Conditions: Schizophrenia
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 60
Healthy volunteers: no

Brief summary:
The primary objective of this study is to investigate whether a single infusion of intravenous sodium nitroprusside (0.5 μg/kg/min for 4 hours) is superior to placebo (5% dextrose solution) at in treating positive and negative symptoms of schizophrenia

Detailed description:
This is a phase II proof of concept (POC), multi-center, prospective, randomized, placebo-controlled, Sequential Parallel Comparison Design (SPCD) study, in which a total of 60 subjects with schizophrenia will be enrolled.

The study will be conducted in two stages. The study treatment will be administered in a double-blind fashion for all subjects throughout both stages of the study. A total of 60 subjects with schizophrenia will be randomized in a 1:1:1 ratio to drug-drug sequence \[n=20; i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at week 0 and week 2\], placebo-drug sequence \[n=20; i.v. placebo at week 0 and i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at week 2\], and placebo-placebo sequence \[n=20; i.v. placebo at week 0 and again at week 2\]. The 4-week double-blind phase of treatment will be divided into two phases: Phase 1, from week 0 to week 2, and Phase 2 from week 2 to week 4. At the end of Phase 1 (week 2), the randomized subjects will be assessed and categorized into responders and non-responders, based on 20% or more reduction from baseline in their PANSS total score as per the evaluations at Randomization Visit (week 0). The data from the patients deemed placebo non-responders in phase 1 who go on to either stay on placebo or to receive treatment with sodium nitroprusside will be pooled with the data from Phase 1 from all subjects, according to SPCD.

Arms:
arm 1: Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside arm 2: Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside arm 3: Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose

Interventions: intervention 1: sodium nitroprusside intervention 2: Placebo
Intervention descriptions: intervention 1: intravenous intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
 
 
 
A Randomized Double-Blind, Placebo-Controlled, Proof 
of Concept Study of Intravenous Sodium Nitroprusside 
in Adults with Symptomatic Schizophrenia 
 
 
 
 
PRINCIPAL INVESTIGATORS, Coordinating Center: Maurizio Fava, MD 
 
Roy Perlis, MD, MSc 
 
 
 
 
 
Funding Provided by: 
Stanley Medical Research Institute 
 
 
 
 
This protocol is the confidential property of MGH CTNI and is intended 
solely for the guidance of this clinical investigation. This protocol may not 
be disclosed to parties not associated with the clinical investigation or 
used for any other purpose without the prior written consent of MGH CTNI. 
 
Clinical Trials.gov registry: NCT02164981 
 


 
 
INVESTIGATIVE SITES: 
 
SITE 100: Massachusetts General Hosptial, Boston, MA 
 
PRINCIPAL INVESTIGATOR:      Oliver Freudenreich, MD   
 
 
 
 
 
 
 
 
 
SITE 200: University of Massachusetts Medical School, Worcester, MA 
 
PRINCIPAL INVESTIGATOR:      Xiaoduo Fan, MD   
 
 
 
 
 
 
 
 
SITE 300: New York University, New York, NY 
 
PRINCIPAL INVESTIGATOR:      Donald Goff, MD  
 
 
 
 
 
 
 
 
 
