 
questionnaire (DeRenzo et al 1998). Per University of Maryland School of Medicine 
IRB regulations, a copy of the signed consent form is given to the participant, a 
copy is placed in the person's medical record, and the original is kept by the PI.  
 
Research assistants obtaining informed consent will be experienced clinicians. 
They will receive detailed and standardized training as to how to obtain informed 
consent from people with serious mental illnesses. They will be observed obtaining 
informed consent from a study participant by senior staff prior to being allowed to 
enroll participants on their own. 
 
The study biostatistician will use a permuted block randomization system (block 
sizes 2 or 4), in which treatment assignment order is random within each block, 
with an equal number of participants assigned to each treatment, to generate a list 
of treatment assignments. Thus, it will be difficult to ascertain the next treatment 
assignment, even if a participant becomes unblinded, while any imbalance in the 
number of participants between the treatment groups will be kept within tight limits. 
All raters, investigators and other staff will be blind to treatment assignment except 


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for the pharmacist. The pharmacist does not participate in the assessment of any 
of the primary symptom or side effect dependent variables and conveys no 
information about treatment assignment to participants or staff except in a medical 
emergency. 
5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
Participants who continue to fulfill inclusion criteria will enter the 10-day double-
blind treatment phase. Participants will be randomly assigned to OEI or placebo-
OEI, with approximately 10 participants in each group. Participants randomized to 
OEI will receive 4 grams of OEI, mixed in water, three times a day for 10 days. We 
chose the 12 grams/day dose, because a previous study suggests that this dose is 
well tolerated and based on data from a pilot study conducted by our co-
investigators. Participants randomized to placebo will receive maltodextrin (4 
grams), mixed in water, three times a day for 10 days. Maltodextrin is a 
polysaccharide composed of glucose units, a mixture of chains that vary from 3 to 
17 glucose units long; and is freely soluble or readily dispersible in water and is a 
quickly digested carbohydrate. Maltodextrin has previously been used in studies 
evaluating the effect of OEI prebiotics (Abrams et al, 2005; Casellas et al, 2007; 
Roller et al, 2007; De Peter et al, 2008; Dehghan et al, 2014), and produces 
minimal changes in inflammatory and metabolic measures (Casellas et al, 2007; 
Dehghan et al, 2014).  
5.2 
Handling of Study Interventions  
The OEI will be provided in bulk by Jackson GI Medical in the form of Prebiotin. 
OEI is considered a food supplement and is being used for its indication to improve 
gut bacteria composition, thus it is not a drug product nor is it being used for any 
other indication. Maltodextrin and OEI have a similar appearance when dissolved 
in water and both have a slightly sweet taste, which will help to preserve the blind. 
A non-blind pharmacist will dispense all study medications. The blind will be broken 
only if a medical emergency requires this information.  
In order to monitor compliance, participants will be observed by research staff while 
they ingest the study medication. Since all participants will be inpatients, we do not 
expect problems with compliance, but we will carefully monitor compliance 
patterns, which will be described within each treatment group as part of any 
presentation of study results. 
5.3 
Concomitant Interventions  
5.3.1 Allowed Interventions 
Participants may continue taking their prescribed antipsychotic, with no dose 
changes in the 14 days prior to signing consent. 


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5.3.2 Required Interventions 
N/A 
5.3.3 Prohibited Interventions 
Participants may not have been taking antibiotic or immune therapy, or 
prebiotic or probiotic treatment within the last three months prior to signing 
consent. 
5.4 
Adherence Assessment  
We will strive to ensure that all participants receive ≥ 90% of their assigned 
medication. The 90% criterion increases the likelihood that participants will receive 
adequate treatment to evaluate the effect of OEI on the biological signature. In 
order to monitor adherence, participants will be observed by research staff while 
they ingest the study medication. Since all participants will be inpatients, we do not 
expect problems with adherence, but we will carefully monitor adherence patterns, 
which will be described within each treatment group as part of any presentation of 
study results. 
6. STUDY PROCEDURES  
6.1 
Schedule of Evaluations 
Schedule of Events 
2-Week 
Evaluation 
Phase 
Baseline, Enrollment, 
Randomization 
Double-Blind 
Treatment Phase 
Encounter # → 
P1V1 
P2V0 
P2V1  
 
P2V2 P2V3 
Day of Study →  
Day -14 to -1 
 
Day -1 
Day 0 
 
Day 
1-9 
Day 
10 
 
Day 
11 
Procedure ↓ 
 
 
 
 
 
 
Informed consent and 
ESC 
X 
 
 
 
 
 
Eligibility Documentation 
X 
 
 
 
 
 
Protocol Initiation Sheet 
X 
 
 
 
 
 
Recommendation for 
Inclusion Form 
X 
 
 
 
 
 
Brief Psychotropic 
Medications Form 
X 
 
 
 
 
X 
Brief Non-Psychotropic 
Medications Form 
X 
 
 
 
 
X 
Demographic Forms 
X 
 
 
 
 
 
Fagerstrom, short 
version 
X 
 
 
 
 
 
SCID-Interview* 
X 
 
 
 
 
 


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Medical History and 
EKG** 
X 
 
 
 
 
 
Physical Exam and 
height** 
X 
 
 
 
 
 
Diet Log 
X 
 
 
 
 
 
CMP-14, CBC  Lipid 
Panel 
X 
 
 
 
 
X 
UA; Urine Pregnancy 
Test (females) 
X 
 
 
 
 
X 
Side Effect Checklist 
 
 
X 
 
X 
 
BPRS 
 
 
X 
 
 
X 
HAM-A 
 
 
X 
 
 
X 
Cytokines, C-reactive 
protein 
 
 
X 
 
 
X 
ASCA and AGA IgG 
 
 
X 
 
 
X 
Tryptophan, Kynurenine, 
KYNA & 3-HK 
 
 
X 
 
 
X 
OEI Challenge 
 
 
X 
 
 
X 
Serum Butyrate: pre-
prandial, 2 hr and 6 hr 
after OEI challenge 
 
 
X 
 
 
X 
OEI or Placebo (Day1-
10) 
 
 
 
X 
X 
 
Fully Digestible Meal 
 
X 
 
 
X 
 
Stool Sample Collection 
 
X 
 
 
X 
 
Vital Signs, including 
weight, BP and pulse 
X 
X 
X 
 
X 
X 
Protocol Participation 
Status Sheet 
X 
X 
X 
 
X 
X 
 
*SCID interview results may be used, if completed within the past 5 years. The Drug 
Misuse section still needs to re-done at time of visit.  
 
**Medical history, EKG, physical exam, height and other screening and baseline 
measures can be collected from the TRP admission assessment if completed within the 
past 2 months. 


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6.2 
Description of Evaluations  
Once participants sign the informed consent form, they will enter a 2-week 
Evaluation Phase (Screening and Baseline), during which they will undergo 
baseline medical, vital sign, and symptom assessments to determine whether they 
meet inclusion criteria. This will include a comprehensive medical history and 
physical examination. We will obtain baseline CBC, Chemistry-14 Panel, lipid panel 
and urinalysis assessments. Weight, height and vital signs (i.e., heart rate, pulse, 
blood pressure) will be assessed weekly throughout the study. The diagnosis of 
schizophrenia or related disorder will be confirmed by a structured psychiatric 
examination, the Structured Clinical Interview for DSM-5. Participants will also have 
baseline symptom assessments completed. Participants continuing into the 
Double-blind Treatment phase will repeat baseline symptom assessments during 
week 2. All participants will receive the identical, standardized diet, provided by a 
registered dietician, which will consist of 3 meals and one or two snacks. The daily 
diet breakdown is approximately 2700 calories with the following composition: 100 
g protein, 400 g carbohydrates, 28 g fiber, 6.7% saturated fat, 28% total fat, 240 
mg cholesterol and 4.4 g sodium. 
 
Participants who continue to fulfill inclusion criteria will enter the 10-day double-
blind treatment phase. Participants will be randomly assigned to OEI or placebo-
OEI, with approximately 10 participants in each group. The OEI will be provided by 
Jackson GI Medical in the form of Prebiotin. OEI is considered a food supplement 
and is being used for its indication to improve gut bacteria composition, thus it is 
not a drug product nor is it being used for any other indication. Participants 
randomized to OEI will receive 4 grams of OEI, mixed in water, three times a day 
for 10 days. We chose the 12 grams/day dose, because a previous study suggests 
that this dose is well tolerated and based on data from a pilot study conducted by 
our co-investigators. Participants randomized to placebo will receive maltodextrin 
(4 grams), mixed in water, three times a day for 10 days. Maltodextrin is a 
polysaccharide composed of glucose units, a mixture of chains that vary from 3 to 
17 glucose units long; and is freely soluble or readily dispersible in water and is a 
quickly digested carbohydrate. Maltodextrin has previously been used in studies 
evaluating the effect of OEI prebiotics (Abrams et al, 2005; Casellas et al, 2007; 
Roller et al, 2007; De Peter et al, 2008; Dehghan et al, 2014), and produces 
minimal changes in inflammatory and metabolic measures (Casellas et al, 2007; 
Dehghan et al, 2014). Maltodextrin and OEI have a similar appearance when 
dissolved in water and both have a slightly sweet taste, which will help to preserve 
the blind. A non-blind pharmacist will dispense all study medications. The blind will 
be broken only if a medical emergency requires this information. If this occurs, the 
participant will be withdrawn from the study. 
 
In order to evaluate the impact of OEI treatment, we will examine change in serum 
butyrate levels following treatment. There will be two test days: a) baseline (Day 0), 
prior to randomization to OEI or placebo; and b) Day 11, following the 10 day 
course of OEI/placebo treatment. We will use OEI for the inulin challenge. On the 
night prior to each test day, participants will receive a completely digestable and 
non-fermentable meal, e.g. lasagna and up to two fully digestable snacks (e.g. 


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chips). They will then fast from midnight until the morning, when they will receive 
their standard, low-fiber breakfast and OEI, 12g. We will collect fasting, 2 hour and 
6-hour blood samples from each participant. Participants will be able to receive a 
light digestable meal 4 hours after OEI administration. The Day 11 change in 
serum butyrate levels following the OEI challenge dose (2 or 6-hour minus fasting 
morning serum butyrate level) will be compared to the Day 0 change in serum 
butyrate levels to determine whether the 10-day OEI treatment regimen modified 
the hypothesized biological signature through increased activity of butyrate-
producing bacteria. Serum butyrate will be quantified by LC-MS/MS, conducted by 
the School of Pharmacy Mass Spectrometry Center. 
 
