Conditions: Schizophrenia Schizoaffective Disorder
Keywords: Schizophrenia Schizoaffective disorder Cognition Magnesium Imaging Negative symptoms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
The goals of this study are to study MMFS-202-302 in a double blind, randomized, placebo-controlled 9-week study of its effect on ameliorating cognitive deficits in 60 patients with schizophrenia or schizoaffective disorder with stable levels of positive symptoms. Secondary end points will include changes in positive and negative symptoms. One dose of MMFS-202-302 will be studied and compared with placebo as adjunctive treatment to atypical antipsychotic drug treatment.

Detailed description:
One of the symptoms of schizophrenia is a problem with specific domains of cognition, even when the positive symptoms have been treated. The primary goal of this study is to determine the effectiveness of 9 weeks of supplementation with MMFS-202-302 as augmentation of atypical antipsychotic medication, to improve a critical specific domain of cognitive function, i.e., working memory, in patients with schizophrenia or schizoaffective disorder. To support this primary goal, global function will be assessed with the Clinical Global Impression assessment of change.

The investigators will also examine the effect of MMFS-202-302 on other domains of cognition (e.g. attention, executive function, declarative memory, etc.); negative symptoms of schizophrenia; positive symptoms of schizophrenia; MRI measures of brain structure, resting state functional connectivity, and function during evaluation of emotional/unemotional and rewarding/aversive images and anticipation and receipt of reward and punishment, and working memory; and EEG measurement of network interactivity during learning and memory recollection.

Arms:
arm 1: MMFS-202: evening dose

MMFS-302: morning dose arm 2: Placebo

Interventions: intervention 1: MMFS-202-302 intervention 2: Placebo
Intervention descriptions: intervention 1: Active ingredient: L-Threonic acid Magnesium salt.

1 g (2 pills) by mouth once daily in the evening for 9 weeks

Drug: MMFS-302 Active ingredient: L-Threonic Acid Magnesium Salt

1 g (2 pills) by mouth once daily in the morning for 9 weeks intervention 2: Two tablets by mouth in the morning, and two tablets by mouth in the evening, daily for 9 weeks.

Protocol document:
Prot_SAP_000.pdf: 
1
Effect of MMFS-202-302 on Cognitive Enhancement in Schizophrenia
Principal Investigator:
Herbert Meltzer, MD
Northwestern University Feinberg School of Medicine 
303 E. Chicago Ave. #12-104
312.503.0309
312.503.0348
h-meltzer@northwestern.edu
Study Drug/Study Device:
MMFS-202-302 
IND/IDE Number:
N/A
IND/IDE Holder Name:
N/A
Funding Source:
Neurocentria
Initial version:
5/16/2014
Amendment 1:
8/26/2014
Amendment 2:
9/17/2014
Amendment 3:
10/2/2014
Amendment 4:
01/23/2015
Amendment 5:
02/26/2015
Amendment 6:
03/25/2015
Amendment 7:
06/08/2015
Amendment 8:
08/25/2015
Amendment 9:
01/06/2016
Amendment 10:
09/29/2016
Amendment 11:
08/25/2017
Amendment  12:
09/11/2017
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TABLE OF CONTENTS
STUDY SCHEMA…………………………………………………………………………………………………….3
SUMMARY……………………………………………………………………………………………………………3
1.0 RATIONALE………….……………………………………………………………………………………….....3
2.0 OVERVIEW OF STUDY DESIGN……………………………………………………………………………..5
3.0 CRITERIA FOR EVALUATION………………………………………………………………………………..6
4.0 PATIENT ELIGIBILITY…………………………………………………………………………………………7
5.0 TREATMENT PLAN…………………………………………………………………………………………….8
6.0 STUDY PROCEDURES………………………………………………………………………………………..8
7.0 RANDOMIZATION METHOD………………………………………………………………………………….9
8.0 STATISTICAL CONSIDERATIONS…………………………………………………………………………..9
9.0 DETAILS OF PROCEDURES……………………………………………………………………………..…11
10.0 REMOVAL OF SUBJECTS FROM STUDY……………………………………………………………….16
11.0 ADVERSE EVENTS………………………………………………………………………………………….16
12.0 STUDY AGENT AND DOSING……………………………………………………………………………..18
13.0 RISKS AND DISCOMFORTS……………………………………………………………………………….19
14.0 STUDY MANAGEMENT…………………………………………………………………………………….20
15.0 REFERENCES………………………………………………………………………………………………..23
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Study Schema
SUMMARY
The goals of this study are to study MMFS-202-302 in a double blind, randomized, placebo-controlled 9- 
week study of its effect on ameliorating cognitive deficits in 60 patients with schizophrenia or 
schizoaffective disorder with stable levels of positive symptoms. Secondary end points will include 
changes in functional measures, and positive and negative symptoms. One dose of MMFS-202-302 will 
be studied and compared with placebo as adjunctive treatment to atypical antipsychotic drug treatment. 
MMFS-202-302 is the clinical code describing the treatment formulation, combining the release profile of 
the compound and the dose of each tablet (i.e. 202 is a 0.5 g 6-hr release tablet and 303 is a 0.5 g 12-hr 
release tablet).
1.0
RATIONALE
1.1
Background and Significance
1.1.1
Cognitive impairment in schizophrenia and schizoaffective disorder
Cognitive deficits of variable severity are present in virtually all patients with schizophrenia and 
schizoaffective disorder at the time of first diagnosis, are often the major reasons for functional 
impairment, and respond only partially to treatment with antipsychotic drugs (APDs) [1]. Even this is 
disputed by some authorities in the field, who attribute improvement to practice effects.  However, it 
is indisputable that many patients can be shown to improve beyond a practice effect size in specific 
cognitive domains, especially semantic memory, declarative memory, and speeded motor testing 
[2-4].  Such improvement can be demonstrated in 6-12-week studies, with additional improvement 
over a six-month total study period. The search for agents which can be used to treat cognitive 
impairment in schizophrenia (CIS) is of the highest priority for these reasons.
Of particular note, working memory (WM) is a particularly impaired process demonstrated across 
the illness spectrum [5]. Of all clinical symptomatology experienced, negative symptoms (NS) have 
shown to be the most intractable, resilient to treatment, and debilitating with regards to functional 
outcome. Notably NS, which include alogia, blunted affect, asociality, avolition, and anhedonia, are 
somewhat associated with WM performance; however, the precise nature of this relationship is 
unclear [6]. Investigation of the reward system has proven particularly insightful in this regard, 
especially given that abnormalities in reward processing are relevant to different aspects of SCZ 
cognition as well as non-cognitive aspects of NS [7], particularly anhedonia and avolition [8]. 
Current research indicates differential areas of preserved and impaired function in aspects of 
reward processing in schizophrenia subjects, including valuation of hedonic experience, decision 
making, and rapid versus slow reinforcement learning [7]. Critically, this evidence also suggests 
WM is an influential intermediate variable in the production of abnormal hedonic experience and 
decision making in schizophrenia, noting that subjects with better WM show less severe deficits in 
these aspects of reward processing [9]. This suggests that previously believed dissociable WM and 
affective functions, subserved respectively by dorsal and orbital prefrontal and infralimbic cortices, 
are both implicated in deficit behavior related to schizophrenia. Given this relationship, it remains 
unclear whether this occurs as a result of faulty neural circuitry or abnormalities related to shared 
dopaminergic inputs, or both. Furthermore, there is strong evidence that the psychobiological 
substrates of negative symptomatology are directly related to both reward [10] and WM [11] 
circuitry. These circuits, and thus functions, are known to be heavily regulated by both mesocortical 
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dopamine (DA) D1, mesolimbic D2 receptors [10, 12], and prefrontal NMDA and GABAA and 
GABAB receptors [13]. From a pharmacologic perspective, this presents an opportunity for 
treatment using novel agents that act upon these receptors.
1.1.2
Preclinical Rationale for Studying L-Threonic acid Magnesium salt (L-TAMS;  clinical 
code: MMFS) to treat CIS, negative symptoms, and possible adjunct for psychosis
Preclinical Evidence:
L-threonic acid magnesium salt (L-TAMS - also known previously as magnesium L-threonate, MgT) 
has shown promise in PCP-induced animal models of schizophrenia as an adjuvant to clozapine in 
the amelioration of cognitive deficits [14]. It is hypothesized this occurs by L-TAMS enhancing the 
effectiveness of atypical antipsychotic NMDA and GABA actions, as Mg is a necessary co-factor in 
NMDA receptor response. In addition, recent data from Professor Xuechu Zhen’s lab at Soochow 
University revealed that L-TAMS treatment improved PCP-induced social interaction in rats, an 
animal analogue widely studied model of NS. These promising findings prompt the investigation of 
this novel compound in the specific treatment of core cognitive and NS in schizophrenia, using both 
imaging modalities and clinical trial methodology. The value of these investigations is that precise 
neurobiological markers of potential change in NS can be identified. 
Initial trials of putative cognitive enhancing drugs should collect data on all major domains of 
cognition, including working, semantic and episodic (declarative) memory, executive function, social 
cognition, attention and speed of processing as our knowledge in this area is limited. Findings from 
initial trials can then guide subsequent trials.
L-TAMS was also shown in a rodent study to improve novel object recognition (NOR) in subchronic 
phencyclidine-treated rats. This is a valuable model as a measure of declarative memory. Atypical 
APDs, including clozapine, have a similar effect on NOR in the PCP rodent model as we and others 
have shown. This model is based on NMDA hypofunction and dysfunction. They also improve other 
domains of cognition, including executive function and working memory. L-TAMS may do the same. 
Mg2+ is a necessary co-factor in NMDA receptor response, and L-Threonate is a critical component 
of L-TAMS for delivery of Mg2+ to the CNS and to neurons. The basis for the effect of the atypicals 
is enhanced DA and ACh efflux in cortex and hippocampus as shown by studies with microdialysis. 
Electrophysiological studies show that the atypicals restore NMDA and GABA currents in cortex and 
hippocampus, respectively. Importantly too, L-TAMS has been shown to improve working memory in 
rats [14].
Clinical Evidence:
Recent studies have shown that L-TAMS (clinical code MMFS) can also improve cognition in 
humans, particularly frontal cortex-mediated executive functions such as working memory. In a 
double-blind, placebo-controlled human trial (n=50), L-TAMS (MMFS-01) significantly improved 
overall cognitive ability in older adults with mild cognitive impairment (MCI) after 6 weeks of oral 
intake [15]. In that study, cognitive ability was assessed with a neuropsychological test battery (NTB; 
Cohen’s d = 0.74, 0.91 at 12 weeks), which was comprised of tests of working memory (Digit Span), 
executive function (trail making test – part B; TMT-B), episodic memory (Face-Name association 
test), and attention (Eriksen Flanker Congruent/Incongruent test). Notably, performance on the Digit 
Span test was significantly improved at 6 weeks by MMFS (Cohen’s d = 0.61, p = 0.023), and a trend 
remained evident at 12 weeks (Cohen’s d = 0.30, p = 0.064), indicating that L-TAMS can improve 
working memory in humans. The current study will help to inform our understanding of the 
generalizability of these procognitive effects to different patient populations, specifically schizophrenia 
and schizoaffective disorder.
1.1.3
Rationale for an RCT of Cognitive Effects of L-TAMS (MMFS-202-302) in 
Schizophrenia and Schizoaffective Disorder
We propose to test the hypothesis that MMFS-202-302, the clinical formulation of the L-TAMS 
compound and dosage regimen, and a novel means to elevate intraneuronal Mg2+ levels in the 
brain, will improve one or more cognitive domains in patients with schizophrenia or schizoaffective 
disorder. This hypothesis is based upon data from Professor Guosong Liu’s lab at Tsinghua 
University and Professor Xuechu Zhen’s lab at Soochow University, that L-TAMS improves several 
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dimensions of cognition in rodents, particularly declarative memory as assessed by NOR and T-
Maze, a measure of working memory. Professor Zhen reported that L-TAMS can augment the ability 
of sub-effective doses of the atypical APD clozapine to reverse the effects of subchronic PCP on 
NOR. We have found that other treatments which have a similar effect also improve other domains 
of cognition. We postulate that MMFS-202-302 will enhance the effectiveness of subeffective and/or 
clinical doses of other atypical APDs in addition to clozapine, as these drugs share many of the 
pharmacologic features of clozapine.
L-TAMS was also shown to improve PCP-induced social withdrawal, suggesting ability to improve 
negative symptoms. It blocked PCP-induced locomotor activity and impairment in PPI, suggesting 
ability to improve positive symptoms as well.
Patients receiving clozapine treatment will be favored for inclusion. L-TAMS has been shown to 
enhance the effect of clozapine to improve cognition and psychosis in PCP-treated rats. Patients 
receiving other atypical antipsychotic drugs that are widely used, i.e. risperidone, aripiprazole, 
quetiapine, lurasidone, or olanzapine will also be eligible. Patients with tardive dyskinesia will be 
excluded because of the evidence that tardive dyskinesia may indicate a treatment resistant form of 
cognitive impairment.
Additionally, this study will evaluate the potential WM enhancing and NS reduction effects of MMFS-
202-302 among a group of individuals with schizophrenia disorder on a series of functional magnetic 
resonance imaging (fMRI) WM and reward tasks. We will evaluate whether MMFS-202-302 + APD 
vs. placebo + APD increases cognitive performance on a task of WM, and associated task-related 
increases in BOLD activation in the dorsolateral prefrontal cortex (DLPFC), and posterior parietal 
cortex (PPC). Additionally, we will assess whether MMFS-202-302 + APD vs. placebo + APD 
enhances reward circuitry (orbitomedial prefrontal cortex [OMPFC], anterior cingulate [ACC], nucleus 
accumbens [NAc], and ventral tegmental area [VTA]) and reward behaviors in the expression of NS. 
Positive findings will provide biomarker evidence for MMFS-202-302 effects on neural systems 
underlying these cognitive processes.
Finally, this study will measure brain network interactivity using electroencephalography (EEG) at 
baseline and end of study to examine any differences in activation or connectivity using learning and 
memory tests over the course of the trial. More information can be found in sections 5.0, 7.4, and 8.1 
below.
2.0  OVERVIEW OF STUDY DESIGN
Patient population
All patients will meet criteria for DSM-V diagnosis of schizophrenia or schizoaffective disorder.  At the 
time of enrollment, they will have been receiving a stable dose of an atypical antipsychotic drug for 2 
months or longer and have stable positive symptoms, i.e. delusions or auditory hallucinations, at the 
screening visit. 60 patients will be enrolled, and randomized in a 1:1 ratio to one dose of MMFS-202-302 
or placebo.
 