SITE 400: Zucker Hillside Hospital, New York, NY 
 
PRINCIPAL INVESTIGATOR:      George Petrides, MD  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
B. Synopsis 
Protocol Number: 
2014P001204 
Title:   
A 
Randomized 
Double-Blind, 
Placebo-Controlled, 
Sequential Parallel Comparison Design (SPCD) Study of 
Intravenous 
Sodium 
Nitroprusside 
in 
Adults 
with  
Symptomatic Schizophrenia  
Design: 
This will be a 6-8 week, randomized, double-blind, 
placebo-controlled, 
Sequential 
Parallel 
Comparison 
Design 
(SPCD) 
study, 
where 
treatment 
will 
be 
intravenously administered twice (at Day 0 and Day 14) 
over 4 hours, with assessments during the infusion and 
weekly assessments post-infusion to assess the efficacy 
and safety of  intravenous sodium nitroprusside (0.5 
μg/kg/min for 4 hours).  
Objectives: 
The primary objective of this study is to investigate 
whether intravenous sodium nitroprusside (0.5 μg/kg/min 
for 4 hours) is superior to placebo (5% dextrose solution) 
in improving the positive and negative symptoms 
associated with schizophrenia as defined by the DSM-IV-
TR. 
The secondary objective of this study is to evaluate the 
safety and tolerability of sodium nitroprusside (0.5 
μg/kg/min for 4 hours) as compared to Placebo (5% 
dextrose solution for 4 hours).  
Enrollment: 
100 subjects total (randomize 60 subjects) 
30 subjects at MGH Site (randomize 20 subjects) 
Clinical Sites: 
Approximately  4 US sites  
Patient Population: 
Men and women, 18-65 (inclusive) years of age with 
stable refractory schizophrenia, on an antipsychotic for 8 
weeks with a stable dose for at least 4 weeks, and who 
meet all study inclusion and exclusion criteria.  
Primary and Secondary 
Outcomes: 
The Structured Clinical Interview for DSM-IV-TR (SCID) 
will be used to confirm the diagnosis of schizophrenia.  
An independent SAFER interview will confirm both 
diagnosis and severity of symptoms.  
PANSS total, positive- and-negative subscale scores will 
be used to measure the primary outcomes. The PANSS 
will be collected at Visits 1, 2, 3, 4 (Hour 3 to 4), 5, 6. 7, 


 
 
(Hour 3 to 4), 8 and 9. 
The SAFTEE and the Abnormal Involuntary Movement 
Scale (AIMS), together with blood pressure and heart 
rate, will be used to assess the secondary outcomes of 
this study (safety and tolerability). AIMS and SAFTEE will 
be collected at Visits 3, 4, 6, 7 and 9.  
 
The MATRICS Consensus Cognitive Battery (MCCB) is 
the standard tool for assessing cognitive change in trials 
of cognitive-enhancing agents in schizophrenia.  The 
MCCB 
domains 
include: 
Speed 
of 
Processing; 
Attention/Vigilance; Working Memory; Verbal Learning; 
Visual Learning; Reasoning & Problem-Solving; and 
Social Cognition and the battery takes about 80 minutes 
to complete. The MCCB is accepted by the US FDA as a 
primary outcome measure for registry trials for cognition 
in schizophrenia. The MCCB composite score represents 
a global measure of cognition and is than outcome 
measure for inclusion in the efficacy analyses. MCCB will 
be collected at Visits 3, 6, and 9. 
The University of California San Diego (UCSD) 
Performance-based Skills Assessment Brief (UPSA-B) 
(Mausbach et al., 2007). The UPSA-B will be 
administered Visits 3, 6, and 9.  The UPSA-B consists of 
two of the five original UPSA domains, finances and 
communication, and has been shown to be highly 
correlated with the long form of the UPSA and to have 
substantial test–retest reliability (Green et al., 2011). 
Each subscale contributes 50 points; total scores range 
from 0 to 100 points with higher scores reflecting better 
performance. The UPSA-Brief requires approximately 
10–15 minutes to complete and may be administered by 
a suitably trained lay professional. 
 
Inclusion Criteria:  
 
 
 
 
Males and Females, 18-65 years of age, inclusive. 
Meets Diagnostic and Statistical Manual of Mental 
Disorders Forth Edition (DSM-IV-TR) criteria for a primary 
diagnosis of Schizophrenia established by a structured 
psychiatric evaluation (SCID) based on DSM-IV-TR 
criteria. 
Written informed consent in compliance with 21 CFR part 
50 and in accordance with the International Conference 