6.2.1 Screening Evaluation 
Consenting Procedure 
Before any screening procedure is performed, informed consent must be obtained. 
There will be a single informed consent form that describes both the screening and 
study procedures. 
 
Research assistants obtaining informed consent will be experienced clinicians. 
They will receive detailed and standardized training as to how to obtain informed 
consent from people with serious mental illnesses. They will be observed obtaining 
informed consent from a study participant by senior staff prior to being allowed to 
enroll participants on their own. 
 
The consent form will include an explanation of the risks and benefits of 
participation; assurances of confidentiality; and an explanation that participation is 
entirely voluntary, the decision to participate will in no way influence or restrict 
services at participating sites, and the participant is free to withdraw at any time 
without negative consequences. As some potential participants will have poor 
reading skills, the consent form will be read aloud to all participants in tandem with 
their own silent reading of the document. The individual securing consent will 
review any points about which the participant is unclear, and the participant will be 
invited to ask questions as needed. Our research staff is carefully trained in 
strategies for interacting with people with severe mental illness, including speaking 
slowly and clearly, stopping to summarize frequently, and providing time for 
questions. They are all supervised by senior staff members. All participants who 
express willingness to provide consent will be queried about the consent form in 
order to ensure that they have adequate understanding of the study requirements.  
This questioning is performed systematically, and research staff members 
document that this review has been completed. After reading the consent, and 
before obtaining a signature, a brief questionnaire is administered to verify that the 
participant is competent to provide consent and has demonstrated comprehension 
of the consent document. This questionnaire is attached to the informed consent 
form and is completed immediately after explaining the informed consent form and 
before obtaining the participant's signature on the form. If the participant does not 
understand the consent form, the recruiter will try to explain points of confusion, 
and administer the questionnaire again. Those failing to answer the questions 


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adequately will not be recruited into the study. The recruiter will also make a clinical 
judgment and not recruit participants who appear unable to grasp key aspects of 
the procedure. This approach, which requires a proactive demonstration on the 
part of the participant that they understand what is being requested, has been used 
extensively by investigators at the MPRC. Included participants must also be 
judged competent to consent by the Evaluation to Sign Consent (ESC) 
questionnaire (DeRenzo et al 1998). Per University of Maryland School of Medicine 
IRB regulations, a copy of the signed consent form is given to the participant, a 
copy is placed in the person's medical record, and the original is kept by the PI. 
Consent for each participant will be documented on the Documentation of Consent 
(DOC) form.  
Screening 
Once participants sign informed consent they will enter a 2-week Evaluation Phase 
(P1V1, Days -14 to -1)), during which they will undergo baseline medical, vital sign, 
and symptom assessments to determine whether they meet inclusion criteria. 
Psychiatric, Medical history, EKG, physical exam, height and other screening and 
baseline measures can be collected from the TRP admission assessment if 
completed within the past 2 months. 
This will include: 
• Demographic information: Documentation of age eligibility  
• SCID-Interview: The diagnosis of schizophrenia from the medical record will 
be confirmed by a structured psychiatric examination, the Structured Clinical 
Interview for DSM-5. The SCID interview can be re-used if completed within 
the past 5 years, with the Drug Misuse section re-completed at time of visit.  
• Medical and safety assessments to rule out excluded medical conditions 
and determine any clinically significant abnormal laboratory values: 
o Medical history 
o Physical examination  
o Electrocardiogram (EKG) 
o CBC 
o Fasting chemistry panel 
o Lipid panel 
o Urinalysis assessments including a pregnancy test for females 
o Vital signs: Blood pressure, heart and respiratory rates, height and 
weight, prior to randomization to the intervention; weight and height 
measurements will be used to calculate BMI, which must be less than 
≤ 40 for eligibility. 
• Dietary assessment: We will review the diet of each participant for up to a 
week prior to their study entry.  
• Smoking form: Document smoking status of participants.  


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• Recommendation for Inclusion Form: Documents clinical stability, absence 
of a history of intellectual disability, and ability to cooperate with study 
procedures. 
• Psychotropic and non-psychotropic concomitant medication forms: We will 
document all current medications including dosage, date started, and route 
of administration. 
• Stool Sample: Participants will provide a baseline stool sample prior to the 
initiation of study medication. 
6.2.2 Enrollment, Baseline, and/or Randomization 
Enrollment 
Enrollment is defined as the randomization date, which will be recorded on a case 
report form and entered into the study database. The allowable window between 
screening and randomization is 14 days.  
Baseline Assessments 
For participants who have successfully been screened for eligibility and are 
enrolled into the study, baseline assessments are performed against which to 
measure the study outcome (P2/V1, Day 0). Participants who continue to fulfill 
inclusion criteria will enter the 10-day double-blind treatment phase. Participants 
will be randomly assigned to OEI or placebo-OEI, with approximately 10 
participants in each group.  
• OEI Challenge: On the night prior to each test day, participants will receive a 
completely digestible and non-fermentable meal, e.g. lasagna. They will 
then fast from midnight until the morning, when they will receive their 
standard breakfast and OEI, 12g.  
• Serum Butyrate: In order to evaluate the impact of OEI treatment, we will 
examine change in serum butyrate levels following treatment. We will collect 
baseline, 2-hour and 6-hour blood samples from each participant. The blood 
samples will be analyzed at the University of Maryland School of Pharmacy 
Mass Spectrometry Center. 
• The Brief Psychiatric Rating Scale (BPRS; Overall and Gorham 1962): the 
BPRS total score will be used to measure global psychopathology. The four 
BPRS positive symptom items - conceptual disorganization, suspiciousness, 
hallucinatory behavior, and unusual thought content - will be used to 
measure positive psychotic symptoms.  
• Hamilton Anxiety Rating Scale (HAM-A; Seedat et al, 2007): The HAM-A will 
be used to measure symptoms of anxiety. 
• Peripheral Cytokines and Other Laboratory Measures: Serum cytokines; 
highly sensitive C-reactive protein (CRP); and adiponectin and leptin. Serum 
cytokines will be measured by the Cytokine Core Laboratory at the 
University of Maryland using Luminex® 100 Multianalyte System or ELISA 
at baseline and endpoint or the Immune Lab at Johns Hopkins. The primary 
cytokines to be analyzed initially will be IL-1β, IL-6, and TNF-α, and the 
acute phase protein C-reactive protein (CRP), which is induced by increased 


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cytokine levels, including IL-6. The other cytokines listed will be initially 
stored and analyzed at a later date. 
• ASCA and AGA IgG: We will use Anti-Saccharomyces Cerevisiae 
Antibodies (ASCA) to measure the integrity of the gut-blood barrier. ASCA 
are antibodies that develop against antigens presented by the cell wall of the 
yeast, Saccharomyces cerevisiae. ASCA are elevated in people with 
intestinal inflammation (e.g. Crohn’s Disease) and increased intestinal 
permeability (Rutgeerts and Vermeire, 1998; Makharia et al, 2007), which 
supports their use as a marker of increased intestinal permeability (Irvine et 
al, 2000; Barta et al, 2003). AGA IgG antibodies have been found to be 
present in about 1/3 people with schizophrenia and linked to diseases such 
as celiac disease and gluten sensitivity and are known to modulate gut 
bacteria and potentially butyrate. ASCA IgA and IgG will be measured, using 
the protocol of the commercially available ELISA kit (Orgentec, Mainz, 
Germany). We will collect ASCA levels at baseline and the end of week 10.   
We will also measure Antigliadin Antibodies (AGA IgG). The blood samples 
will be analyzed at the University of Maryland School of Pharmacy Mass 
Spectrometry Center. 
• Vital Signs: Blood pressure, heart and respiratory rates, height and weight, 
prior to randomization to the intervention; weight and height measurements 
will be used to calculate BMI.  
• Side Effect Checklist (SEC): The SEC will be used to assess the baseline 
presence of potential side effects. 
Randomization 
The study biostatistician will use a permuted block randomization system (block 
sizes 2 or 4), in which treatment assignment order is random within each block, 
with an equal number of participants assigned to each treatment, to generate a list 
of treatment assignments. Thus, it will be difficult to ascertain the next treatment 
assignment, even if a participant becomes unblinded, while any imbalance in the 
number of participants between the treatment groups will be kept within tight limits. 
6.2.3 Blinding 
All study clinical, laboratory, medical and safety assessments will be done by 
research assistants, who are blind to treatment assignment. The study 
biostatistician will be blinded until the final lock of the database. The P.I. and the 
co-investigators will be blinded until all study analyses have been completed.  
 
Only the research pharmacist will be unblinded. The research pharmacist will be 
responsible for requesting the treatment assignment from the study biostatistician, 
who will use a permuted block randomization system (block sizes 2 or 4), in which 
treatment assignment order is random within each block, with an equal number of 
participants assigned to each treatment, to generate a list of treatment 
assignments. The research pharmacist will be responsible for preparing the study 
interventions based on the treatment assignment he receives from the 
biostatistician. Maltodextrin and OEI have a similar appearance when dissolved in 
water and both have a slightly sweet taste, which will help to preserve the blind. 


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The study biostatistician will have no access to the data, nor will he have any 
influence on the conduct of any of the outcome assessments. 
 
The blind will be broken only if a medical emergency requires this information. 
The data analyst will be blinded to treatment assignment and will prepare any 
requested blinded reports for the Data Safety Monitoring Board (DSMB) . If the 
DSMB requests unblinded study reports, then the data analyst will work with the 
DSMB to prepare these reports (see attached DSMB roster: Appendix III). 
 