2.1
STUDY OBJECTIVES
1.
To determine the effectiveness of 9 weeks’ supplementation with MMFS-202-302 as 
augmentation of atypical antipsychotic medication, to improve working memory or other specific 
domains of cognitive function, e.g. attention, executive function, declarative memory, etc., in 
patients with schizophrenia or schizoaffective disorder. The primary outcome measure will be a 
main effect of group on the 9-wk-change-from-baseline working memory subscale of the 
MATRICS Cognitive Consensus Battery (MCCB). The MCCB consists of 10 cognitive tests 
covering seven domains. This will be augmented by additional neuropsychological measures of 
verbal fluency (FAS Phonemic Fluency), working memory (Brown-Peterson’s Auditory 
Consonant Trigrams) and executive function (the Wisconsin Card Sorting Test). The MCCB 
composite score, and each of the additional cognitive domain subscales listed above will be 
secondary outcome measures.
2.
To determine the effect of MMFS-202-302 on global function, as measured by the Clinical 
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Global Impressions Scale (CGI) assessment of change (CGI-C).
3.
To determine the effect of MMFS-202-302 on negative symptoms of schizophrenia, as 
measured by the Brief Negative Symptom Scale (BNSS) and PANSS negative subscale, and 
imaging of brain reward networks (OMPFC, ACC, NAc, VTA).
4.
To determine the effect of MMFS-202-302 on positive symptoms of schizophrenia, as measured 
by the PANSS positive subscale.
5.
To determine the effect of MMFS-202-302 as augmentation of atypical antipsychotic medication 
on both the behavioral performance and activation patterns in schizophrenia patients during a 
WM neuroimaging paradigm. Specifically, investigation in whether improvement from baseline 
task performance occurs for the MMFS-202-302 + APD group, and if this improvement is 
associated with increases in WM-related brain region activation (DLPFC & PPC).
6.
To evaluate whether MMFS-202-302 results in greater functional connectivity within identified 
reward and working memory circuits in subjects with schizophrenia.
7.
To determine whether MMFS-202-302 stimulates an overall enhancement or restoration of 
typical structural brain abnormalities in schizophrenia, as measured by cortical volume and 
thickness of the neocortex.
8.
To examine the effect of MMFS-202-302 on neural connectivity and activation in EEG 
assessment, using measurements of learning and memory.
3.0
CRITERIA FOR EVALUATION
Primary Efficacy Endpoint

The primary efficacy endpoint will be the change from baseline to 9 weeks of MMFS treatment on 
the working memory MCCB subscale T-score, compared to placebo. The working memory subscale 
of the MCCB was selected as the primary outcome measure because working memory deficit is 
known to be a core feature of cognitive symptoms in schizophrenia and schizoaffective disorder 
patients, and contributes to deficits in other cognitive domains [16-18].Our previous preclinical data 
[14] and clinical trial data with MMFS in mild cognitive impairment [15] demonstrate that MMFS is 
capable of improving working memory. 
Secondary Efficacy Endpoint

Clinical Global Impression of Change (CGI-C) – this clinician-administered interview is important for 
demonstrating that improvements in cognition correspond to an overall functional improvement - an 
FDA requirement for approval of a cognition-enhancing drug for schizophrenia patients. 
Tertiary/Exploratory Efficacy Endpoints

MCCB composite score – a common efficacy endpoint in trials of drugs for cognition enhancement 
in schizophrenia and schizoaffective disorder, providing evidence of global cognitive improvement. 

MCCB individual subscales and supplementary cognitive tests – these subscales and tests will 
provide additional information regarding the efficacy of MMFS for improving specific cognitive 
domains in patients with schizophrenia or schizoaffective disorder. We believe that MMFS may 
improve other aspects of cognition in addition to working memory, especially those that involve 
frontal cortex function. 