 
 
on Harmonization (ICH) Good Clinical Practice (GCP) 
Guidelines. 
Positive and Negative Syndrome Scale (PANSS) (Kay et 
al., 1994) total score ≥ 70 with a score of > 4 on two or 
more of the following PANSS items: delusions, conceptual 
disorganization, hallucinatory behavior, suspiciousness, 
and unusual thought content.  
A score of ≥ 4 on the Clinical Global Impression—Severity 
(CGI-S) (Guy, 1976).  
Confirmation of both diagnosis and severity of psychosis 
symptoms by an independent SAFER interview. 
Must have ongoing antipsychotic treatment for at least 8 
weeks, with a stable dose for at least 4 weeks. Subjects 
who have failed to achieve clinically-recognized symptom 
reduction to at least 1 marketed antipsychotic agent, 
given at a Physician Desk Reference (PDR)-defined 
therapeutic dose for ≥ 8 weeks during the past 12 months, 
as assessed by the MGH FAST, will be eligible. 
Understands and is able, willing, and (in the opinion of the 
investigator) likely to fully comply with the study 
procedures and restrictions. 
Exclusion Criteria: 
 
Subjects with renal insufficiency, congestive heart failure, 
cardiac arrhythmias or history of myocardial infarction. 
Subjects with a history of symptomatic orthostatic 
hypotension defined as supine  to standing systolic blood 
pressure < 90mmHg or diastolic blood pressure < 60mm 
Hg with any of the following symptoms: lightheaded or 
dizzy upon standing up, blurry vision, weakness, fainting 
(syncope),confusion, nausea. 
Subjects with any clinically significant abnormalities as 
determined by medical history, physical exam, clinical and 
lab evaluation suggestive of an underlying disease state 
that may, in the opinion of the investigator, may confound 
the results of study, increase risk to the subject or lead to 
difficulty complying with the protocol.  
Subjects on chlorpromazine, PDE-5 inhibitors, nitrites and 
any medication with CNS effects with the exception of 
antipsychotic 
drugs 
(other 
than 
chlorpromazine), 
anticholinergics, b-adrenergic antagonists, amantadine, 
biperiden, diphenhydramine, lorazepam, zolpidem, and 
temazepam (see Appendix 3). 
 


 
 
Medications which in the opinion of the PI, and in 
conjunction with the medical monitor, may be expected to 
significantly interfere with the metabolism or excretion of 
sodium nitroprusside, and/or may be associated with a 
significant drug interaction with sodium nitroprusside that 
may pose a significant risk to subjects’ health and/or 
confound the study data. 
Pregnant 
or 
breast-feeding 
patients. 
Women 
of 
childbearing potential must have a negative pregnancy 
test performed at screening visit prior to randomization 
and prior to baseline at visits 3 and 6. Women enrolled in 
this trial must use adequate birth control. 
Subjects with a current (within the last 3 months) DSM-IV-
TR diagnosis of alcohol or substance use disorder or 
dependence (excluding nicotine) as established by the 
clinical assessment (SCID) at the screening visit (Visit 1) 
will be excluded.  
Has tested positive for any of the following: cannabis, 
opioids, cocaine, amphetamines, barbiturates methadone, 
methamphetamine and phencyclidine at the screening or 
baseline visits. If positive, the urine drug toxicology screen 
may be repeated once based on investigator judgment, 
but due to safety concerns, the result must be negative for 
the subject to continue in the study.  
 
Subjects at imminent risk of suicide or injury to self or 
others or history of significant suicide attempt within the 
last 12 months as measured by the Columbia Suicide 
Severity Rating Scale (C-SSRS) together with the opinion 
of the trial investigator. 
Subjects that have taken an investigational drug or taken 
part in a clinical trial within 30 days prior to screening. 
In the opinion of the investigator, participation for any 
reason would compromise patient safety or integrity of the 
study 
Statistical Methodology 
To test the hypothesis that a statistically significant 
difference exists in the degree of improvement over 2 
weeks between intravenous sodium nitroprusside (0.5 
μg/kg/min for 4 hours) and placebo, treatment effect 
estimates and two-sided 95% confidence intervals (CIs) 
for sodium nitroprusside and placebo will be provided. A 
constrained longitudinal data analysis (cLDA) model (Liu 
et al., 2009) including terms for treatment group, time (as 


 
 
a categorical variable), and treatment by time will be used 
to evaluate the mean difference in slope between sodium 
nitroprusside and placebo for the primary efficacy 
endpoint over 2 weeks. All time point data starting at the 
baseline measurement will be included in the analysis 
model, and treatment difference estimates at specific time 
points (e.g., Day 0, 7, 14, 21 and 28) will also be provided 
to assess the time course of effects. 
 