6.2.4 Double-Blind Treatment Phase 
Study visits must be performed on the weeks indicated in the Schedule of 
Evaluations.  
• Days 1-9: 
 OEI or Placebo 
 Stool Sample (after Day 5) 
• Day 10 (P2V2): 
 OEI or Placebo 
 Vital signs 
 SEC 
6.2.5 Completion/Final Evaluation 
• Day 11 (P2V3): 
 OEI Challenge 
 CBC 
 Fasting chemistry panel 
 Lipid panel 
 Urinalysis assessments including a pregnancy test for females 
 BPRS 
 HAM-A 
 Peripheral cytokines and other laboratory measures (C-reactive protein, 
Tryptophan, Kynurenine, KYNA, and 3-HK) 
 ASCA and AGA IgG 
 Serum butyrate 
 Vital signs 
 Psychotropic and non-psychotropic concomitant medications 
The DSMB or IRB will conduct a safety review of AE's and SAE's, which will yield a 
decision to cease enrollment for the study. Participants may also request to be 
withdrawn from the study at any time. Once a participant is discontinued from the 


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study for whatever reason, completion ratings will be performed if possible. This 
includes all laboratory tests and rating scales below. The study team will record all 
reportable events with start dates occurring any time after informed consent is 
obtained until the last day of study participation, or until the resolution or stabilization 
of an event. At each study visit, the study team will inquire about the occurrence of 
AE/SAEs since the last visit.  Events will be followed for outcome information until 
resolution or stabilization.  
7. SAFETY ASSESSMENTS  
Participant safety will be monitored once an individual is enrolled in the study. The study 
medication, OEI in the form of Prebiotin, may be associated with adverse effects. The 
most common side effects are flatulence, bloating, and abdominal discomfort. We will 
make every attempt to minimize all study-related risks. We will carefully monitor patients 
and psychiatric symptoms throughout the study. All patients are in the inpatient setting 
with 24 monitoring and care. 
7.1 
Specification of Safety Parameters 
All participants will receive a complete medical history and physical examination, 
including vital signs: blood pressure, heart and respiratory rates, height and weight, 
prior to randomization to the intervention; weight and height measurements will be 
used to calculate BMI. We will collect baseline EKG and baseline and end of 
studyCBC; complete metabolic panel (CMP), including BUN/Creatinine, 
electrolytes, glucose, LFTs, and lipid panel; and U/A assessments. The CMP will 
be collected after fasting for at least 8 hours. Female participants of child-bearing 
potential will have a pregnancy test at baseline and Day 11.   
 
The Side Effect Checklist (SEC) is designed to assess medication side effects 
commonly associated with pharmacological treatments. In addition, if not already 
assessed, the SEC is modified for the purpose of the assessment of specific side 
effects associated with the particular intervention under study; in this case OEI. 
The SEC version to be used in the proposed study rates 35 potential side effects, 
and comprehensively covers the side effects that have been previously reported 
with OEI, i.e., bloating, flatulence, and abdominal pain. In addition, there are three 
“other” spaces for idiosyncratic participant complaints, which are not usually 
associated with medication treatment. The SEC will be conducted at baseline and 
Day 10. 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
OEI is considered a food supplement and is being used for its indication to improve 
gut bacteria composition, thus it is not a drug product nor is it being used for any 
other indication. Participants randomized to OEI will receive 4 grams of OEI, mixed 
in water, three times a day for 10 days. We chose the 12 grams/day dose, because 
a previous study suggests that this dose is well tolerated and based on data from a 
pilot study conducted by our co-investigators.  
 


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Participants randomized to placebo will receive maltodextrin (4 grams), mixed in 
water, three times a day for 10 days. Maltodextrin is a polysaccharide composed of 
glucose units, a mixture of chains that vary from 3 to 17 glucose units long; and is 
freely soluble or readily dispersible in water and is a quickly digested carbohydrate. 
Maltodextrin has previously been used in studies evaluating the effect of OEI 
prebiotics (Abrams et al, 2005; Casellas et al, 2007; Roller et al, 2007; De Peter et 
al, 2008; Dehghan et al, 2014), and produces minimal changes in inflammatory and 
metabolic measures (Casellas et al, 2007; Dehghan et al, 2014).  
7.3 
Adverse Events and Serious Adverse Events  
An adverse event (AE) is any untoward medical occurrence in a participant during 
participation in the clinical study or with use of the experimental agent being 
studied. An adverse finding can include a sign, symptom, abnormal assessment 
(laboratory test value, vital signs, electrocardiogram finding, etc.), or any 
combination of these regardless of relationship to participation in the study. 
Adverse events are to be recording regardless of their relationship to the study 
intervention.   
A serious adverse event (SAE) is one that meets one or more of the following 
criteria: 
• Results in death. 
• Results in persistent or significant disability/incapacity. 
• Results in or prolongs an existing inpatient hospitalization (even if the 
hospitalization is a precautionary measure for observation). 
• Is a congenital anomaly/birth defect in offspring of subjects taking the product 
regardless of time to diagnosis.  
• Is cancer.  
• Is the result of an overdose, whether accidental or intentional.  
• Is a suicide attempt (not suicidal ideation only).  
 
An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
 
The study team will record all reportable events with start dates occurring any time 
after informed consent is obtained until the last day of study participation, or until 
the resolution or stabilization of an event. At each study visit, the study team will 
inquire about the occurrence of AE/SAEs since the last visit.  Events will be 
followed for outcome information until resolution or stabilization.  
 
Laboratory assessments that we will collect are EKG; CBC; complete metabolic 
panel (CMP), including BUN/Creatinine, electrolytes, glucose, LFTs, and lipid 
panel; and U/A assessments. Female participants of child-bearing potential will 
have a pregnancy test.  Clinically significant abnormal laboratory values are 
defined as any values outside the reference range for a laboratory.  
 


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The Side Effect Checklist (SEC) is designed to assess medication side effects 
commonly associated with pharmacological treatments. In addition, if not already 
assessed, the SEC is modified for the purpose of the assessment of specific side 
effects associated with the particular intervention under study; in this case OEI. 
The SEC version to be used in the proposed study rates 35 potential side effects, 
and comprehensively covers the side effects that have been previously reported 
with OEI, i.e., bloating, flatulence, and abdominal pain. In addition, there are three 
“other” spaces for idiosyncratic participant complaints, which are not usually 
associated with medication treatment. The SEC rates each side effect on a 4-point 
scale (1: none to 4: severe).  The SEC will be conducted at baseline and Day 10.  
 
The following definitions will be used to define an adverse event: 
• Any SEC item for which there is a two-point increase over the baseline 
assessment of the item; and  
• Any SEC item that is rated “4” at Day 10, but was not rated “4” in the baseline 
assessment.  
7.4 
Reporting Procedures 
The Study PI and Independent Monitoring Committee will be responsible for 
determining whether an AE is expected or unexpected. An adverse event will be 
considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the intervention.   
To assess relationship of an event to study intervention, the following guidelines 
are used: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 
b. There is a temporal relationship between the intervention and event 
onset. 
c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event 
onset. 
b. An alternate etiology has been established. 
 
The following scale will be used to grade adverse events when reporting to the 
Data Safety Monitoring Board. This scale is used when reporting all adverse 
events, including side effects assessed with the SEC: 
1. Mild: no intervention required; no impact on activities of daily living (ADL) 
(SEC item score=2) 
2. Moderate: minimal, local, or non-invasive intervention indicated; moderate 
impact on ADL (SEC item score=3) 
3. Severe: significant symptoms requiring invasive intervention; subject seeks 
medical attention, needs major assistance with ADL (SEC item score=4) 
 


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Serious adverse events will be reported to the DSMB, the UMB IRB, and NCCIH by 
the Principal Investigator (P.I.) or their designated POC in accordance with 
requirements.   
• All serious AEs will be reported to the NCCIH Program Officer, the DSMB, 
and the UMB IRB within 3 business days of the investigator becoming aware 
of the event. Any follow-up reports are to be submitted as new information 
regarding the event becomes available. Adverse events that are determined 
to be unexpected and probably related to study procedures, regardless of 
severity, will be reported to NCCIH and the UMB IRB within 5 business 
days. These AEs will be reported to the DSMB with the annual report.  
• Anticipated or unrelated AEs will be handled in a less urgent manner but will 
be reported to the DSMB, UMB IRB, and to NCCIH on an annual basis.    
Incidents of pregnancy will be reported to all oversight committees along with the 
annual reports. Participants determined to be pregnant will be withdrawn from the 
study.  
7.5 
Follow-up for Adverse Events 
At each study visit, the study team will inquire about the occurrence of AE/SAEs 
since the last visit. Events will be followed for outcome information until resolution 
or stabilization.  
7.6 
Safety Monitoring  
The Data and Safety Monitoring Board (DSMB) for this study consists of two 
research/practicing psychiatrists; one community psychiatrist; one internal and one 
external biostatistician and one research pharmacist.  
 
The DSMB will 1) review proposed protocols and consent forms prior to the start of 
enrollment to assess how the PI will report adverse events, early withdrawals and 
terminations; 2) evaluate recruitment and rate of enrollment in relation to study 
targets; 3) monitor the occurrence of adverse events, serious adverse events, and 
early withdrawals or terminations; 4) evaluate study outcomes, when available; 5) 
monitor study throughout its progress. Any serious adverse event (SAE) that 
occurs to a subject enrolled in this study will be reported to the DSMB within 5 
working days; or within 48 hours if it is directly related to the research intervention. 
Unexpected adverse events will be reported in accord with NIH and Federal 
requirements. Non-serious, expected adverse events will be reported annually to 
the IRB. Once a protocol has been initially reviewed, the DSMB will determine the 
frequency of review for the study, at minimum yearly. 
 
The DSMB will review with the research team the data management system and 
study progress. This DSMB has existed for over 10 years and has monitored 
numerous protocols. The DSMB will receive side effect/adverse event updates 
whenever this protocol is discussed (although we do not expect any treatment 
related adverse events since the treatment and the measurements have minimal or 
no risk). Any serious adverse events (SAEs) will be reported to governing 
authorities per each agency’s established guidelines. 


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8. INTERVENTION DISCONTINUATION  
The DSMB or IRB will conduct a safety review of AE's and SAE's, which will yield a 
decision to continue or terminate the study. 
 
Participants may request to be withdrawn from the study at any time, either because of an 
inability to tolerate the study medication or some other reason. Once a participant is 
discontinued from the study medication, for whatever reason, we will make every attempt 
to complete the remainder of the scheduled assessments. This includes laboratory tests 
and rating scales.  
 
9. STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues  
We hypothesize that OEI, compared to placebo, will produce a greater increase in 
serum butyrate levels secondary to the stimulatory effects of OEI on the activity of 
known butyrate-producing bacteria. 
 