A working memory composite score derived from the two MCCB working memory subscale tests 
along with the Brown-Peterson’s Auditory Consonant Trigrams test. Deriving a composite score from 
3 working memory tests may be superior to the MCCB working memory subscale, which is a 
composite comprised of only 2 working memory tests. This possibility will be tested to identify the 
best composite measure of working memory for future trials. 

Responder analysis – the number of subjects achieving a clinical significance cutoff of improving at 
least one half of a standard deviation (T-score change > 5) on the working memory subscale of the 
MCCB, to evaluate the clinical significance of any MMFS treatment effects; an analogous approach 
will be employed for secondary outcomes.

Positive and negative symptoms – Positive symptoms will be assessed with the PANSS positive 
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scale, and negative symptoms will be assessed with the PANSS negative scale and the BNSS. We 
hypothesize that MMFS-202-302 may significantly improve negative and positive symptoms, at least 
partially independently from its cognition enhancing effects.
Exploratory Subgroup Efficacy Analyses
Exploratory subgroup efficacy analyses will be carried out to inform enrichment of the study sample for 
future efficacy studies. MMFS is developed to improve cognition in patients with cognitive deficits, not as 
a general cognitive enhancer per se. Therefore, we plan to conduct subgroup analyses on the patients 
with cognitive deficits. Specifically, for the primary efficacy endpoint (MCCB working memory subscale), 
the data will be reanalyzed using ANCOVA as described above, restricted to the subgroup of subjects 
whose baseline score is at or below median for healthy age-matched norms (T-score of 50 or below on 
the working memory subscale). A similar analysis will be carried out using more conservative cutoffs of 
one half and one standard deviation (T-score of 45 and 40 or below), to further evaluate more severely 
deficient subsets of subjects. The purpose of these analyses is that we believe MMFS will be most 
efficacious for improving working memory in the subset of subjects who have working memory deficits 
upon entering the study. Analogous subgroup analyses will be carried out for the MCCB composite and 
other subscale scores, using the aforementioned cutoffs for the respective scores at baseline.
Safety Assessments
Safety will be evaluated with Fisher’s exact tests, by comparing the following assessments between the 
MMFS-202-302 and Placebo groups: adverse events, laboratory test results, vital signs, body weight, and 
subjective remarks. The safety population will include all subjects who had at least one exposure to a 
study compound, and who had any subsequent encounter with the study staff.
4.0
PATIENT ELIGIBILITY
Subjects must meet all of the inclusion and exclusion criteria to be registered to the study. Study 
treatment may not begin until a subject is registered.
4.1
Inclusion Criteria
1.
All patients must be capable of giving written informed consent.
2.
Male or female subjects of any race; between 18 to 60 years of age, inclusive.
3.
No hospitalization other than for evaluation in the past four months
4.
Resides in a stable living situation, according to the investigator’s judgment.
5.
Diagnosis of schizophrenia or schizoaffective disorder of at least one year duration, as 
established by the SCID-I, and verified with medical records and/or confirmation of diagnosis by 
treating clinician. The illness is in a nonacute phase as determined by the subject’s primary 
treating clinician
6.
Current psychotropic drug treatment consists of monotherapy with an atypical antipsychotic drug.
7.
No more than a mild level of EPS as determined by the Simpson Angus Scale (SAS) total score: 
≤ 6
8.
Not taking anticholinergic medication for EPS
9.
No evidence of tardive dyskinesia
10. Subjects healthy enough to complete a 9-week clinical trial
11. Women of childbearing potential must have a negative pregnancy test at screening and 
baseline, and agree to use adequate protection (i.e. double barrier method) for birth control.
12. Able to complete cognition assessments in English
13. General intellectual abilities falling broadly within the average estimated IQ > 80, as measured 
by the Wide Range Achievement Test – 4th Edition (WRAT-IV).
4.2
Exclusion Criteria
1.
Failure to perform screening or baseline examinations
2.
Hospitalization within 8 weeks before screening, or change of antipsychotic medication or dose 
within 2 months prior to screening
3.
Subjects who have participated in another clinical trial with an experimental medication within the 
past 2 months.
4.
Patient has had cognitive battery similar to those used in this study within the last 12 months
5.
Subjects with other DSM-V Axis I or Axis II primary diagnoses
6.
Diagnosis of alcohol or substance abuse or dependence within the past 3 months,
7.
Significant suicide risk as determined by the Columbia Suicide Severity Rating Scale (C-SSRS)
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8.
Subjects who plan to begin a new course of cognitive remediation therapy, or have been 
receiving cognitive remediation therapy for less than one year.
9.
History of myocardial infarction, unstable angina, uncontrolled hypotension or hypertension 
within 3 months before screening.
10. Clinically significant abnormality on screening ECG
11. Alanine transaminase (ALT) or aspartate transaminase (AST) > 2.5 times the upper limit of 
normal (ULN)
12. History of stroke, brain tumor, head trauma with loss of consciousness, or other clinically 
significant neurological condition within 12 months before screening
13. Subjects with other uncontrolled medical conditions, in the opinion of the investigator
14. Polypharmacy with two or more antipsychotic drugs or mood stabilizers
15. Use of benzodiazepines
16. Individuals with kidney dysfunction will not be enrolled, as dysfunctional kidneys may have 
difficulty clearing the magnesium from the body
17. Individuals who are currently taking magnesium supplements
5.0     TREATMENT PLAN
5.1 Study Design 
Design of Clinical Trial
After providing written informed consent and completing baseline assessments, patients with 
schizophrenia or schizoaffective disorder will be randomized to placebo or MMFS-202-302. We will 
make every effort to enroll subjects who have had a recent fMRI assessment as part of the 
Northwestern University Psychiatric Clinical Research Program. This would provide valuable pre-dose 
information regarding any structural abnormality. No patients with tardive dyskinesia will be admitted 
because of the evidence for its deleterious effect on cognition.
Patients will be recruited primarily from three mental health clinics in the Chicago area, at which the 
principal investigator been successfully recruiting for the last 28 months: the Stone Mental Health Center 
which is a part of the Northwestern Medicine system, Community Counseling Centers of Chicago (C4), 
and Clayton House, a residential treatment center. Other mental health facilities in the area will also be 
referral sources. We expect to recruit 4-5 patients per month for this study without difficulty. We expect 
the recruitment to be complete within 12 months or less after approval by the Northwestern University 
Institutional Review Board and study initiation.
All patients who are screened must provide written informed consent. Our lab has trained and certified 
coordinators and research assistants who will be assigned to this study as their primary responsibility. 
We have used the MATRICS cognitive battery in many studies over the last five years. Because of our 
20- year interest in cognitive impairment in schizophrenia, there are a few other cognitive tests we 
collect on all of our research patients. These include a measure of phonemic verbal fluency (FAS), the 
Brown- Peterson Auditory Consonant Trigrams test of working memory (ACT), and the Wisconsin Card 
Sorting Test (WCST). We have experienced no difficulty in administering the MATRICS battery and this 
group of tests, which takes another 30 minutes to our patients.
We propose to study a total of 60 randomized participants, 30 receiving MMFS-202-302 and 30 
randomized to placebo.
6.0
STUDY PROCEDURES
Study visits will include screening and 5 treatment visits (baseline, Weeks 1, 3, 6, and 9). Patients will be 
contacted by telephone at Weeks 2, 4, 5, 7, and 8 for monitoring of medication compliance, change in 
concomitant medication, and adverse events. Please see Appendix 1 – Schedule of Assessments.
At screening, the Structured Clinical Interview for Diagnosis for DSM Disorders (SCID) will be completed 
for confirmation of psychiatric diagnosis. A medical/psychiatric history will also be collected and a 
physical exam will be performed. Vital signs including weight, height, waist and hip measurement will be 
obtained at screening to record body mass index.
Subjects will be administered MMFS-202-302 at a fixed single dose of 2 grams (1 gram twice per day), 
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or placebo after the completion of the baseline assessments.
Methods:
A)
Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) 
battery, including some supplemental cognitive assessments (FAS, ACT, WCST )
B)
Positive and Negative Syndrome Scale (PANSS) for schizophrenia and schizoaffective disorder
C) MRI assessments:
a.
Structure: MPRAGE (T1), T2
b.
Function: Resting connectivity
c.
Function: Reward/aversion and attention: fMRI paradigm of IAPS (standardized images 
selected to be neutral, pleasurable, or arousing) and Spinner Task
d.
Function: Capacity working memory task
D) A set of cognitive psychological paradigms performed outside of the magnet following the MRI 
scan:
a.
Keypress task for an adaptation of the International Affective Picture Set (IAPS)
b.
A spinner wheel rating task of the reward/aversion associated with monetary 
gains/losses
E)
Brief Negative Symptom Scale (BNSS)
F)
Calgary Depression Scale for Schizophrenia
G) Clinical Global Impression of Severity (CGI-S) and Change (CGI-C)
H) Measurement of RBC Mg at baseline and end of study
I)
EEG evaluation, measuring connectivity and activation using learning and memory tests
7.0
RANDOMIZATION METHOD
Those who meet the study inclusion criteria will be randomized into one of two treatment groups, one to 
receive adjunctive therapy of MMFS-202-302 and the other to receive placebo. Using SAS software, a 
computer-generated randomization sequences for each treatment arm will be assigned using permuted 
block method limiting imbalance in numbers between groups. To assign the randomization, the SAS 
procedure PROC PLAN will be used [19]. Until the trial is concluded, the randomization sequence will be 
blind to the study participants as well as research coordinators and raters. Randomization list will be 
provided by assigned statistician, Karu Jayathilake, and will be held by unblinded study drug manager at 
680 N. Lakeshore Dr., Suite 1520; Chicago, IL 60611-7101.
8.0
STATISTICAL CONSIDERATIONS
8.1
Analysis of Clinical Data
Data will first be analyzed for efficacy on a per-protocol basis. The per-protocol population will include 
all subjects who complete all scheduled visits (+/- 5 days from planned visit time), have no protocol 
deviations that in the judgment of the principal investigator would invalidate their efficacy data, and 
achieve medication compliance of 80-120% (determined by pill counting; if pill packs are not available 
for confirmation, self-report of compliance will be used). Participants whose assessment falls +10 days 
or less from the scheduled visit will be included in per-protocol population, only if they were taking the 
study compound throughout. Data will secondarily be analyzed for efficacy on an intent-to-treat basis, 
with last observation carried forward (LOCF) for missing values or dropouts; subjects who did not 
receive any study compound will be excluded from the full analysis set, preserving the intent-to-treat 
principle. The primary analysis will be a univariate ANCOVA adjusting for baseline differences in the 
dependent measures of interest. We would also examine some variables categorically. The MATRICS 
working memory subscale T-score at 9 weeks will be the primary endpoint. Secondary endpoints will 
include the Clinical Global Impression of Change (CGI-C); the MCCB composite score; other individual 
cognitive domain subscale T-scores of the MCCB; a working memory composite score comprised of the 
2 MCCB working memory subscale tests and the ACT test; and the PANSS positive and negative 
scales and BNSS. All endpoints will be evaluated as 9-weeks change from baseline, except for PANSS, 
which will be evaluated at both 6 and 9 weeks compared to baseline. Responder analyses will also be 
carried out using a chi-square test for the MCCB working memory subscale as a secondary endpoint 