 


 
 
 
Table of Contents 
C. 
Introduction and Background.................................................................... 9 
D. 
Study Rationale ...................................................................................... 11 
E. 
Objectives .............................................................................................. 11 
F. 
Study Design .......................................................................................... 11 
G. 
Study Population .................................................................................... 17 
H. 
Study Assessments – Plan and Methods ............................................... 20 
I. 
Treatment............................................................................................... 42 
J. 
Ethical Considerations............................................................................ 46 
K. 
Data Handling and Record Keeping ....................................................... 47 
L. 
Monitoring and Oversight ....................................................................... 48 
M. 
Data Analysis ......................................................................................... 50 
N. 
Publication Policy ................................................................................... 57 
O. 
Protocol Signature Page ........................................................................ 58 
P. 
Appendices ............................................................................................ 59 
Appendix 1: Schedule of Events .................................................................................... 59 
Appendix 2: MGH- Fast Additive Summary of Treatment  of Antipsychotic Medications 60 
Appendix 3: Concomitant  Medications Allowed ............................................................ 63 
Appendix 4: Literature Cited .......................................................................................... 69 
Appendix 5: Study Scales ............................................................................................. 72 
 
 
 
 
 


 
 
C. 
INTRODUCTION AND BACKGROUND 
Statement of Intent 
The design, conduct and reporting of this trial shall be conducted in accordance with the 
protocol, the United States 45 Code of Federal Regulations (CFR) part 46 known as 
“The Common Rule”, 45 CFR 164.502(d), and 164.514(a)-(c) known as “The Privacy 
Rule” of the Health Insurance Portability and Accountability Act (HIPAA), and the 
International Conference on Harmonization (ICH)/Good Clinical Practice (GCP). The 
data collection will also comply with 21 CFR part 11. All Investigators will have 
documented training in The Collaborative Institutional Training Initiative (CITI Program) 
in Biomedical Research and GCP. Independent monitoring of the trial will be conducted 
by a Contract Research Organization (CRO). 
Background  
The typical and atypical antipsychotic medications have been repeatedly demonstrated 
to be efficacious for the treatment of schizophrenia. However, these treatments have 
substantial limitations which have prompted aggressive, but thus far, unsuccessful 
efforts to find more effective and better tolerated alternatives. In particular,                              
current pharmacologic treatments for schizophrenia are ineffective for negative 
symptoms and require weeks to produce antipsychotic effects; during this period of 
delay, patients continue to experience distress associated with delusions and 
hallucinations, are often incarcerated, and are at high risk for injury.  Refractory 
symptoms are common and, if clozapine is not effective, no other treatment options have 
demonstrated efficacy.  Antidepressant therapeutics faced a similar situation of delayed 
therapeutic response and limited treatment options for refractory symptoms until the 
recent finding that a single ketamine infusion produces rapid, persistent and marked 
symptom response in refractory cases.  Ketamine infusion is now increasingly offered in 
cases of refractory depression and is being studied as an acute emergency room-based 
treatment for suicidal depression (Machado-Vieria et al., 2009).    
 
A similar approach could fundamentally change treatment of psychosis.  Several years 
ago it was hypothesized that a single dose of an agent acting on the N-Methyl-D-
aspartate (NMDA)/ nitric oxide synthase (NOS) / cyclic guanosine monophosphate 
(cGMP) pathway might produce just such an effect. Nitric oxide diffuses across cell 
membranes 
to 
activate 
guanylate 
cyclase 
and 
produce 
cyclic 
guanosine 
monophosphate.  In smooth muscles, cGMP causes vasodilation; in neurons cGMP 
promotes neuroplasticity.  Activation of NMDA receptors similarly produces intracellular 
release of diffusible nitric oxide via activation of neuronal nitric oxide synthase (nNOS).  
The NMDA/nNOS/cGMP pathway is involved in long term potentiation (LTP) and 
neuroplasticity, including memory, which is mediated in part by cGMP’s role in regulating 
the phosphorylation of CREB and AKT (Mohn et al. 1999, Allen et al. 2008). 
 