Our hypothesis will be confirmed if either item 1 or 2 are met: 
1. The relative response rate of OEI responders to placebo responders is ≥ 
3 for the between group comparison of the end of study post-inulin 
challenge butyrate level to the baseline post-inulin challenge butyrate 
level. "Responders" will be defined as those whose change in post-/pre-
OEI treatment increases in serum butyrate levels following the inulin 
challenge is >20%. 
2. The effect size of the change in pre-inulin challenge serum butyrate 
levels between treatment groups is ≥ 0.4 and the relative response rate 
is ≥ 3, with “responder” defined as a 10% difference in change in serum 
butyrate levels following the inulin challenge. 
• 
Note that we will not propose a transition if one of the above 
biomarker(s) achieves a medium effect size (defined as Cohen’s d 
≥ 0.5) in the opposite direction of prediction 
 
If one or the other of the response criterion is met, then we would request a 
transition to the R33 phase. 
9.2 
Sample Size and Randomization 
Sample Size 
The proposed sample size is 20; the participants will be of either sex and any race, 
and between 18-60 years old. They will meet Diagnostic and Statistical Manual of 


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Mental Disorders (DSM)-5 criteria for schizophrenia or schizophreniform or 
schizoaffective disorder. 
Treatment Assignment Procedures 
The study biostatistician will use a permuted block randomization system (block 
sizes 2 or 4), in which treatment assignment order is random within each block, 
with an equal number of participants assigned to each treatment, to generate a list 
of treatment assignments. Thus, it will be difficult to ascertain the next treatment 
assignment, even if a participant becomes unblinded, while any imbalance in the 
number of participants between the treatment groups will be kept within tight limits. 
All raters, investigators and other staff will be blind to treatment assignment except 
for the pharmacist. The pharmacist does not participate in the assessment of any 
of the primary symptom or side effect dependent variables and conveys no 
information about treatment assignment to participants or staff except in a medical 
emergency. The non-blind pharmacist will dispense all study medications. The 
blind will be broken only if a medical emergency requires this information.  
9.3  
Definition of Populations 
All participants who are randomized will be included in the primary outcome 
efficacy analyses. 
All participants who receive at least one dose of the proposed intervention will be 
included in the safety analyses. 
9.4 
Interim Analyses and Stopping Rules 
We do not plan to conduct interim analyses on any of our primary or secondary 
outcome measures. 
 
This study will be stopped prior to its completion if: (1) the intervention is 
associated with adverse effects that call into question the safety of the intervention; 
(2) difficulty in study recruitment or retention will significantly impact the ability to 
evaluate the study endpoints; (3) any new information becomes available during 
the trial that necessitates stopping the trial; or (4) other situations occur that might 
warrant stopping the trial.  
9.5 
Outcomes  
Data collected for this study will be entered into the MPRC research data base 
using the usual procedures developed for MPRC clinical trials. This study will be 
reviewed by the UMB IRB and by a Data Safety Monitoring Board (DSMB). The 
DSMB will evaluate study outcomes when they become available. All members of 
the committee will be masked to individual participants’ treatment assignments.  
 
9.5.1 Primary Outcome   
The primary outcome will be the change in serum butyrate levels from baseline to 
Day 11 (i.e., post 10 days of OEI treatment). We will measure serum butyrate 
levels on the two inulin challenge test days: a) baseline (Day 0), prior to 


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randomization to OEI or placebo; and b) Day 11, following the 10-day course of 
OEI/placebo treatment.  
 
9.5.2 
Secondary Outcomes   
N/A 
9.6 
Data Analyses  
We will use an intent-to-treat approach to evaluate the change in butyrate 
production following 10 days of OEI treatment. We will use two approaches to 
assess the effect of OEI on serum butyrate levels: 1) we will compare end of study 
to baseline changes in serum butyrate levels following an inulin challenge; and 2) 
we will compare baseline pre-inulin challenge serum butyrate to end of study pre-
inulin challenge serum butyrate levels. A clinically meaningful change in the 
response to the inulin challenge will be evaluated through the comparison of the 
relative response rate to treatment; the relative response rate is the ratio of (OEI 
responders/all OEI participants) to (placebo responders/all placebo participants), 
and is statistically analogous to calculating the relative risk. We will define 
"responders" as those whose change in post-/pre-OEI treatment increases in 
serum butyrate levels following the inulin challenge is >20%. We chose the 20% 
criterion for responder, because we wanted to minimize the potential for false 
positives.  
We will also evaluate the effect of OEI on serum butyrate levels through the 
comparison of baseline and end of study pre-inulin challenge serum butyrate 
levels. We will measure the butyrate levels the morning of the inulin challenge 
days, prior to the administration of the inulin. All participants will have received the 
same standardized meal the night before the blood draw.  
If the relative response rate of OEI responders to placebo responders is ≥ 3 (e.g. 8 
of 10 OEI participants are responders versus 2 of 10 placebo participants are 
responders), then we would meet our Go/No-go criterion for proceeding to the R33 
study. We would have power ≥82% to detect a significant difference in the 
biological signature between the two groups in the proposed R33 study. If the 
relative response rate is < 3, then we will examine the change in pre-inulin 
challenge serum butyrate levels. If the effect size of the change in pre-inulin 
challenge serum butyrate levels between treatment groups is ≥ 0.4 and the relative 
response rate is ≥ 3, with “responder” defined as a 10% difference in change in 
serum butyrate levels following the inulin challenge, then we would consider this 
adequate evidence for an effect of OEI on our biological signature and would 
request to proceed to the R33 study. 
We will review the extent of missing data for each of the demographic, clinical, and 
outcome variables. If needed, we will impute missing data by multiple imputation 
(MI). The assumption of missing at random (MAR) will be used. A sensitivity 
analysis will be performed to assess the MI.  


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10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms  
Blinded research staff, including therapists, a nurse, and a pharmacist, will collect 
and record information for each participant on the CRF’s. Careful procedures will 
be used to protect the privacy of participants and the confidentiality of the 
data.  Names will only appear on consent forms and on a master list that links them 
with study ID numbers (different from medical record numbers). This list will be 
stored in locked files in a separate location from the data.  At the conclusion of the 
project, the list will be destroyed, unless continuation is planned and approved by 
the Institutional Review Board. All data (whether on forms or electronic data files) 
will be collected, analyzed, and reported according to the study ID-number and will 
contain no names or other personal identifiers. Paper-based data will be stored in 
locked files. Electronic data files reside on desktop computers and are password 
protected. 
10.2 Data Management  
Data collected for this study will be recorded on paper Case Report Forms (CRF’s), 
then entered into the MPRC research data base using the usual procedures 
developed for MPRC clinical trials. This study will be reviewed by the UMB IRB and 
by a Data Safety Monitoring Board (DSMB). The DSMB will review this study at 
least annually. If there are any concerns about study safety, then the DSMB may 
choose to review the study more frequently.  Meeting minutes will be reported to 
the UMB IRB on an annual basis. The DSMB consists of two research/practicing 
psychiatrists; one community psychiatrist; one internal and one external 
biostatistician and one research pharmacist.  
 
10.3 Quality Assurance  
10.3.1 Training 
At the beginning of the protocol, the PI and senior research staff will hold a study 
Protocol Initiation Meeting (PIM). At this time all study aspects are reviewed and all 
personnel working on the project attend. This meeting details the procedures of the 
study. We also develop standard operating procedures for the study and assign a 
primary research staff member to keep all information up to date. All personnel are 
told of their role on the study and we hold regular meetings with research 
personnel to go over study procedures and progress. In addition, all MPRC faculty 
and staff receive ongoing training on a variety of research issues yearly. 
 
10.3.2 Quality Control Committee  
This study will have a Data Safety Monitoring Board.  The DSMB will review this 
study at least annually.  DSMB meeting minutes will be sent to the IRB of record 
and the NCCIH program officer on an annual basis. 
 
Careful procedures will be used to protect the privacy of participants and the 
confidentiality of the data. Names will only appear on consent forms and on a 


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master list that links them with study ID numbers (different from medical record 
numbers). This list will be stored in locked files in a separate location from the data. 
At the conclusion of the project, the list will be destroyed, unless continuation is 
planned and approved by the Institutional Review Board. All data (whether on 
forms or electronic data files) will be collected, analyzed, and reported according to 
the study ID number and will contain no names or other personal identifiers. Paper-
based data will be stored in locked files. Electronic data files reside on desktop 
computers and are password protected. 
 
10.3.3 
Metrics 
We will strive to ensure that all participants receive ≥ 90% of their assigned 
medication. The 90% criterion increases the likelihood that participants will receive 
adequate treatment to evaluate the effect of OEI on the biological signature. In 
order to monitor adherence, participants will be observed by research staff while 
they ingest the study medication. Since all participants will be inpatients, we do not 
expect problems with adherence, but we will carefully monitor adherence patterns, 
which will be described within each treatment group as part of any presentation of 
study results. 
 
10.3.4 Protocol Deviations 
Protocol deviations for any reason will be captured on a Study Deviation Log. 
Failure to follow the protocol due to the action or inaction of the investigator or 
research staff will be reported to the oversight IRB and the NCCIH program officer 
within 5 business days.   
10.3.5 Monitoring 
Designated research staff is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.  All source documents should be 
completed in a neat, legible manner to ensure accurate interpretation of data.  
Adequate case histories of study subjects, including accurate case report forms 
(CRFs), and source documentation will be maintained. Data collection and 
accurate documentation are the responsibility of the study staff under the 
supervision of the investigator.  All source documents and laboratory reports must 
be reviewed by the study team and data entry staff, who will ensure that they are 
accurate and complete. Data entered into the database will be reviewed for 
completeness and accuracy on a weekly basis.  Unanticipated problems and 
adverse events must be reviewed by the investigator or designee.   
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review  
This protocol and the informed consent document (Appendix II) will be reviewed 
and approved by the UMB IRB, who is responsible for oversight of the study. Any 
subsequent modifications to the protocol will first be reviewed by NCCIH for 
approval prior to sending them to the UMB IRB for their approval. 