evaluating clinical significance, using a cutoff of 0.5 standard deviation improvement (T-score 
improvement of > 5 points). Finally, separate exploratory subgroup analyses will be performed on the 
MCCB working memory subscale T-score restricted to the subset of subjects who score 0, 0.5, or 1.0 
SD or below the mean for normal age-matched normative data for that subscale. Analogous subgroup 
analyses will also be performed for the MCCB composite score, and the other MCCB subscale scores. 
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Alpha will be set at 0.05 for all analyses. The individual scores for each of the 6 other 
neuropsychological MCCB subscales, and supplementary cognitive tests (ACT, WCST, FAS), as well 
as the CGI-C measure of functional change will be evaluated to provide supporting information for 
primary and secondary measures. 
Assumptions for the power analysis included random assignment into one group receiving placebo and 
one MMFS-202-302. The MCBB, as the primary instrument will be collected at baseline and at end 
point (9 weeks).  Using univariate ANCOVA with baseline score as covariate, the time average 
difference in the response variable will be compared between groups to detect treatment difference. 
Based on Javitt  et al, 2012, we assume the mean baseline working memory score will be 36.4, SD 11.7 
for both groups.  We assume the placebo group will show no improvement with an SD of change of 6.5, 
while the treatment group will improve a mean of 5 points with the same SD of change, a medium 
effect. We assume the correlation coefficient of repeated observation to be 0.5 and the covariance 
structure to be compound symmetry. The power calculation was conducted with alpha level of 0.05. Full 
results are available upon request. With a two-sided test, the analysis reveals that 28 subjects per 
group are required assuming 5 points of improvement of the treatment group compared to the placebo 
for the desired power of 80% with alpha level of 0.05. We plan to recruit 30 per group to account for 
drop outs. Thus, allowing for attrition up to 20%, this sample size will provide 74-83% power to detect 
the hypothesized medium treatment effect.
We will assess MMFS-202-302 effects on negative and positive symptoms as additional endpoints, as 
measured by the BNSS and PANSS. Further, we will analyze the effect on drug tolerability as 
determined by the following: body weight, body mass index (BMI), waist circumference, and movement 
rating scales.
8.2
Analysis of Structural Imaging Data
Structural MRI will be processed with the FreeSurfer (FS) image analysis suite 
(http://surfer.nmr.mgh.harvard.edu/) [20], followed by FS+LDDMM [21] for the high-dimensional mappings 
of the subcortical and cortical ROIs. These automated methods produce anatomic measures that are 
equivalent to measures made by experts, but with increased reproducibility and decreased manual effort 
[22]. Maps of longitudinal change are then computed by applying within-subject FS+LDDMM where the 
subject’s baseline scan becomes a template and each of the follow-up scans becomes the target, which 
carry the baseline ROIs into follow-up scans. Subcortical ROI volumes at each time point are calculated 
as volumes occupied by the mapped subcortical ROI. Subcortical ROI shape at each time point will be 
computed using principal components analysis (PCA) represented by the associated subject scores [22]. 
Cortical thickness, volume and metric distortion (representing local volume and folding change) at each 
time point are provided by FS [23].
8.3
Analysis of Functional Imaging Data
Mixed effects models and analysis of variance will be used to evaluate behavioral performance on tasks 
administered in the scanner to characterize working memory performance and reward valuation across 
task conditions and to contrast performance between MMFS-202-302 vs. placebo treated groups. Event-
related fMRI analyses will be carried out using SPM v8.0 (Statistical Parametric Mapping version 8.0 
http://www.fil.ion.ucl.ac.uk/spm/software/spm8/) in a MATLAB environment. A fixed effect analysis will be 
used to model activation associated during events of interest in each subjects’ time series data. 
Activation maps from these analyses will be carried forward to higher-level mixed effects analyses to 
model each group’s activation during the events of interest allowing for separate estimations of 
variances for each group. Analyses contrasting activation in the MMFS-202-302 vs. placebo groups will 
include both whole brain and a priori regions of interest (i.e., DLPFC, PPC, OMPFC, ACC, NAc).
8.4
Analysis of EEG data
EEG data will be analyzed using custom scripts designed by the laboratory of the PI and Co-I using 
MATLAB software (www.mathworks.com). Statistical analysis methods will be used that are standard for 
behavioral data in learning and memory experiments for EEG data. These include individual as well as 
group-level statistics that permit inferences regarding the population (e.g., ANOVA, MANCOVA, Causal 
Modeling, ICA, etc.). To address the hypotheses, we will identify EEG patterns of variation across 
experimental tasks and determine how these patterns change across the age groups listed above.
Analysis of clinical. imaging, and EEG data will be completed by Derin Cobia, PhD, Joel Voss, PhD, and 
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Karu Jayathilake, MS, all of whom are experts in biostatistics and analytics.
9.0
DETAILS OF PROCEDURES
9.1
Study Materials
9.1.1
Structured Clinical Interview for DSM-IV (SCID)
The SCID-CT is a short semi-structured interview. With an administration time of approximately 15 
minutes, it was designed to meet the need for a short but accurate structured psychiatric interview for 
multicenter clinical trials and epidemiology. The SCID-CT will be administered by raters at the study site. 
The SCID-CT must be administered by a site study staff member listed on the site delegation of authority 
log with at least 2 years of experience with the population under study. The results of this assessment 
will be used to confirm the diagnosis of schizophrenia or schizoaffective disorder and rule out any 
exclusionary diagnosis. The SCID will be administered at the screening visit.
9.1.2
MATRICS Consensus Cognitive Battery (MCCB)
The MCCB includes 10 tests that assess 7 cognitive domains: speed of processing, attention/vigilance, 
working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. 
The tests will be administered together in one 60-to 90-minute session. For subjects who use nicotine, 
the MCCB will be performed at least 30 minutes after nicotine intake. Though not strictly required by the 
protocol, whenever possible, the MCCB should be administered at the same time of day (± 1 hour). The 
MCCB is a hybrid battery comprising multiple independently owned and published tests. Normative data 
for demographic corrections are derived from a single representative sample to which the tests were 
administered together as a unit, called “co-norming” [24]. The MCCB’s high test-retest reliability makes it 
a sensitive and accurate measure of cognitive change, and its minimal practice effects ensure that it is 
appropriate for repeat testing [25]. The MCCB was developed by the National Institute of Mental Health 
(NIMH) MATRICS initiative. The MATRICS was designed to stimulate the development of 
psychopharmacological agents to improve cognition in schizophrenia. The selection of tests included in 
the MCCB involved a broad-based interdisciplinary consensus process that is described in more detail 
on the MATRICS website (www.matrics.ucla.edu). Details of administration are included in the study-
specific MCCB manual. The MCCB will be administered at baseline and end of study.
9.1.3
Positive and Negative Syndrome Scale (PANSS)
The PANSS is an interview-based measure of the severity of psychopathology in adults with psychotic 
disorders. The measure is comprised of 30 items and 3 scales: the Positive scale assesses 
hallucinations, delusions, and related symptoms; the Negative scale assesses emotional withdrawal, 
lack of motivation, and similar symptoms; and the General Psychopathology scale addresses other 
symptoms such as anxiety, somatic concern, and disorientation. An anchored Likert scale from 1-7, 
where values of 2 and above indicate the presence of progressively more severe symptoms, is used to 
score each item. Individual items are then summed to determine scores for the 3 scales, as well as a 
total score. A Composite scale score (Positive scale score - Negative scale score) can also be 
calculated to show the relative valence of positive and negative symptoms. Total time required for the 
PANSS interview and scoring is approximately 30-40 minutes. PANSS raters will be required to meet 
specific training and education criteria before they are certified to rate for this study. In addition, raters 
will receive specific training and education regarding all the following assessments prior to study 
initiation. The PANSS will be administered at baseline, week 6, and end of study.
9.1.4
fMRI Procedures
MRIs will be performed on all subjects that meet criteria for scanning (i.e. those that will fit in the scanner 
and do not have metal in their body). Scanning will be performed on a 3.0T Siemens TIM Trio MRI 
scanner with a UNIX based host computer (Sun Microsystems), actively shielded gradients, and echo-
planar capability. Positioning calipers are used to fixate the head and reduce patient motion during the 
study. Once the MR technician and research personnel have position the subject comfortably in the 
scanner, the subject is then monitored with a wide angle and a telephoto camera. An auditory system 
provides two-way communication making it easier to explain the task to the subject. A slim line 
headphone set is used for maximum patient comfort. Visual stimuli are delivered to a custom rear 
projection screen placed inside the bore of the magnet approximately 24" from the subject. The subject 
views the stimuli via a mirror attached to the head coil that can be adjusted easily.
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Structural imaging
1.
T2 structural images: A series of T2-weighted images will be acquired for clinical 
neuroradiological examination and review for incidental findings.
2.
T1 structural images: A series of T1-weighted images will be acquired to provide high resolution 
anatomic images of the brain for morphometric analysis and for aligning functional images for averaging 
data across subjects.
Functional imaging
Functional images will be acquired using echo-planar imaging. Acquisition parameters will be optimized 
according to task completed. Tasks will be performed for 8-12 minutes depending on the behavioral 
paradigm. Pauses are provided between tasks to allow subjects to rest and for providing instructions.
Manual button press responses will be record using an MR compatible button box.
3.
IAPS Decision-Making Task: For this task each subject is presented with a series of picture sets 
from the International Affective Picture System that present either positive, negative, or neutral stimuli. 
Participants will be asked to specifically quantify positive and negative preferences involving (i) decision-
making regarding the valence of behavior, and (ii) judgments that determine the magnitude of reward 
valuation and aversion.
4.
“Spinner” Monetary Game of Chance Task: For this task, a $50 endowment is provided, and the 
subjects were told that during the game, they might lose some or all of this stake, retain it, or increase it. 
They are presented one of three spinners, which are subdivided into three equal sectors—each labeled 
with a different monetary value. The image of an arrow rotates around the center of the spinner during 
the prospect phase, and then stops at one sector at the start of the “outcome” phase. The amount of 
money indicated on that sector would be added to or subtracted from the subject’s total, but the 
cumulative winnings or losses are not displayed. The timing of the prospect and outcome phases made 
it possible to distinguish hemodynamic signals associated with anticipation from those associated with 
the experience of outcomes. During control trials, the display consists of a stationary fixation point. The 
design is in a single-trial format, and the trial sequence will be counter-balanced.
5.
C
apacity Working Memory Task: This task is a spatial variant of the Sternberg Item Recognition paradigm, 
a paradigm which field experts have identified as promising for imaging biomarkers in clinical trials 
evaluating effects on working memory. During a brief encoding phase, subjects view an array of 
containing a variable number of items (3,5, or 7 items). They are to remember the location of items over 
a delay period of variable duration (2,4, or 6 sec) and then respond during response phase whether the 