 
 
Indeed, initial studies with the nitric oxide donor nitroprusside completely attenuated 
behavioral effects of PCP in rats, a standard albeit limited rodent model of psychosis and 
antipsychotic action, and blocked PCP-induced c-fos expression in all brain regions 
without producing behavioral change when administered alone (Wang et al 2011). 
Nitroprusside also inhibited cocaine-induced immediate early gene expression in the 
frontal cortex and striatum (Thirlet et al. 2002). While the precise means by which NO 
donors may exert therapeutic effects remains unclear, these animal studies suggest that 
effects on NMDA signaling and/or modulation of excess corticostriatal dopamine may be 
relevant.  
 
The recent report by Hallak et al. (Hallak 2013) of a positive placebo-controlled trial of 
nitroprusside infusion provides the first human data supporting the use of nitric oxide 
donors to achieve rapid, robust antipsychotic effect.  Hallak and colleagues randomly 
assigned 20 symptomatic subjects with schizophrenia to a single 4 hour infusion of 
nitroprusside 0.5 μg/kg/min or placebo and observed a large improvement of positive 
and negative symptoms (effect size of approximately 1.7) which achieved statistical 
significance at 2 hours and persisted for 28 days.  Although high-dose nitroprusside may 
produce hypotension and cyanide toxicity, the investigators observed no side effects at 
the substantially lower doses used in their pilot study.  This novel approach is supported 
by converging evidence from human genetics and animal models and represents a 
potential paradigm shift in the treatment of schizophrenia.  If replicated, the potential 
impact on clinical care might include both emergency-room treatment of acute psychosis 
and office-based treatment of refractory symptoms.  Once efficacy and safety are 
established, future studies can examine repeated administration for maintenance 
treatment while pursuing other agents targeting this pathway.  Drugs acting on this 
pathway are currently in development for Alzheimer’s disease (Lahti et al 1995). 
 
Sodium Nitroprusside 
Intravenous sodium nitroprusside was approved by the FDA in 1979 for management of 
hypertension and reduction of intra-operative blood loss; it releases nitric oxide by 
interacting with oxyhemoglobin, and thus represents a balanced arterial and venous 
vasodilator. It has been widely used clinically for related indications including 
exacerbation of congestive heart failure (Carlson 2013).  
 
Summary of Prior Clinical Studies 
In the only prior investigation of intravenous (i.v) sodium nitroprusside (SNP) in a 
psychiatric population, described above (Hallak et al), i.v. SNP or placebo was 
administered to 20 subjects at a dose of 0.5 μg/kg/min over 4 hours. No subjects 
experienced significant adverse effects and none were discontinued from the study 
because of safety or tolerability concerns. 


 
 
As noted above, SNP has been used therapeutically for more than 30 years in a variety 
of acute cardiac settings. Systematic reviews conclude that i.v. SNP remains a generally 
safe and efficacious medication despite the availability of newer vasodilators. Another 
recent review of pediatric populations also concludes that i.v. SNP can be safely 
administered, with low risk of cyanide toxicity (Thomas 2009). 
Because of its established safety profile, there are relatively few recent investigations of 
sodium nitroprusside. In one of the largest, SNP was studied in comparison with other 
anti-hypertensives in cardiac surgery. While efficacy was less than the calcium channel 
blocker clevidipine, safety profile among the agents studied was similar (Aronson 
2008).One recent study examining control of hypertension in neurosurgical intensive 
care unit confirmed its safety. (Ritberg 2008). Likewise, a head-to-head study with IV 
adenosine for assessments of cardiac perfusion, also indicated safety. (Rudzinski 2013) 
D. 
STUDY RATIONALE 
We plan to conduct a Phase II or Proof of Concept (POC), randomized, double-blind,  
placebo-controlled, multi-center study using a Sequential Parallel Comparison Design 
(SPCD) to demonstrate  the efficacy and safety of sodium nitroprusside (0.5 μg/kg/min 
for 4 hours) in treating the positive and negative symptoms of subjects with  
schizophrenia.  
E. 
OBJECTIVES 
 
Primary Objective 
The primary objective of this study is to evaluate the effectiveness of sodium 
nitroprusside (0.5 μg/kg/min for 4 hours) as compared to Placebo (5% dextrose solution 
for 4 hours), in improving the positive symptoms and negative symptoms associated with 
schizophrenia.  
 