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11.2 Informed Consent Forms 
Research assistants obtaining informed consent will be experienced clinicians. 
They will receive detailed and standardized training as to how to obtain informed 
consent from people with serious mental illnesses. They will be observed obtaining 
informed consent from a study participant by senior staff prior to being allowed to 
enroll participants on their own. 
 
The consent form will include an explanation of the risks and benefits of 
participation; assurances of confidentiality; and an explanation that participation is 
entirely voluntary, the decision to participate will in no way influence or restrict the 
participants access to clinical services and care at participating sites, and the 
participant is free to withdraw at any time with no negative consequences. As some 
potential participants will have poor reading skills, the consent form will be read 
aloud to all participants in tandem with their own silent reading of the document. 
The individual securing consent will review any points about which the participant is 
unclear, and the participant will be invited to ask questions as needed. 
 
11.3 Participant Confidentiality  
All research activities will occur in a private room, behind a closed door. Careful 
procedures will be used to protect the privacy of participants and the confidentiality 
of the data. Names will only appear on consent forms and on a master list that links 
them with study ID numbers (different from medical record numbers). This list will 
be stored in locked files in a separate location from the data. At the conclusion of 
the project, the list will be destroyed, unless continuation is planned and approved 
by the Institutional Review Board. All data (whether on forms or electronic data 
files) will be collected, analyzed, and reported according to the study ID number 
and will contain no names or other personal identifiers. Paper-based data will be 
stored in locked files. Electronic data files reside on desktop computers and are 
password protected. 
11.4 Study Discontinuation  
The study may be discontinued at any time by the IRB, the NCCIH, the OHRP, the 
FDA, or other government agencies as part of their duties to ensure that research 
participants are protected.  
12. COMMITTEES 
N/A 
13. PUBLICATION OF RESEARCH FINDINGS  
Any presentation, abstract, or manuscript will be made available for review by the 
sponsor and the NCCIH prior to submission.  
14. REFERENCES  
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24332524 
 
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Diaz Heijtz R, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A, Hibberd ML, Forssberg 
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Dinan TG, Borre YE, Cryan JF.  Genomics of schizophrenia: time to consider the gut 
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Dixon LB, Dickerson F, Bellack AS, Bennett M, Dickinson D, Goldberg RW, Lehman A, 
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PMCID:PMC2800143 
 
Douglas-Escobar M, Elliott E, Neu J.  Effect of intestinal microbial ecology on the developing 
brain.  JAMA Pediatr 167(4):374-379, 2013.  PMID :23400224 
 
Dwork AJ, Mancevski B, Rosoklija G.  White matter and cognitive function in schizophrenia.  
Int J Neuropsychopharmacol 10:513-536, 2007.  PMID:17313699 
 
Edgar RC, Haas BJ, Clemente JC, Quince C, Knight R.  UCHIME improves sensitivity and 
speed of chimera detection.  Bioinformatics 27:2194-2200, 2011.  PMCID:PMC3150044 
 
Eloe-Fadrosh EA, Brady A, Crabtree J, Drabek EF, Ma B, Mahurkar A, Ravel J, Haverkamp 
M, Fiorino  A-M, Botelho C, Andreyeva I, Hibberd PL, Fraser CM.  Functional dynamics of the 
gut microbiome in  elderly people during probiotic consumption.  MBio 6(2). pii: e00231-15, 
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dual-indexing approach for multiplexed 16S rRNA gene sequencing on the llumina MiSeq 
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First MB, Williams JBW, Karg RS, Spitzer RL.  Structured Clinical Interview for DSM-5—
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Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, Allensworth D, 
Guzman-Bonilla A, Clement B, Ball MP, Kutnick J, Pender V, Martin LF, Stevens KE, Wagner 
BD, Zerbe GO, Soti F, Kem WR.  Initial phase 2 trial of a nicotinic agonist in schizophrenia.  
American Journal of Psychiatry 165(8):1040-1047, 2008.  PMCID: PMC3746983 
 
Gajer P, et al.  Temporal dynamics of the human vaginal microbiota.  Sci Transl Med 
4(132):132ra52, 2012.  PMCID:PMC3722878 
 
Green MF.  What are the functional consequences of neurocognitive deficits in 
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Green MF, Kern RS, Heaton RK.  Logitudinal studies of cognition and functional outcome in 
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The Human Microbiome Consortium.  Structure, function, and diversity of the healthy human 
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Irvine EJ, Marshall JK. Increased intestinal permeability precedes the onset of Crohn's 
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Kern RS, Nuechterlein KH, Green MF, Baade LE, Fenton WS, Gold JM, et al.  The MATRICS 
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Keefe RSE, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, et al.  Neurocognitive 
effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial.  
Arch Gen Psychiatry 64:633-647, 2007.   PMID:17548746 
 
Langille MG, et al.  Predictive functional profiling of microbial communities using 16S rRNA 
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Lieberman JA, Dunbar G, Segreti AC, Girgis RR, Seoane F, Beaver JS, Duan N, Hosford DA.  


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A randomized exploratory trial of an α-7 nicotinic receptor agonist (TC-5619) for cognitive 
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Makharia GK, Sachdev V, Gupta R, Lal S, Anti-Saccharomyces cerevisiae antibody does not 
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Masella AP, Bartram AK, Truszkowski JM, Brown DG, Neufeld JD.  PANDAseq: Paired-end 
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Nemani K, Hosseini Ghomi R, McCormick B, Fan X.  Schizophrenia and the gut-brain axis.  
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Russell J, Tacket CO, Brotman RM, Davis CC, Ault  K, Peralta L, Forney LJ.  Vaginal 
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enriched with oligofructose in combination with the probiotics Lactobacillus rhamnosus and 
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15. SUPPLEMENTS/APPENDICES 
 
I. Procedures Schedule 
 
Schedule of Events 
2-Week 
Evaluation 
Phase 
Baseline, 
Enrollment, 
Randomization 
Double-Blind Treatment Phase 
Encounter # → 
P1V1 
P2V1  
 
P2V2 
P2V3 
Day of Study →  
Day -14 to -1 
 
Day 0 
 
Day1-9 
Day 10 
 
Day 11 
Procedure ↓ 
 
 
 
 
 
Informed consent and ESC 
X 
 
 
 
 
Demographic Forms 
X 
 
 
 
 
Smoking form 
X 
 
 
 
 
SCID-Interview* 
X 
 
 
 
 
Medical History and EKG** 
X 
 
 
 
 
Physical Exam and 
height** 
X 
 
 
 
 
Dietary Assessment 
X 
 
 
 
 
CMP-14, CBC  Lipid Panel 
X 
 
 
 
X 
UA; Urine Pregnancy Test 
(females) 
X 
 
 
 
X 
BPRS 
 
X 
 
 
X 
HAM-A 
 
X 
 
 
X 
Cytokines, C-reactive 
protein 
 
X 
 
 
X 
ASCA and AGA IgG 
 
X 
 
 
X 
Tryptophan, Kynurenine, 
KYNA and 3-HK 
 
X 
 
 
X 
OEI Challenge 
 
X 
 
 
X 
Serum Butyrate: 
preprandial, 2 hr and 6 hr 
after OEI challenge 
 
X 
 
 
X 
OEI or Placebo (Day1-10) 
 
 
X 
X 
 
Vital Signs, including 
weight, BP and pulse 
X 
X 
 
X 
X 
SEC 
 
X 
 
 
X 
Psychotropic and Non-
psychotropic Concomitant 
Medications 
X 
 
 
 
X 
 
*SCID interview can be re-used if completed within the past 5 years, with the Drug Misuse section 
re-completed at time of visit.  
 
**Medical history, EKG, physical exam, height and other screening and baseline measures can be 
collected from the TRP admission assessment if completed within the past 2 months. 
 
 
II. Informed Consent Form Template 


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RESEARCH CONSENT FORM 
 
Protocol Title:  
Prebiotic Treatment in People with Schizophrenia 
 
Study No.:   
 
HP-00081820 
 
Principal Investigator: Robert W. Buchanan, M.D. 
 
 
 
 
410-402-7876 
Co-Investigator:  
Deanna L. Kelly, PharmD.  
 
 
 
 
410-402-6861 
 
• Before you agree to participate in this study, it is important that you read and understand the 
following explanation of the procedures.   
• This statement describes the purpose, procedures, benefits, risks, discomforts, and precautions of 
the study.   
• Also described are the other procedures available to you, and your right to withdraw from the study 
at any time.  
• It is important for you to understand that no guarantee or assurance can be made as to the outcome 
of your participation in this study.  
• Please ask as many questions as you like before deciding to participate and during participation in 
this research study.   
• Your participation in this study is voluntary. 
• If you are court-ordered for treatment, or a prisoner, your participation in this study will have no 
effect on your release date, or parole. 
 
PURPOSE OF STUDY 
 
There will be about 30 people enrolled in this study at MPRC/Spring Grove Hospital Center.  You are 
being asked to participate in this study because you have a diagnosis of schizophrenia or 
schizoaffective disorder. 
 
The purpose this study is to examine if gut bacteria change levels of a fatty acid called butyrate after 
you receive 10 days of a prebiotic nutritional supplement in a drink or placebo (sugar like powder 
mixed in a drink); a prebiotic nutritional supplement is a natural plant fiber that beneficially nourishes 
the good bacteria already in the large bowel or colon.   
 
Thirty patients at Spring Grove Hospital Center (SGHC) will be enrolled in this study; the study is 
being conducted by researchers from the Maryland Psychiatric Research Center (MPRC).  You are 
being asked to participate in this study because you have a diagnosis of schizophrenia or 
schizoaffective disorder, and therefore, may have changes in the bacteria that normally live in your 
intestine.  These changes might worsen, or even cause the symptoms of schizophrenia or 
schizoaffective disorder.  The bacteria in your intestines normally produce a small compound called 
butyrate, which is important for maintaining the healthy functioning of our intestines, and which seems 


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to positively regulate our immune system, which fights infections and keeps us healthy.  People with 
schizophrenia and schizoaffective disorder have been found to have reduced levels of butyrate, 
possibly leading to unhealthy intestines, an over-active immune system, and impaired brain 
functioning.  Prebiotin is a natural plant fiber and nutritional supplement that is known to feed the 
healthy bacteria in our intestines that produce butyrate.  By taking prebiotin, we might increase the 
production of butyrate in our intestines, and thereby improve the health of our intestines, our immune 
system, and our brain.  The purpose of this study is to see if taking prebiotin for 10 days leads to an 
increase in butyrate in your blood. 
 