presented probe appears in the location of one of the items presented in the array. Activation in the 
DLPCF and related regions during the delay period of correctly performed trails will be evaluated.
6.
Resting State: During this task subjects will be asked to keep their eyes open and fixate a 
central crosshair.
fMRI task order will be pseudo randomized across groups to account for order effects. Start and stop 
time of the scan session will be recorded.  MRI procedures take up to 2 hours to complete.
9.1.5
Brief Negative Symptom Scale
The Brief Negative Symptom Scale (BNSS): [26] was developed in response to the consensus 
conference and the NIMH MATRICS initiative on negative symptoms. It includes assessment of the 5 
domains included in the Consensus Development Conference: blunted affect, alogia, asociality, avolition 
and multiple aspects of anhedonia (e.g., anticipatory pleasure and frequency of pleasurable activities). It 
has demonstrated strong inter-rater reliability, internal consistency, stability, and convergent/discriminant 
validity [27, 28]. The BNSS yields subscale scores for each domain, as well as a total global score.
9.1.6
Clinical Global Impressions Scale (CGI)
The Clinical Global Impressions (CGI) Severity and Change Scale will be used for repeated evaluations 
of global psychopathology. The CGI scale is widely used in schizophrenia research. The CGI-S is a 
single Likert scale rating severity of psychopathology on a scale of 1 (normal, not ill) to 7 (very severely 
ill). The CGI-C is a single Likert scale rating change of psychopathology during the trial on a scale of 1 
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(very much improved) to 7 (very much worse). The CGI will be completed at baseline and end of study.
9.1.7
Calgary Depression Scale for Schizophrenia
CDSS: The CDSS is a clinician-administered psychiatric symptom rating scale intended to measure the 
level, duration, and frequency of depressive symptoms in patients diagnosed with schizophrenia or 
schizoaffective disorder. The CDSS, developed at the University of Calgary [29], has good construct 
validity, internal reliability, and interrater reliability. The type and level of depression measured by this 
scale is also reported to have divergent validity from symptoms associated with schizophrenia and 
schizoaffective disorder. Clinicians administering this scale ask patients about their depressive 
symptoms since the last study visit. Each of the 9 items of the CDSS is scored between 0 (absent) and 3 
(severe). The 9 items are then added together to yield a single total score in the range of 0 to 27. A 
score of 7 or higher is considered to be 85% sensitive to a diagnosis of major depressive disorder. For 
study eligibility, a CDSS score of ≤ 10 (minimal level of depression) will be required. The CDSS is used 
in this study as both a screening assessment and a safety assessment for depressive symptoms. The 
CDSS will be performed at baseline, and the final study visit.
9.1.8
Physical Examination
The physical exams must be performed by the PI or designee (or a licensed medical practitioner such as 
a physician’s assistant or nurse practitioner) listed on the site delegation of authority log.
A complete physical examination includes the following assessments: general appearance, head, eyes, 
ears/nose/throat, neck, lymph nodes, skin, lungs, heart, abdomen, musculoskeletal, and neurologic 
evaluations. If the subject is discontinued for any reason during the treatment phase, every attempt 
should be made to perform a final physical examination.
9.1.9
Vital Signs
Arterial systolic and diastolic blood pressure and radial artery pulse rate will be measured while the 
patient is seated at the scheduled visits designated in the Schedule of Events in Appendix 1.
9.1.9.1 Height and Body Weight
Height will be measured at the screening visit. Patients will be measured without shoes. Body 
weight will be recorded at screening, baseline and every visit through the 9-week treatment 
phase.
9.1.9.2 Body Mass Index (BMI)
Body mass index (BMI) will be determined with the patient’s height and weight at the screening 
visit and subsequent treatment visits. BMI must be calculated using the following formula: A 
person’s (Weight in pounds divided by their height in inches squared) x 703.
9.1.9.3 Waist and Hip Circumference
Waist and hip circumference will be recorded at screening, baseline, and all study visits.
9.1.10
Electrocardiogram (12-Lead ECG)
The PI or a physician listed on the site delegation of authority log must review, initial, and date the 
report, which must be filed in the subject’s study chart. Results will be captured in the subject’s study 
chart, not in the electronic database. Clinically significant findings from the screening report must be 
captured in the medical history. Eligibility for study entry must be assessed by the principal investigator. 
Any clinically significant changes compared with baseline must be captured as AEs in the electronic 
database.
Subjects are to be supine for at least 5 minutes prior to ECG assessments. A central facility will be used 
in this study for interpretation and analysis of ECGs. All subjects will have standard resting 12-lead 
ECGs performed and interpreted. The time the ECG is performed will be recorded (using a 24-h clock). 
In addition, the time that the subject took their last dose of study medication (prior to the ECG) will be 
recorded on the CRF page.
9.1.11
Adverse Event (AE) Monitoring
The PI or a designee (eg, a licensed, qualified medical practitioner such as a physician’s assistant or a 
nurse practitioner) listed on the site delegation of authority log must assess the severity and relationship 
to study medication(s) of all AEs. All observed or volunteered AEs regardless of treatment group or 
suspected causal relationship to the investigational product(s) will be recorded on the AE page(s) of the 
eCRF.
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For all AEs, the investigator must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as an SAE requiring 
immediate notification to the Sponsor or its designated representative.
For all AEs, sufficient information should be obtained by the investigator to determine the causality of the 
AE. The investigator is required to assess causality and indicate that assessment on the eCRF. For AEs 
with a causal relationship to the investigational product, follow-up by the investigator is required until the 
event or its sequelae resolve or stabilize at a level acceptable to the investigator.
Adverse events (serious and non-serious) should be recorded on the CRF from the date the informed 
consent form (ICF) was signed until the end of their participation in the study, ie, the subject has 
discontinued or completed the study.
9.1.12
Concomitant Medications
Concomitant Medications will be documented using the Concomitant Medications form at Baseline and 
all study visits.
9.1.13
Study Medication Adherence
Participants will be asked about his/her medication adherence at each appointment. Study personnel will 
count and record the number of pills in the patient’s study medication bottles and provide immediate 
feedback, reinforcing the behaviors of patients who appear to be taking medications as prescribed and 
problem-solving with those who appear not to be. Clinicians will review with patients the use of pill-
minder boxes, as needed.
9.1.14
Laboratory Test Assessments
Northwestern Medicine Laboratory will be used for analysis of fasting lab assessments required during 
the study. Blood will be drawn from each patient at the screening visit, and at end of study as noted in 
the study Schedule of Events in Appendix 1. The fasting tests will include: Hematology and chemistry 
panels; pregnancy (women of childbearing potential only), serum creatinine, and urine drug screen 
(UDS).
Note: At screening and throughout study participation, a positive UDS or blood alcohol screen is not 
necessarily exclusionary and/or may not require a subject be withdrawn from the study. This decision 
will be per the discretion of the principal investigator.
A blood sample will be collected and analyzed for plasma Mg2+, Red blood cell Mg2+ (RBC-Mg) and 
total RBC cell count.
9.1.14.1 Genetic Testing
All subjects will be consented to obtain a blood sample for genetic studies to search for possible 
markers for response to MMFS-202-302 in participants with schizophrenia. DNA from patients 
already studied by the PI will be available for comparison.
9.1.15
EEG Assessments
Research participants will undergo EEG recording while participating in learning and memory tests at 
baseline and end of study visits. Prior to the experiment, research participants will be familiarized with 
EEG and prepared for the EEG recording session. Research staff will inform the research participants 
about the EEG procedures, and will ask the research participants to perform familiarization activities 
such as wearing the elastic caps that will be worn during the actual experiment (but without EEG 
recording) and showing the research participants informational videos and images of other individuals 
engaged in EEG recording.
After this familiarization process has finished, research participants will be prepared for EEG recording. 
This involves placing an elastic cap on the head of the research participant. Recording electrodes are 
embedded within the elastic cap, and these electrodes record the electrical activity of the research 
participants’ brains non-invasively. The EEG apparatus is battery-powered, and poses no serious risk of 
physical harm to the research participant. Each recording electrode is filled with a non-toxic, 
hypoallergenic electrolytic gel so that the electrode makes contact with the participant’s skin. The gel is 
injected using a blunt, plastic-tip syringe that poses minimal risk of skin abrasion because it is blunt and 
made of plastic. Electrodes are also affixed to the cheeks, temple area, and behind the ears using 
medical-grade tape that can be easily removed after the experiment. Participants then take part in the 
learning/memory testing during EEG recording. When the experiment is finished, the elastic cap is 
removed and participants are given the option to either wash the gel out of their hair in a sink provided in 
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the same laboratory (with help from the research staff as needed), or to simply leave and wash the gel 
out at home. Participants are then debriefed and dismissed. There are no known lasting physical 
ramifications of the EEG procedure. The only known risk to the research participant is the mild 
discomfort associated with wearing the EEG cap and possible frustration with the learning and memory 
tasks.
Research staff is trained to identify participant discomfort and frustration during the experiment. In 
response, research staff will adjust the EEG cap for comfort, introduce rest breaks as necessary, and 
provide positive feedback regarding performance when possible to reduce potential frustration.
9.2
Safety Scales
9.2.1
Abnormal Involuntary Movement Scale (AIMS)
The AIMS is a clinician-rated assessment of abnormal movements consisting of unobtrusive observation 
of the subject at rest (with shoes removed) and several questions or instructions directed toward the 
subject. Using a severity scale ranging from 0 (none) to 4 (severe), clinicians rate dyskinesia in several 
body regions, including the facial area, extremities, and trunk.
9.2.2
Barnes Akathisia Rating Scale (BAS)
The BAS is a rating scale geared toward assessment of neuroleptic-induced akathisia, though it can be 
used to measure akathisia associated with other drugs as well. [30, 31]. The BAS will be administered 
by a qualified rater at the site.
9.2.3
Simpson-Angus Scale (SAS)
The SAS is a clinician-rated assessment of neuroleptic-induced Parkinsonism consisting of 10 items. 
Items are anchor-based, rated on a 5-point scale and address rigidity, gait (bradykinesia), tremor, 
glabellar tap, and salivation [32]. The SAS will be administered by a qualified rater at the site. 
9.2.4
Columbia Suicide Severity Rating Scale
The C-SSRS was developed by a team of researchers at Columbia University to address the need for 
standardized classification of suicide reports to assess suicide risk. This scale consists of a baseline 
evaluation that assesses the lifetime experience of the subject with suicide events and suicidal ideation 
and a post-baseline evaluation that focuses on suicidality since the last study visit. A baseline C-SSRS 
will be completed at the screening visit. The C-SSRS Since Last Visit form will be completed at all 
subsequent visits.
10.0
REMOVAL OF SUBJECTS FROM STUDY
Individuals can be taken off the study treatment and/or study at any time at their own request, or they 
may be withdrawn at the discretion of the investigator for safety, behavioral or administrative reasons. 
The reason(s) for discontinuation will be documented and may include:

Individual voluntarily withdraws from treatment (follow-up permitted);

Individual withdraws consent (termination of treatment and follow-up);

Individual is unable to comply with protocol requirements;

Individual experiences toxicity that makes continuation in the protocol unsafe;

Physician judges continuation on the study would not be in the patient’s best interest;

Individual becomes pregnant (pregnancy to be reported along same timelines as a serious 
adverse event).
11.0
ADVERSE EVENTS
During the first week, common side effects are a slight drowsiness and a feeling of increased blood flow 
in the head. As with any mineral product, people with kidney deficiency should not take this product.
Some individuals have reported dizziness or slight headaches when first taking MMFS-202-302.
11.1
Contraindications:
None
11.2
Special Warnings and Precautions for Use
None
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11.3
Interaction with other medications
None.
11.4
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of subjects enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial.
Additionally, certain adverse events must be reported in an expedited manner to allow for optimal 
monitoring of patient safety and care.
All individuals experiencing an adverse event, regardless of its relationship to study drug/device, will be 
monitored until:

the adverse event resolves or the symptoms or signs that constitute the adverse event 
return to baseline;

any abnormal laboratory values have returned to baseline;

there is a satisfactory explanation other than the study drug for the changes observed; or

death.
11.5
Definitions
11.5.1
Definition of Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention.
11.5.2
Severity of Adverse Events
The severity of an AE is graded as follows:
Mild (grade 1): the event causes discomfort without disruption of normal daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily activities.
Severe (grade 3): the event makes the patient unable to perform normal daily activities or 
significantly affects his/her clinical status.
Life-threatening (grade 4): the patient was at risk of death at the time of the event. 
Fatal (grade 5): the event caused death.
11.5.3
Serious Adverse Events
A “serious” adverse event is defined in regulatory terminology as any untoward medical 
occurrence that:

Results in death.
o
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.

Is life-threatening.
o
(the patient was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe).

Requires in-patient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours judged to be caused by study medication or procedures.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect

Is an important medical event
Any event that does not meet the above criteria, but that in the judgment of the investigator 
jeopardizes the patient, may be considered for reporting as a serious adverse event. The event 
may require medical or surgical intervention to prevent one of the outcomes listed in the 
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definition of “Serious Adverse Event.”
For example: allergic bronchospasm requiring intensive treatment in an emergency room or at 
home; convulsions that may not result in hospitalization; development of drug abuse or drug 
dependency.
11.6
Steps to Determine If an Adverse Event Requires Expedited Reporting
Step 1: Identify the type of adverse event
Step 2: Grade the adverse event
Step 3: Determine whether the adverse event is related to the protocol therapy 
Attribution categories are as follows:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly.
Step 4: Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in:

the current known adverse events listed in the Agent Information Section of this 
protocol;

the GRAS dossier for the supplement;
11.7
Reporting Requirements for Adverse Events 
Expedit

The Principal Investigator must be notified within 24 hours of learning of 
any serious adverse events, regardless of attribution, occurring during the 
study or within 30 days of the last administration of the study drug.

The investigator will inform the sponsor within 24 hours of notification of 
any serious adverse event by phone or fax, with follow-up with a written 
narrative of the event within 48 hours.

The Northwestern University Institutional Review Board must be notified 
within 10 business days of “any unanticipated problems involving risk to 
subjects or others”
The following events meet the definition of UPR:
1. Any serious event (injuries, side effects, deaths or other problems), 
which in the opinion of the Principal Investigator was unanticipated, 
involved risk to subjects or others, and was possibly related to the 
research procedures.
2. Any serious accidental or unintentional change to the IRB-approved 
protocol that alters the level of risk.
3. Any deviation from the protocol taken without prior IRB review to 
eliminate apparent immediate hazard to a research subject.
4. Any new information (e.g., publication, safety monitoring report, 
updated sponsor safety report), interim result or other finding that 
indicates an unexpected change to the risk/benefit ratio for the 
research.
5. Any breach in confidentiality that may involve risk to the subject or 
others.
6. Any complaint of a subject that indicates an unanticipated risk or that 
cannot be resolved by the Principal Investigator.