Secondary Objectives 
The secondary objective of the study is to evaluate the safety and tolerability of sodium 
nitroprusside (0.5 μg/kg/min for 4 hours) as compared to Placebo (5% dextrose solution 
for 4 hours). 
F. 
STUDY DESIGN 
This is a phase II proof of concept (POC), multi-center, prospective, randomized, 
placebo-controlled, Sequential Parallel Comparison Design (SPCD) study, in which a 
total of 60 subjects with schizophrenia will be randomized studywide.  


 
 
The study will be conducted in two phases. The study treatment will be administered in a 
double-blind fashion for all subjects throughout both phases of the study. A total of 60 
subjects with schizophrenia will be randomized in a 1:1:1 ratio to one of three treatment 
sequences: drug-drug, placebo-drug, or placebo-placebo. Subjects will be randomized 
directly following confirmation of eligibility (at completion of Visit 2). Subjects randomized 
to the drug-drug sequence (n=20) will receive i.v. sodium nitroprusside (0.5 μg/kg/min for 
4 hours) at Day 0 and Day 14. Subjects randomized to the placebo-drug sequence 
(n=20) will receive i.v. placebo at Day 0 and i.v. sodium nitroprusside (0.5 μg/kg/min for 
4 hours) at Day 14. Subjects randomized to the placebo-placebo sequence (n=20) will 
receive i.v. placebo at Day 0 and again at Day 14. The double-blind treatment will be 
divided into two phases: Phase 1 from Day 0 to Day 14, and Phase 2 from Day 14 
through Day 28.  
At the end of Phase 1 the randomized subjects will be assessed and categorized into 
responders and non-responders, based on 20% or more reduction in their PANSS total 
score between Visit 4 (Baseline, Day  0) and Visit 7(Day 14). The data from the subjects 
deemed placebo non-responders in Phase 1 who go on to either stay on placebo or to 
receive treatment with sodium nitroprusside will be pooled with the data from Phase 1 
from all subjects, according to SPCD. 


 
 
Figure 1 – 
 
 
 
 
 


 
 
Figure 2 – Study Schemata 
 
Study Visit Overview 
Screening 
 
Visit 1 (Screening Visit, Day -28 to -14): Consists of signing a HIPAA compliant 
informed consent form and study qualification based on evaluation of 
inclusion/exclusion criteria. Medical records will be requested from the 
participant’s primary care physician for confirmation of relevant eligibility criteria. 
 
Visit 2 (Remote Independent Interview, Day -13 to -3): Consists of independent 
assessment to confirm the diagnosis and the appropriateness of the subject for 
the study. Eligibility will also be assessed at this visit by conducting a PANSS, 
C
O
N
S
E
N
T 
R
A
N
D
O
M
I
Z
E 
Patients 
with 
symptomatic 
schizophrenia 
Screening 
Treatment 
Phase 1 
Treatment 
Phase 2 
Consent/Screening 
Visit 
Visit 1 
Day -28  
to -14 
Visit 2 
Day 13   
to -3 
MGH 
SAFER 
Visit 
(Independent 
Rater) 
 
Visit 3 
Day 
 -2 to-1 
 
Visit 4 
Day 0 
 
Visit 
5 
Day 7 
Visit 6 
Day 13 
Visit 7 
Day 14 
 
Visit 8 
Day 21 
Visit 9 
Day 28 
Phase 1 
Baseline 
Visit 
Phase 1 
Infusion 
Visit 
Phase 1 
Follow-Up 
Visit 
Phase 2 
Baseline 
Visit 
Phase 2 
Infusion 
Visit 
Phase 2 
Follow-Up 
Visit 
Phase 2 
Final Follow-Up / 
Study Completion 
Visit 
SNP 0.5mcg/kg/min x 4hrs 
(N = 20) 
SNP 0.5mcg/kg/min x 4hrs 
(N = 20) 
SNP 0.5mcg/kg/min x 4hrs 
(N = 20) 
Placebo x 4hrs 
(N = 20) 
Placebo x 4hrs 
(N = 20) 
Placebo x 4hrs 
(N = 20) 
- Assess eligibility 
- 
Confirm 
diagnosis 
and 
disease severity 


 
 
and reviewing the SCID, MGH FAST and CGI-S. Pending confirmation of 
eligibility, the subject will be randomized.  
 