PROCEDURES 
 
Overview:  
• If you agree to participate you will be enrolled in the study for about 3 and one-half weeks.  This 
will include up to 2 weeks of an evaluation phase, when information is collected to make sure you 
are eligible to proceed in the study.  IF you meet the study requirements, then you will proceed to a 
10-day treatment phase. 
• You will have your blood work drawn at the beginning and the end of the study.  The total amount 
of blood drawn over the course of the study is approximately 10 tablespoons. 
• You will collect stool samples at the beginning and the end of the study 
• 
During the treatment phase, you will take either prebiotin or matching placebo 3 times a day for 10 
days AND all participants will receive a prebiotin dose at the beginning and the end of the study. 
• Neither you nor your doctor will know whether you are taking prebiotin or placebo for the 10 days 
in between the two doses. 
 
Description of Evaluation Phase Visit(s): At the first evaluation phase visit, we will perform a standard 
medical workup including a physical exam, and EKG.  We will collect blood for the following 
laboratory measures: CBC, Chemistry Panel, liver enzymes, and lipid panel.  The total blood drawn is 
about three tablespoons (about 45 ml).  A urine sample will be collected for urinalysis and urine 
pregnancy test (if female).  We will ask you questions about your medical, psychiatric, and smoking 
history.  In addition, you will be shown how to collect stool samples.  This visit will take about 3 to 4 
hours and may be done over two or more days. 
 
Description of the Treatment Phase Visits: If you meet inclusion criteria, you will be randomized to 
receive either the prebiotic nutritional supplement or placebo.  Randomization is like the flip of a coin 
(a "50-50 chance") to determine whether you will be given the prebiotic or placebo. You will be given 
the prebiotic nutritional supplement, 3 times a day, with each of your meals, for 10 days.  Your weight, 
height and vital signs (i.e., heart rate, pulse, and blood pressure) will be assessed at the beginning and 
end of the 10 days.  You will also have approximately 2 stool samples collected at the beginning and 
end of the 10 days.   
 
In order to evaluate the impact of the prebiotic treatment on butyrate levels, we will test the ability of 
your gut bacteria to produce butyrate before and after treatment. There will be two test days: a) prior to 
treatment with prebiotic or placebo; and b) following the 10 day course of prebiotic or placebo 
treatment.  On the night prior to the test day, you will receive a completely digestible and low fiber, 
e.g. lasagna.  You will then fast from midnight until the morning, when you will receive your standard 
breakfast and a 12 gram dose of the prebiotic.  Prior to your meal, we will collect blood for the 
following laboratory assessments: blood markers of inflammation, intestinal lining leakiness, and 
butyrate.  Two and 6 hours after your meal, we will collect blood samples for butyrate.  You will 


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receive a light, low fiber meal 4 hours after you receive the prebiotin. ALL participants will receive the 
prebiotin dosing at baseline and endpoint. 
 
We will repeat the same procedures after you complete the 10 day course of either the prebiotic or 
placebo. If any of these measures come back positive, then we will refer you for medical follow-up 
with the appropriate specialist, even if your participation in the study has ended. Any follow-up 
treatment with a specialist will not be part of the research study and you or your insurer will be 
responsible for any costs related to treatment. Please initial yes or no if you agree or do not agree to be 
contacted about follow-up treatment after your study participation has ended.     
Yes________    No_________ 
 
At the beginning of each test day, we will ask you questions about your symptoms.  The total blood 
drawn for each test day is about five tablespoons (about or 75 ml.).  At day 11, you will have a urine 
sample collected for analysis and if you are female, you will also have a urine pregnancy test 
completed.  The total time for each test day visit will be about 7 hours. 
 
WHAT ARE MY RESPONSIBILITIES IF I TAKE PART IN THIS RESEARCH? 
 
If you take part in this research, you will be expected to: attend study visits as scheduled, consume the 
prebiotic or placebo as scheduled, follow protocol diet, allow for the drawing of blood samples, 
cooperate with obtaining stool samples, and take part in the study assessments.   
POTENTIAL RISKS/DISCOMFORTS: 
 
The major risks of this study are the risk for embarrassment from the collection of stool samples.  You 
may have discomfort and bruising from the blood draw.  You may find the symptom ratings and tests 
stressful, and possibly frustrating, boring, or upsetting.  You may experience some embarrassment 
discussing personal information during interviews.  You may ask to take a break at any time. 
 
We are protecting your personal information but there is still a small risk that your research records 
would be viewed by someone not authorized to see it.  To minimize this risk of someone being able to 
access your personal information, your research records will be kept in a secure location. 
The prebiotic supplement is not absorbed into the body, but may cause gas or stomach discomfort in 
some people. 
POTENTIAL BENEFITS 
 
By providing blood and stool samples as part of the study, you may learn of abnormal results and be 
referred for treatment for conditions which would have otherwise gone undetected or evaluated.  There 
is also the possibility that there will be no direct benefit from participating in the study, however the 
following clinical and research-related benefits may occur: 
1) Potential clinical benefits for participation in the trial that are not present independent of study 
participation: 
a) You will have additional meetings with clinical and research staff for psychiatric 
symptoms and information and evaluation of study participation  
b) You will have access to life skills, illness education group, cognitive behavioral 
therapy and if a woman, women’s trauma group during your stay 


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c) You have the opportunity to spend Day 0 and Day 11 in the research suite. This 
provides access to private lounge, videogaming, quiet space and private time 
d) You will receive counseling on diet and can participate in healthy cooking groups 
 
2) Potential research-related benefits for participation in the trial that are not present independent 
of study participation 
a) You will have extra visits for clinical symptom ratings. These include assessment of 
positive and negative psychiatric symptoms and assessments for anxiety symptoms. 
These are not routinely completed. The doctors will receive your full results of the 
symptom ratings and may help your doctor plan better treatment 
b) You will receive standard study assessments that are above and beyond routine care. 
These include EKG, additional vital signs and bloodwork 
c) You will be monitored daily for diet and food intake and the clinical staff will have 
access to full accountability of food intake for better and more personalized 
treatment planning 
d) You will have blood drawn for inflammatory markers (cytokines) and markers for 
the gut permeability. These are not routine laboratory measures. These results will 
help clinicians know if inflammation may play a role in your illness and if 
additional treatment strategies could potentially help their psychiatric symptoms. 
e) You will have a detailed medical history completed and have daily observation. You 
will receive referrals for advanced care if needed from any clinical or research 
findings. 
f) You will learn about prebiotin and will receive information about how to get this 
treatment if they wish to continue outside of the study. 
g) You will have assessments for adverse effects. This will include a private interview 
and asking of 25 adverse effects. These may or may not be study related but allows 
for you to discuss all issues you may be having and adverse effects that you are 
dealing with. This information will help your doctor better address your problems 
which may not have been addressed previously. This may include constipation, 
indigestion, enuresis, etc. 
 
Additionally, researchers may increase their understanding of whether, and how the activity of bacteria 
in the intestines affects the symptoms of schizophrenia. Your bowel movements may be more regular 
while taking the prebiotic nutritional supplement. This benefit could occur in either group as both will 
receive prebiotin at some point in the study. 
 
  
ALTERNATIVES TO PARTICIPATION 
 
You may choose not to participate in this study.  If you choose not participate in this study, your 
treatment at any facility or clinic including MPRC and Spring Grove Hospital will not be affected.   
You will be informed in a timely manner of any new findings which may affect your willingness to 
participate in this study. 
COSTS TO PARTICIPANTS 
It will not cost you anything to take part in this study. 


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PAYMENT TO PARTICIPANTS 
You will receive $75 for completion of the evaluation phase visits and $50 for completion of the 
double-blind study visits.  The total payment for study completion is $125.   
 
You will be paid by cash or check.  If paid by cash, then you will be paid at the end of each visit.  If 
paid by check, then it may take up to 4-6 weeks to receive payment. 
CONFIDENTIALITY AND ACCESS TO RECORDS 
 
All forms with information about you will have only a code number and your initials, not your full 
name.  With some exceptions, information that identifies you will not be given to people who are not 
working on this study, unless you give permission. 
 
When you sign this consent form, you are letting us use your screening data (the information you 
provided when being screened for this study).  Your signature also allows us to use the data that we 
collect during the study itself. We also ask for approval to contact you again in the future about this 
study, or other studies you may qualify for.  Please initial yes or no if you agree or do not agree to be 
contacted.     
Yes________    No_________ 
 
The data from the study may be published. However, you will not be identified by name. People 
designated from the institutions where the study is being conducted auditors may be allowed to inspect 
sections of your medical and research records related to the study.  Everyone using study information 
will work to keep your personal information confidential.   
  
Efforts will be made to reveal your personal information, including research and medical records, only 
to people who have a need to review this information. We cannot promise complete secrecy. 
Organizations that may inspect and copy your information include the IRB and other representatives of 
this organization.  The monitors, auditors, and the IRB will be granted direct access to your medical 
records for verification of the research procedures and date. By signing this document, you are 
authorizing this access.   
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
RIGHT TO WITHDRAW 
 
Your participation in this study is voluntary. You do not have to take part in this research.   You are 
free to withdraw your consent at anytime.  Refusal to take part or to stop taking part in the study will 
involve no penalty or loss of benefits to which you are otherwise entitled and will not adversely affect 
your treatment at MPRC, University of Maryland or Spring Grove Hospital.  If you decide to stop 
taking part, if you have questions, concerns, or complaints, or if you need to report a medical injury 
related to the research, please contact the principal investigator, Robert W. Buchanan at 410-402-7876.  
 


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There are no adverse consequences (physical, social, economic, legal, or psychological) of your 
decision to withdraw from the research.  If you wish to no longer participate in the study, please notify 
a member of the research team. The results from the research will not provide information on your 
health. You will not receive any individual results.  
If you withdraw from this study, already collected data may not be removed from the study database.  
 
CAN I BE REMOVED FROM THE RESEARCH? 
 