The FDA will be notified within 7 business days of any unexpected fatal or 
life-threatening adverse event with possible relationship to study drug, and 
15 business days of any event that is considered: 1) serious, 2) 
unexpected, and 3) at least possibly related to study participation.
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Routine Reporting

All other adverse events- such as those that are expected, or are unlikely 
or definitely not related to the study participation- are to be reported 
annually as part of regular data submission.
11.8
Unblinding Procedures
The blind should not be broken unless subject has completed all study procedures and the data has 
been locked. Emergency unblinding is expected to be infrequent.
Emergency unblinding should occur only if the principal investigator (or other treating physician) 
considers breaking the blind medically relevant. All subjects who have the blind broken will be 
discontinued from the study. Documentation of the reasons for unblinding, including date and time will 
be recorded in the source documents and the electronic case report form (eCRF).
12.0
STUDY AGENT AND DOSING
MMFS-202-302 will be provided by Neurocentria, with a a detailed Certificate of Analysis attesting to the 
contents of the product.
Neurocentria has provided the following list of ingredients for MMFS-202-302:
Product 1 – MMFS-202
Active ingredients: L-TAMS (500 mg – 6-hour release profile)
Inactive ingredients: polyvinyl pyrolidone, microcrystalline cellulose, silicon dioxide, talc, and 
magnesium stearate
Product 2 – MMFS-302
Active ingredients: L-TAMS (500 mg – 12-hour release profile)
Inactive ingredients: polyvinyl pyrolidone, microcrystalline cellulose, silicon dioxide, talc, and 
magnesium stearate
Product 3– Placebo
Inactive ingredients: talc, magnesium stearate, povidone K-90, colloidal silicon dioxide, 
microcrystalline cellulose, sodium carboxymethylcellulose, carbopol 974P, starcap 1500
The target dosage will be 2 g/day, administered as two 0.5 g tablets twice per day (2 -302 tablets in the 
morning and 2 - 202 tablets in the evening). The placebo comparator will be also given as 2 tablets twice 
per day, preserving the blind. The product should be taken with a full glass of water.
L-TAMS has been self-affirmed by an expert panel convened by its manufacturer Neurocentria as being 
produced using good manufacturing practices, and fulfilling the FDA’s criteria for GRAS (generally 
regarded as safe) status. (AIDP, Inc. (2011, July 15). L-TAMS Self-Affirmed as GRAS [Press release]. 
Retrieved from http://www.magtein.com/press/AIDP-Magtein-7.15.pdf)
Study clinicians will be responsible for dispensing MMFS-202 and MMFS-302 at our research office. An 
unblinded study drug manager will receive and label and distribute the product for dispensing during the 
study.
After the study, subjects can obtain L-TAMS by purchase on the open market. Study clinicians, in 
cooperation with the subject and the subject’s clinical treatment team, may develop a plan for continued 
L-TAMS treatment after the completion of the study. At the baseline and end of study visits, measures of 
safety and effectiveness will be administered and subjects will be evaluated for response and side 
effects to the treatment. To assess adherence to dosing of the agent, the study medication will be 
returned and counted.
Subjects will be instructed not to take any medications or supplements which contain any forms of 
magnesium compounds to avoid unsafe levels of magnesium. All new medications and supplements 
started during the study will be reviewed by the PI.
12.1
Return and Retention of Study Drug
The investigator will return used and unopened vials of study drug to the manufacturer at the end of the 
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trial. The clinical research manager will maintain copies of study drug shipping receipts, drug 
accountability records, and records of return or final disposal of study drug.
13.0
RISKS AND DISCOMFORTS
All efforts are made to minimize risks to subjects. Consistent with good clinical practice, safety will be 
monitored by the Principal Investigator, and will reflect the oversight of co-investigator study clinicians. 
Adverse events will be recorded and reported according to institutional policies. Risks of the study agent 
have been incorporated into the exclusionary criteria for this proposal.
Study Agent – L-TAMS: L-TAMS is considered a dietary supplement that the manufacturer has self- 
certified as fulfilling the FDA criteria for agents that are Generally Regarded as Safe. There are few risks 
to taking L-TAMS orally. Magnesium is known to cause gastrointestinal discomfort, nausea, vomiting, or 
diarrhea. Although occurrences are rare, very large amounts of magnesium might cause 
hypermagnesemia with symptoms including thirst, hypotension, drowsiness, confusion, loss of tendon 
reflexes, muscle weakness, respiratory depression, cardiac arrhythmias, coma, cardiac arrest, and 
death. There have been only two reports of death from hypermagnesemia (Therapeutic Research 
Faculty (2014). Natural Medicines Comprehensive Database Retrieved May 30, 2014, from 
http://naturaldatabase.therapeuticresearch.com/nd/Search.aspx?s=ND&cs=NDPTL~CP&pt=103&sh=7&
i d=89669&ft=4#reactions).
MRI risks are minimal for subjects who are thoroughly screened and deemed safe for scanning. These 
include feelings of claustrophobic fear while being scanned, and minor physical discomfort because of 
remaining still throughout the scanning procedure.
EEG risks include the participant finding the tasks boring, tiring, and/or frustrating. If this happens, 
research staff will allow the participant to rest and then attempt continue. Participants might find the EEG 
cap to be uncomfortable. If this occurs, research staff will attempt to adjust the EEG cap so that it is 
more comfortable.
14.0
STUDY MANAGEMENT
14.1
Conflict of Interest
All investigators will follow the University conflict of interest policy.
14.2
Institutional Review Board (IRB) Approval and Consent
It is expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations. The IRB should approve the consent form and protocol.
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles 
that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the study 
and will be given the opportunity to review the consent form. Each consent form must include all the 
relevant elements currently required by the FDA Regulations and local or state regulations. Once this 
essential information has been provided to the patient and the investigator is assured that the patient 
understands the implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the patient and by the person who conducted the informed consent discussion.
14.3
Data Management and Monitoring/Auditing
A database in the RedCap system will be used for data entry and will be formatted to simulate the hard 
copy data entry forms. Once entered into this database, the data files can be extracted into Excel or 
SAS project databases, which are maintained on a networked directory under the direct supervision of 
the PI and biostatistician.  Back-ups are routinely performed to assure the preservation of the database. 
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Data are checked for range, consistency, missing values, etc. During data analysis, combined datasets 
are created as needed. Data are maintained in the master system datasets using a source/derived data 
approach, where source datasets are maintained unmodified, while the derived datasets are modified as 
needed. Thus, alterations that prove to be incorrect are easily rectified. The confidentiality of all data is 
maintained using the HIPAA compliance standards of Northwestern University. No confidential 
information is posted to the web under any circumstances. All possible efforts are made to retain only 
the necessary information in all cases.
Regarding de-identification of the data set: No identifiable information for any subjects (i.e. name, initials 
or date of birth) will be collected in the analyzable RedCap database or directly linked to study data.
Subjects will be coded only with study-specific unique ID numbers.
14.4
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and well-being of the 
study patient requires alternative treatment, the study shall be conducted exactly as described in the 
approved protocol.
14.5
Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior IRB approval.
For any such emergency modification implemented, a IRB modification form must be completed within 
five (5) business days of making the change.
14.6
Other Protocol Deviations/Violations
All other planned deviations from the protocol must have prior approval by the Principal Investigator and 
the IRB. According to the IRB, a protocol deviation is any unplanned variance from an IRB approved 
protocol that:

Is generally noted or recognized after it occurs

Has no substantive effect on the risks to research participants

Has no substantive effect on the scientific integrity of the research plan or the value of 
the data collected

Did not result from willful or knowing misconduct on the part of the investigator(s).
An unplanned protocol variance is considered a violation if the variance:

Has harmed or increased the risk of harm to one or more research participants.

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the investigator(s).