Phase 1: 
 
Visit 3 (Phase 1 Baseline, Day -2 to -1): Subjects will undergo full battery of study 
efficacy and safety evaluations. Subjects will also have a urine drug screen, vital 
signs, 12-lead ECG, and concomitant medications. Visit 4 must occur the day 
after Visit 3.  
 
 
Visit 4 (Phase 1 Study Treatment, Day 0): Anthropometrics, vital signs, 
concomitant medications, CBC, electrolytes, urinalysis, and urine pregnancy test 
will be assessed between Hours -1 and 0, before the infusion begins. 
Randomized i.v. study treatment will be administered from Hours 0 to 4. During 
these hours there will be safety monitoring (See: Infusion Monitoring and 
Discharge Procedures). During Hours 5 to 7 following the infusion, there will be a 
post-infusion debrief, neurological assessment, and assessment of adverse 
events. Should an infusion room be unavailable on Day 0, the infusion may be 
scheduled one day before or one day after with prior notification provided to 
CTNI. 
 


 
 
 
 Visit 5 (Phase 1 Follow-up, Day 7): Subjects will undergo full battery of study 
efficacy and safety evaluations. Subjects will also have vital signs, 12-lead ECG, 
and concomitant medications.  
 
Phase 2: 
 
Visit 6 (Phase 2, Day 13): Subjects will undergo full battery of study efficacy and 
safety evaluations. Subjects will also have urine drug screen, vital signs, 12-lead 
ECG, and concomitant medications. Visit 7 must occur the day after Visit 6.  
 
 
Visit 7 (Phase 2 Study Treatment Day 14): Anthropometrics, vital signs, 
concomitant medications, CBC, electrolytes, urinalysis, and urine pregnancy will 
be assessed between Hours -1 and 0, before the infusion begins. Randomized 
i.v. study treatment will be administered from Hours 0 to 4. During these hours 
there will be safety monitoring (See: Infusion Monitoring and Discharge 
Procedures). During Hours 5 to 7 following the infusion, there will be a post-
infusion debrief, neurological assessment, and assessment of adverse events.    
Should an infusion room be unavailable on Day 7, the infusion may be scheduled 
one day before or one day after with prior notification provided to CTNI. 
 
 
Visit 8 (Phase 2 Follow-up, Day 21): Subjects will undergo full battery of study 
efficacy and safety evaluations. Subjects will also have vital signs, 12-lead ECG, 
and concomitant medications.  
 
 
Visit 9 (Final Follow-up/Study Completion, Day 28): Subjects will undergo full 
battery of study efficacy and safety evaluations. Subjects will also have 
laboratory assessments, urinalysis, vital signs, 12-lead ECG, and concomitant 
medications. 
 
Screening will ensure the subject meets inclusion/exclusion criteria and is appropriate for 
a clinical trial. An independent Massachusetts General Hospital (MGH) SAFER interview 
will confirm both diagnosis and severity of symptoms.  Studies have revealed that 
external, site-independent assessment of patient eligibility and symptom severity prior to 
randomization can improve the patient selection process (Fava et al., 2003).  The MGH-
SAFER assessment will be administered by CTNI trained staff psychiatrists and 
psychologists from MGH. 
Subjects will be recruited from out-patient clinics and those who meet the DSM-IV-TR 
diagnostic criteria for Schizophrenia and have a total PANSS score of 70 or greater upon 
screening, with a score of 4 or greater on at least two of the following five items of the 
PANSS positive subscale: hallucinatory behavior, delusions, conceptual disorganization, 
suspiciousness, and unusual thought content will be eligible for the trial. If the diagnosis 