The person in charge of the research study, the medically responsible physicians or the agencies that 
monitor the study can remove you from the research study without your approval. Possible reasons for 
removal include failure to follow instructions of the research staff, if the person in charge decides that 
the research study is no longer in your best interest, or you are unwilling or unable to comply with the 
research schedule.  The study doctor will tell you about this and you will have the chance to ask 
questions if this were to happen. 
UNIVERSITY STATEMENT CONCERNING RESEARCH RISKS  
 
The University of Maryland, Baltimore (UMB) is committed to providing participants in its research the 
rights due them under State and federal law. You give up none of your legal rights by signing this consent 
form or by participating in the research project. This research has been reviewed and approved by the 
Institutional Review Board (IRB). Please call the Institutional Review Board (IRB) if you have questions 
about your rights as a research subject. 
 
Participating in research may result in an injury, as explained above. If you suffer an injury directly 
related to your participation in this project, UMB and/or one of its affiliated institutions or health care 
groups will help you obtain medical treatment for the specific injury and provide referrals to other 
health care facilities, as appropriate. UMB and/or its affiliated institutions or health care groups will 
not provide you with financial compensation or reimbursement for the cost of care provided to treat a 
research-related injury or for other expenses arising from a research-related injury. The institution or 
group providing medical treatment will charge your insurance carrier, you, or any other party 
responsible for your treatment costs. If you incur uninsured medical costs, they are your responsibility. 
The study staff can give you more information about this if you have a study injury. 
 
By signing this Consent Form, you are not giving up any legal rights. If this research project is 
conducted in a negligent manner and you are injured as a direct result, you may be able to recover the 
costs of care and other damages from the individuals or organizations responsible for your injury. 
 
If you have questions, concerns, complaints, or believe you have been harmed through participation in 
this research study as a result of researcher negligence, you can contact members of the IRB or the 
Human Research Protections Office (HRPO) to ask questions, discuss problems or concerns, obtain 
information, or offer input about your rights as a research participant. The contact information for the 
IRB and the HRPO is: 
 
University of Maryland Baltimore 
Human Research Protections Office  


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620 W. Lexington Street, Second Floor 
Baltimore, MD 21201 
410-706-5037 
 
Signing this consent form indicates that you have read this consent form (or have had it read to you), 
that your questions have been answered to your satisfaction, and that you voluntarily agree to 
participate in this research study. You will receive a copy of this signed consent form. 
 
If you agree to participate in this study, please sign your name below. 
 
 
 
 
________________________________ 
Participant’s Signature 
 
 
Date:___________________________ 
 
 
________________________________ 
Designee Obtaining Consent Signature 
 
 
Date:___________________________ 
 
 
 
 
 
_______________________________ 
Investigator  
 
 
 
Date:___________________________ 
 
 
_______________________________ 
Witness 
 
 
 
Date:___________________________ 
 
 


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III. Data Safety Monitoring Board (DSMB) Roster 
 
MARYLAND PSYCHIATRIC RESEARCH CENTER 
DSMB BOARD MEMBERS 
 
Chair: 
 
SAaronson@sheppardpratt.org  
Scott Aaronson, M.D. is the Director of Clinical Research Programs at Sheppard and Enoch 
Pratt Hospital. 
 
Address: 
Scott Aaronson, M.D. 
Sheppard and Enoch Pratt Hospital 
6501 North Charles Street 
Towson, MD 21285 
Work Phone: (410) 938-3000 
 
Board Members: 
 
BobMcMahon666@gmail.com  
External Biostatistician 
Robert McMahon, Ph.D. 
 
Address: 126 Rosewood Drive 
Greenbelt, MD 20770 
Phone: 443-427-2451 
 
Glendaj6@cs.com  
Dr. Glenda Housel is a community-practicing psychiatrist in Maryland.  
 
Address: 
Glenda Housel, M.D. 
2 Esther Ann Way 
Reisterstown, MD 21136 
  
CRICHARD@som.umaryland.edu  
Charles Richardson, M.D. is a Spring Grove Hospital psychiatrist who is in charge of the 
Inpatient Treatment Program  
 
Address: 
Charles Richardson, M.D. 
Spring Grove Hospital Center, Tawes Bldg. 
Treatment Research Program (TRP) 
Baltimore, MD 21228 
Work Phone: 410-402-6871  


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Jkreyenb@som.umaryland.edu  
Julie.Kreyenbuhl@va.gov  
Julie Kreyenbuhl, Pharm.D., Ph.D. is a pharmacologist and currently a UMB, IRB Board 
Member as well. She is the Associate Director, Research Core of the VA VISM 5 MIRECC 
 
Address: 
Julie Kreyenbuhl, Pharm.D., Ph.D. 
Associate Professor 
Department of Psychiatry, Division of Services Research  
University of Maryland School of Medicine 
Baltimore VAMC 
10 North Greene Street, Suite 6A  
(BT-MIRECC) 
Baltimore, MD 21201 
Office Phone: 410-637,1864; Secondary Phone: 410-706-3211 
Office Fax: 410-637-1880 
 
CLBrown@som.umaryland.edu 
Clayton H. Brown, Ph.D. is an Associate Professor in the Department of Epidemiology, UMB 
School of Medicine. Dr. Brown is also the Director of the Biostatistics Core for the V.A. 
Capitol Healthcare Network MIRECC  
 
Address: 
Clayton H. Brown, Ph.D. 
Associate Professor 
Department of Epidemiology and Preventive Medicine, 
University of Maryland School of Medicine 
660 West Redwood Street 
Howard Hall, Room 112 
Baltimore, Maryland 21201 
410-706-1058 
fax 410-706-3808 
 
 
 

ICF_000.pdf: 
Page 1 of 8
RESEARCH CONSENT FORM
Protocol Title: 
Prebiotic Treatment in People with Schizophrenia
Study No.: 
HP-00081820
Principal Investigator: Robert W. Buchanan, M.D.
410-402-7876
Co-Investigator:
Deanna L. Kelly, PharmD. 
410-402-6861

Before you agree to participate in this study, it is important that you read and understand the 
following explanation of the procedures.  

This statement describes the purpose, procedures, benefits, risks, discomforts, and 
precautions of the study.  

Also described are the other procedures available to you, and your right to withdraw from the 
study at any time. 

It is important for you to understand that no guarantee or assurance can be made as to the 
outcome of your participation in this study. 

Please ask as many questions as you like before deciding to participate and during 
participation in this research study.  

Your participation in this study is voluntary.

If you are court-ordered for treatment, or a prisoner, your participation in this study will have 
no effect on your release date, or parole.
PURPOSE OF STUDY
There will be about 30 people enrolled in this study at MPRC/Spring Grove Hospital Center.  
You are being asked to participate in this study because you have a diagnosis of schizophrenia or 
schizoaffective disorder.
The purpose this study is to examine if gut bacteria change levels of a fatty acid called butyrate 
after you receive 10 days of a prebiotic nutritional supplement in a drink or placebo (sugar like 
powder mixed in a drink); a prebiotic nutritional supplement is a natural plant fiber that 
beneficially nourishes the good bacteria already in the large bowel or colon.  
Thirty patients at Spring Grove Hospital Center (SGHC) will be enrolled in this study; the study 
is being conducted by researchers from the Maryland Psychiatric Research Center (MPRC).  You 
are being asked to participate in this study because you have a diagnosis of schizophrenia or 
schizoaffective disorder, and therefore, may have changes in the bacteria that normally live in 
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your intestine.  These changes might worsen, or even cause the symptoms of schizophrenia or 
schizoaffective disorder.  The bacteria in your intestines normally produce a small compound 
called butyrate, which is important for maintaining the healthy functioning of our intestines, and 
which seems to positively regulate our immune system, which fights infections and keeps us 
healthy.  People with schizophrenia and schizoaffective disorder have been found to have 
reduced levels of butyrate, possibly leading to unhealthy intestines, an over-active immune 
system, and impaired brain functioning.  Prebiotin is a natural plant fiber and nutritional 
supplement that is known to feed the healthy bacteria in our intestines that produce butyrate.  By 
taking prebiotin, we might increase the production of butyrate in our intestines, and thereby 
improve the health of our intestines, our immune system, and our brain.  The purpose of this 
study is to see if taking prebiotin for 10 days leads to an increase in butyrate in your blood.
PROCEDURES
Overview: 

If you agree to participate you will be enrolled in the study for about 3 and one-half weeks.  
This will include up to 2 weeks of an evaluation phase, when information is collected to 
make sure you are eligible to proceed in the study.  IF you meet the study requirements, then 
you will proceed to a 10-day treatment phase.

You will have your blood work drawn at the beginning and the end of the study.  The total 
amount of blood drawn over the course of the study is approximately 10 tablespoons.

You will collect stool samples at the beginning and the end of the study

During the treatment phase, you will take either prebiotin or matching placebo 3 times a day 
for 10 days AND all participants will receive a prebiotin dose at the beginning and the end of 
the study.