Demonstrates serious or continuing noncompliance with federal regulations, State laws, 
or University policies.
14.7
Amendments to the Protocol
Should amendments to the protocol be required, the amendments will be originated and documented by 
the Principal Investigator. It should also be noted that when an amendment to the protocol substantially 
alters the study design or the potential risk to the patient, a revised consent form might be required.
The written amendment, and if required the amended consent form, must be sent to the IRB for approval 
prior to implementation.
14.8
Record Retention
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents 
(e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary for the evaluation and reconstruction of the clinical research study.
Government agency regulations and directives require that the study investigator must retain all study 
documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug seeking 
regulatory approval and marketing, these documents shall be retained for at least two years after the 
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Page 21 of 26
last approval of marketing application in an International Conference on Harmonization (ICH) region. In 
all other cases, study documents should be kept on file until three years after the completion and final 
study report of this investigational study.
14.9
Obligations of Investigators
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator 
is responsible for personally overseeing the treatment of all study patients. The Principal Investigator 
must assure that all study site personnel, including sub-investigators and other study staff members, 
adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all the required 
data will be collected and entered onto the Case Report Forms. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. At the completion of the study, all case report forms will be reviewed 
by the Principal Investigator and will require his/her final signature to verify the accuracy of the data.
14.10
Benefits and Compensation
14.10.1 Potential Benefits
The possible benefits to the subjects who participate in this study are improvement in cognitive 
function, but there may be no direct benefit. Research staff could provide information from 
screening evaluations to the subject’s clinical treatment team if requested by the subject. 
Findings from this study may benefit others. Participation will allow us to learn  about  the  
potential cognitive enhancing effects of MMFS-202-302 in patients with schizophrenia or 
schizoaffective disorder, which would inform further studies evaluating its use to treat cognitive 
deficits among various clinical populations.
14.11
Risk Benefit Assessment
The risks from the study procedures include:
Magnesium is known to cause gastrointestinal discomfort, nausea, vomiting, or diarrhea. Although 
occurrences are rare, very large amounts of magnesium might cause excessive magnesium levels in the 
blood (hypermagnesemia) with symptoms including thirst, hypotension, drowsiness, confusion, loss of 
tendon reflexes, muscle weakness, respiratory depression, cardiac arrhythmias, coma, cardiac arrest, 
and death. There have been only two reports of death from hypermagnesemia.
MRI risks:
Subjects may find some of the computer tasks and learning and memory tasks boring or frustrating, but 
may take as many breaks as they wish.
Subjects may be anxious or physically uncomfortable from lying in the MRI scanner, and it is also 
possible that subjects may feel claustrophobic. Direct communication with research staff is available 
during the scan and subjects can tell staff whenever they want the scan to be stopped or interrupted. For 
the MRI scan, we will screen subjects for any metal parts inside and outside the body.
The clinical interview questions may result in temporary discomfort when asking the subject about a 
potentially difficult time in the past or the psychiatric symptoms they experience in the case of psychiatric 
participants. There may be temporary discomfort/ bruising at the site of venipuncture.
It is believed the potential benefits outweigh the risks for this trial.
14.12
Costs and Payments
There are no costs to subjects for participation in this study.  Subjects will be compensated at the rate of
$40/visit for their completion of study procedures. If the MRI assessments are completed, subjects will 
receive an additional $20/ hour during the baseline and end of study visits. The total amount for MRI 
assessments will be prorated based upon the time and participation in the scanner. Subjects will have 
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Page 22 of 26
the option to be paid either via a check that will be mailed to them or with a non-traceable prepaid debit 
card. The total amount for visit compensation will be prorated based on subject’s time and participation. 
Up to
$20 per visit will also be provided to cover subjects’ transportation and parking expenses.
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Page 23 of 26
15.0     REFERENCES
1.
Meltzer, H.Y. and S.R. McGurk, The effects of clozapine, risperidone, and olanzapine on 
cognitive function in schizophrenia. Schizophr Bull, 1999. 25(2): p. 233-55.
2.
Bilder, R.M., et al., Neurocognitive effects of clozapine, olanzapine, risperidone, and 
haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J 
Psychiatry, 2002. 159(6): p. 1018-28.
3.
Meltzer, H.Y., et al., Translating the N-methyl-D-aspartate receptor antagonist model of 
schizophrenia to treatments for cognitive impairment in schizophrenia. Int J 
Neuropsychopharmacol, 2013. 16(10): p. 2181-94.
4.
Woodward, N.D., et al., A meta-analysis of neuropsychological change to clozapine, 
olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol, 
2005. 8(3): p. 457-72.
5.
Bressi, S., Miele, L., Bressi, C., Astori, S., et al, Deficit of central executive component of 
working memory in schizophrenia. New Trends in Experimental & Clinical Psychiatry, 
1996. 12(4): p. 243-252.
6.
Harvey, P.D., et al., Negative symptoms and cognitive deficits: what is the nature of their 
relationship? Schizophr Bull, 2006. 32(2): p. 250-8.
7.
Gold, J.M., et al., Reward processing in schizophrenia: a deficit in the representation of 
value. Schizophr Bull, 2008. 34(5): p. 835-47.
8.
Gold, J.M., et al., Negative symptoms and the failure to represent the expected reward 
value of actions: behavioral and computational modeling evidence. Arch Gen Psychiatry, 
2012. 69(2): p. 129-38.
9.
Heerey, E.A. and J.M. Gold, Patients with schizophrenia demonstrate dissociation 
between affective experience and motivated behavior. J Abnorm Psychol, 2007. 116(2): 
p. 268-78.
10.
Ward, R.D., et al., Dissociation of hedonic reaction to reward and incentive motivation in 
an animal model of the negative symptoms of schizophrenia. 
Neuropsychopharmacology, 2012. 37(7): p. 1699-707.
11.
Nejad, A.B., et al., Neural markers of negative symptom outcomes in distributed working 
memory brain activity of antipsychotic-naive schizophrenia patients. Int J 
Neuropsychopharmacol, 2013. 16(6): p. 1195-204.
12.
Abi-Dargham, A., et al., Prefrontal dopamine D1 receptors and working memory in 
schizophrenia. J Neurosci, 2002. 22(9): p. 3708-19.
13.
Castner, S.A. and G.V. Williams, Tuning the engine of cognition: a focus on NMDA/D1 
receptor interactions in prefrontal cortex. Brain Cogn, 2007. 63(2): p. 94-122.
14.
Slutsky, I., et al., Enhancement of learning and memory by elevating brain magnesium. 
Neuron, 2010. 65(2): p. 165-77.
15.
Liu, G., et al., Efficacy and Safety of MMFS-01, a Synapse Density Enhancer, for 
Treating Cognitive Impairment in Older Adults: A Randomized, Double-Blind, Placebo-
Controlled Trial. J Alzheimers Dis, 2016. 49(4): p. 971-90.
16.
Lett, T.A., et al., Treating working memory deficits in schizophrenia: a review of the 
neurobiology. Biol Psychiatry, 2014. 75(5): p. 361-70.
17.
Goldman-Rakic, P.S., Working memory dysfunction in schizophrenia. J Neuropsychiatry 
Clin Neurosci, 1994. 6(4): p. 348-57.
18.
Forbes, N.F., et al., Working memory in schizophrenia: a meta-analysis. Psychol Med, 
2009. 39(6): p. 889-905.
19.
Zhang, e.a., A Dynamic SAS/IntrNet Example with Help of ASP and JavaScript: Online 
Clinical Trial Randomization List Generator.  In SAS PharmaSUG Proceedings: Internet 
and the Web, in PharmaSUG 2005. 2005: Phoenix, Arizona 
20.
Dale, A.M., B. Fischl, and M.I. Sereno, Cortical surface-based analysis. I. Segmentation 
and surface reconstruction. Neuroimage, 1999. 9(2): p. 179-94.
21.
Khan, A.R., L. Wang, and M.F. Beg, FreeSurfer-initiated fully-automated subcortical 
brain segmentation in MRI using Large Deformation Diffeomorphic Metric Mapping. 
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Page 24 of 26
Neuroimage, 2008. 41(3): p. 735-46.
22.
Csernansky, J.G., et al., Computational anatomy and neuropsychiatric disease: 
probabilistic assessment of variation and statistical inference of group difference, 
hemispheric asymmetry, and time-dependent change. Neuroimage, 2004. 23 Suppl 1: 
p. S56-68.
23.
Fischl, B., M.I. Sereno, and A.M. Dale, Cortical surface-based analysis. II: Inflation, 
flattening, and a surface-based coordinate system. Neuroimage, 1999. 9(2): p. 195-207.
24.
Kern, R.S., et al., The MATRICS Consensus Cognitive Battery, part 2: co-norming and 
standardization. Am J Psychiatry, 2008. 165(2): p. 214-20.
25.
Nuechterlein, K.H., et al., The MATRICS Consensus Cognitive Battery, part 1: test 
selection, reliability, and validity. Am J Psychiatry, 2008. 165(2): p. 203-13.
26.
Kirkpatrick, B., et al., The brief negative symptom scale: psychometric properties. 
Schizophr Bull, 2011. 37(2): p. 300-5.
27.
Strauss, G.P., et al., Factor structure of the Brief Negative Symptom Scale. Schizophr 
Res, 2012. 142(1-3): p. 96-8.
28.
Strauss, G.P., et al., Next-generation negative symptom assessment for clinical trials: 
validation of the Brief Negative Symptom Scale. Schizophr Res, 2012. 142(1-3): p. 88-
92.
29.
Addington, D., J. Addington, and B. Schissel, A depression rating scale for 
schizophrenics. Schizophr Res, 1990. 3(4): p. 247-51.
30.
Barnes, T.R., A rating scale for drug-induced akathisia. Br J Psychiatry, 1989. 154: p. 
672-6.
31.
Barnes, T.R., The Barnes Akathisia Rating Scale--revisited. J Psychopharmacol, 2003. 
17(4): p. 365-70.
32.
Simpson, G.M. and J.W. Angus, A rating scale for extrapyramidal side effects. Acta 
Psychiatr Scand Suppl, 1970. 212: p. 11-9.
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Appendix 1
Schedule of Assessments:
Study Day
Screen
1
7
14
21
28
35
4
2
4
9
5
6
6
3
Event/Assessment
Informed Consent
X
Medical History & 
Demographics
X
Physical Examination
X
Electrocardiogram
X
X
Vital Signs
X
X
X
X
X
X
Clinical Safety Laboratory 
Tests
X
X
Measurement of Mg in 
blood samples
X
X
DNA blood sample
X
Drug Screen
X
Inclusion/Exclusion CriteriaX
SCID-I
X
Calgary 
Depression 
Scale for 
Schizophrenia
X
X
C-SSRS
X
X
X
X
X
X
AIMS
X
X
BARS
X
X
SAS
X
X
BNSS
X
X
MCCB extended battery
X
X
fMRI assessments
X
X
EEG assessments
X
X
CGI-S/C
X
X
PANSS
X
X
X
Adverse event monitoring
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
Medication management
X
X
X
X


Page 26 of 26
Telephone Contact 
for Compliance 
Monitoring
X
X
X
X
X