Neither you nor your doctor will know whether you are taking prebiotin or placebo for the 10 
days in between the two doses.
Description of Evaluation Phase Visit(s): At the first evaluation phase visit, we will perform a 
standard medical workup including a physical exam, and EKG.  We will collect blood for the 
following laboratory measures: CBC, Chemistry Panel, liver enzymes, and lipid panel..  The total 
blood drawn is about three tablespoons (about 45 ml).  A urine sample will be collected for 
urinalysis and urine pregnancy test (if female).  We will ask you questions about your medical, 
psychiatric, and smoking history.  In addition, you will be shown how to collect stool samples.  
This visit will take about 3 to 4 hours and may be done over two or more days.
Description of the Treatment Phase Visits: If you meet inclusion criteria, you will be randomized 
to receive either the prebiotic nutritional supplement or placebo.  Randomization is like the flip 
of a coin (a "50-50 chance") to determine whether you will be given the prebiotic or placebo. 
You will be given the prebiotic nutritional supplement, 3 times a day, with each of your meals, 
for 10 days.  Your weight, height and vital signs (i.e., heart rate, pulse, and blood pressure) will 
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13August2019 v.4
be assessed at the beginning and end of the 10 days.  You will also have approximately 2 stool 
samples collected at the beginning and end of the 10 days.  
In order to evaluate the impact of the prebiotic treatment on butyrate levels, we will test the 
ability of your gut bacteria to produce butyrate before and after treatment. There will be two test 
days: a) prior to treatment with prebiotic or placebo; and b) following the 10-day course of 
prebiotic or placebo treatment.  On the night prior to the test day, you will receive a completely 
digestible and low fiber, e.g. lasagna.  You will then fast from midnight until the morning, when 
you will receive your standard breakfast and a 12 gram dose of the prebiotic.  Prior to your meal, 
we will collect blood for the following laboratory assessments: blood markers of inflammation, 
intestinal lining leakiness, and butyrate.  Two and 6 hours after your meal, we will collect blood 
samples for butyrate.  You will receive a light, low fiber meal 4 hours after you receive the 
prebiotin.  ALL participants will receive the prebiotin dosing at baseline and endpoint.
We will repeat the same procedures after you complete the 10 day course of either the prebiotic 
or placebo. If any of these measures come back positive, then we will refer you for medical 
follow-up with the appropriate specialist, even if your participation in the study has ended. Any 
follow-up treatment with a specialist will not be part of the research study and you or your 
insurer will be responsible for any costs related to treatment. Please initial yes or no if you agree 
or do not agree to be contacted about follow-up treatment after your study participation has 
ended.    
Yes________    No_________
At the beginning of each test day, we will ask you questions about your symptoms.  The total 
blood drawn for each test day is about five tablespoons (about or 75 ml.).  At day 11, you will 
have a urine sample collected for analysis and if you are female, you will also have a urine 
pregnancy test completed.  The total time for each test day visit will be about 7 hours.
WHAT ARE MY RESPONSIBILITIES IF I TAKE PART IN THIS RESEARCH?
If you take part in this research, you will be expected to: attend study visits as scheduled, 
consume the prebiotic or placebo as scheduled, follow protocol diet, allow for the drawing of 
blood samples, cooperate with obtaining stool samples, and take part in the study assessments.  
POTENTIAL RISKS/DISCOMFORTS:
The major risks of this study are the risk for embarrassment from the collection of stool samples.  
You may have discomfort and bruising from the blood draw.  You may find the symptom ratings 
and tests stressful, and possibly frustrating, boring, or upsetting.  You may experience some 
embarrassment discussing personal information during interviews.  You may ask to take a break 
at any time.
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We are protecting your personal information but there is still a small risk that your research 
records would be viewed by someone not authorized to see it.  To minimize this risk of someone 
being able to access your personal information, your research records will be kept in a secure 
location.
The prebiotic supplement is not absorbed into the body, but may cause gas or stomach 
discomfort in some people.
POTENTIAL BENEFITS
By providing blood and stool samples as part of the study, you may learn of abnormal results and 
be referred for treatment for conditions which would have otherwise gone undetected or 
evaluated.  There is also the possibility that there will be no direct benefit from participating in 
the study, however the following clinical and research-related benefits may occur:
1)
Potential clinical benefits for participation in the trial that are not present independent of study 
participation:
a)
You will have additional meetings with clinical and research staff for psychiatric 
symptoms and information and evaluation of study participation 
b)
You will have access to life skills, illness education group, cognitive behavioral 
therapy and if a woman, women’s trauma group during your stay
c)
You have the opportunity to spend Day 0 and Day 11 in the research suite. This 
provides access to private lounge, videogaming, quiet space and private time
d)
You will receive counseling on diet and can participate in healthy cooking groups
2)
Potential research-related benefits for participation in the trial that are not present independent of 
study participation
a)
You will have extra visits for clinical symptom ratings. These include assessment of 
positive and negative psychiatric symptoms and assessments for anxiety symptoms. 
These are not routinely completed. The doctors will receive your full results of the 
symptom ratings and may help your doctor plan better treatment
b)
You will receive standard study assessments that are above and beyond routine care. 
These include EKG, additional vital signs and bloodwork
c)
You will be monitored daily for diet and food intake and the clinical staff will have 
access to full accountability of food intake for better and more personalized treatment 
planning
d)
You will have blood drawn for inflammatory markers (cytokines) and markers for the 
gut permeability. These are not routine laboratory measures. These results will help 
clinicians know if inflammation may play a role in your illness and if additional 
treatment strategies could potentially help their psychiatric symptoms.
e)
You will have a detailed medical history completed and have daily observation. You 
will receive referrals for advanced care if needed from any clinical or research 
findings.
f)
You will learn about prebiotin and will receive information about how to get this 
treatment if they wish to continue outside of the study.
g)
You will have assessments for adverse effects. This will include a private interview 
and asking of 25 adverse effects. These may or may not be study related but allows 
for you to discuss all issues you may be having and adverse effects that you are 
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13August2019 v.4
dealing with. This information will help your doctor better address your problems 
which may not have been addressed previously. This may include constipation, 
indigestion, enuresis, etc.
Additionally, researchers may increase their understanding of whether, and how the activity of 
bacteria in the intestines affects the symptoms of schizophrenia. Your bowel movements may be 
more regular while taking the prebiotic nutritional supplement. This benefit could occur in either 
group as both will receive prebiotin at some point in the study.
 
ALTERNATIVES TO PARTICIPATION
You may choose not to participate in this study.  If you choose not participate in this study, your 
treatment at any facility or clinic including MPRC and Spring Grove Hospital will not be 
affected.  
You will be informed in a timely manner of any new findings which may affect your willingness 
to participate in this study.
COSTS TO PARTICIPANTS
It will not cost you anything to take part in this study.
PAYMENT TO PARTICIPANTS
You will receive $75 for completion of the evaluation phase visits and $50 for completion of the 
double-blind study visits.  The total payment for study completion is $125.  
You will be paid by cash or check.  If paid by cash, then you will be paid at the end of each visit.  
If paid by check, then it may take up to 4-6 weeks to receive payment.
CONFIDENTIALITY AND ACCESS TO RECORDS
All forms with information about you will have only a code number and your initials, not your 
full name.  With some exceptions, information that identifies you will not be given to people 
who are not working on this study, unless you give permission.
When you sign this consent form, you are letting us use your screening data (the information you 
provided when being screened for this study).  Your signature also allows us to use the data that 
we collect during the study itself. We also ask for approval to contact you again in the future 
about this study, or other studies you may qualify for.  Please initial yes or no if you agree or do 
not agree to be contacted.    
Yes________    No_________
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The data from the study may be published. However, you will not be identified by name. People 
designated from the institutions where the study is being conducted auditors may be allowed to 
inspect sections of your medical and research records related to the study.  Everyone using study 
information will work to keep your personal information confidential.  
 
Efforts will be made to reveal your personal information, including research and medical 
records, only to people who have a need to review this information. We cannot promise complete 
secrecy. Organizations that may inspect and copy your information include the IRB and other 
representatives of this organization.  The monitors, auditors, and the IRB will be granted direct 
access to your medical records for verification of the research procedures and date. By signing 
this document, you are authorizing this access.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
RIGHT TO WITHDRAW
Your participation in this study is voluntary. You do not have to take part in this research.   You 
are free to withdraw your consent at anytime.  Refusal to take part or to stop taking part in the 
study will involve no penalty or loss of benefits to which you are otherwise entitled and will not 
adversely affect your treatment at MPRC, University of Maryland or Spring Grove Hospital.  If 
you decide to stop taking part, if you have questions, concerns, or complaints, or if you need to 
report a medical injury related to the research, please contact the principal investigator, Robert 
W. Buchanan at 410-402-7876. 
There are no adverse consequences (physical, social, economic, legal, or psychological) of your 
decision to withdraw from the research.  If you wish to no longer participate in the study, please 
notify a member of the research team. The results from the research will not provide information 
on your health. You will not receive any individual results. 
If you withdraw from this study, already collected data may not be removed from the study 
database. 
CAN I BE REMOVED FROM THE RESEARCH?
The person in charge of the research study, the medically responsible physicians or the agencies 
that monitor the study can remove you from the research study without your approval. Possible 
reasons for removal include failure to follow instructions of the research staff, if the person in 
charge decides that the research study is no longer in your best interest, or you are unwilling or 
unable to comply with the research schedule.  The study doctor will tell you about this and you 
will have the chance to ask questions if this were to happen.
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13August2019 v.4
UNIVERSITY STATEMENT CONCERNING RESEARCH RISKS 
The University of Maryland, Baltimore (UMB) is committed to providing participants in its 
research the rights due them under State and federal law. You give up none of your legal rights 
by signing this consent form or by participating in the research project. This research has been 
reviewed and approved by the Institutional Review Board (IRB). Please call the Institutional 
Review Board (IRB) if you have questions about your rights as a research subject.
Participating in research may result in an injury, as explained above. If you suffer an injury 
directly related to your participation in this project, UMB and/or one of its affiliated institutions 
or health care groups will help you obtain medical treatment for the specific injury and provide 
referrals to other health care facilities, as appropriate. UMB and/or its affiliated institutions or 
health care groups will not provide you with financial compensation or reimbursement for the 
cost of care provided to treat a research-related injury or for other expenses arising from a 
research-related injury. The institution or group providing medical treatment will charge your 
insurance carrier, you, or any other party responsible for your treatment costs. If you incur 
uninsured medical costs, they are your responsibility. The study staff can give you more 
information about this if you have a study injury.
By signing this Consent Form, you are not giving up any legal rights. If this research project is 
conducted in a negligent manner and you are injured as a direct result, you may be able to 
recover the costs of care and other damages from the individuals or organizations responsible for 
your injury.
If you have questions, concerns, complaints, or believe you have been harmed through 
participation in this research study as a result of researcher negligence, you can contact members 
of the IRB or the Human Research Protections Office (HRPO) to ask questions, discuss 
problems or concerns, obtain information, or offer input about your rights as a research 
participant. The contact information for the IRB and the HRPO is:
University of Maryland Baltimore
Human Research Protections Office 
620 W. Lexington Street, Second Floor
Baltimore, MD 21201
410-706-5037
Signing this consent form indicates that you have read this consent form (or have had it read to 
you), that your questions have been answered to your satisfaction, and that you voluntarily agree 
to participate in this research study. You will receive a copy of this signed consent form.
If you agree to participate in this study, please sign your name below.
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13August2019 v.4
________________________________
Participant’s Signature
Date:___________________________
________________________________
Designee Obtaining Consent Signature
Date:___________________________
_______________________________
Investigator 
Date:___________________________
_______________________________
Witness
Date:___________________________
HP-00081820 UM IRB Approval Date 9/8/2021
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