 
 
and appropriateness of the patient for the study is confirmed by an independent SAFER 
rater, and the subject meets all of the inclusion criteria and none of the exclusion criteria, 
the subject will be eligible for Phase 1 and will be randomized to one of three treatment 
sequences:  intravenous SNP in Phase 1 and intravenous SNP in Phase 2;  placebo in 
Phase 1 and placebo in Phase 2; or placebo in Phase 1 and intravenous SNP in Phase 
2 (1:1:1 ratio) to  be administered over 4 hours in a controlled and medically monitored 
intensive care-type setting (as per institutional guidelines). After a post-treatment 
debriefing and period of observation (2-3 hours total), the subject will be permitted to 
return home. Follow-up visits will be conducted in the outpatient setting at Day 7 (Phase 
1) and Day 21 (for Phase 2). A final follow-up outpatient visit will be conducted at Day 
28. Efficacy, safety and cognitive outcome measures will be collected at each of the 
study visits.  
G. 
STUDY POPULATION 
Sample Size  
The study will be conducted at approximately 4 centers within the USA, including 
hospitals and outpatient psychiatric clinics. A 20% discontinuation rate is anticipated for 
this SPCD study, thus, a total of 60 subjects will be initially randomized to have at least 
48 subjects complete the study. To account for potential screen failures, up to 100 
subjects may be consented in order to randomize 60 subjects total. 
Subject Eligibility 
Inclusion Criteria 
Each subject must meet all of the following criteria to be eligible for this study: 
1. Males or Females aged 18-65 years inclusive. 
2. Primary diagnosis of Schizophrenia established by a structured psychiatric 
evaluation (SCID) based on Diagnostic and Statistical Manual of Mental 
Disorders Forth Edition (DSM-IV-TR) criteria. 
3. Written informed consent in compliance with 21 CFR part 50 and in accordance 
with the International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) Guidelines. 
4. A Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1994) total score 
≥ 70 with a score of > 4 on two or more of the following PANSS items: delusions, 
conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual 
thought content.  
5. A score of ≥4 on the Clinical Global Impression—Severity (CGI-S) (Guy, 1976).  
6. Confirmation of both diagnosis and severity of psychosis symptoms by an 
independent MGH SAFER interview.  


 
 
7. Must have ongoing antipsychotic treatment for at least 8 weeks, with a stable 
dose for at least 4 weeks. Subjects who have failed to achieve clinically-
recognized symptom reduction to at least 1 marketed antipsychotic agent, given 
at a Physician Desk Reference (PDR)-defined therapeutic dose for ≥ 8 weeks 
during the past 12 months, as assessed by the MGH FAST, will be eligible 
8. Understands and is able, willing, and (in the opinion of the investigator) likely to 
fully comply with the study procedures and restrictions. 
 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Subjects with a history of renal insufficiency, congestive heart failure, cardiac 
arrhythmias or history of myocardial infarction. 
2. Subjects with a history of symptomatic orthostatic hypotension defined as sitting to 
standing systolic blood pressure < 90mmHg or diastolic blood pressure < 60mm 
Hg with any of the following symptoms: lightheaded or dizzy upon standing, blurry 
vision, weakness, fainting (syncope), confusion, or nausea. 
3. Subjects with any clinically significant abnormalities as determined by medical 
history, physical exam, clinical and lab evaluation suggestive of an underlying 
disease state that may, in the opinion of the investigator, confound the results of 
study, increase risk to the subject, or lead to difficulty complying with the protocol.  
4. Subjects on chlorpromazine, PDE-5 inhibitors, nitrites and any medication with 
CNS effects with the exception of antipsychotic drugs (other than chlorpromazine) 
anticholinergics, 
b-adrenergic 
antagonists, 
amantadine, 
biperiden, 
diphenhydramine, lorazepam, zolpidem, and temazepam. 
5. Medications which in the opinion of the PI, and in conjunction with the medical 
monitor, may be expected to significantly interfere with the metabolism or 
excretion of sodium nitroprusside, and/or may be associated with a significant 
drug interaction with sodium nitroprusside that may pose a significant risk to 
subjects’ health and/or confound the study data. 
6. Pregnant or breast-feeding patients. Women of childbearing potential must have a 
negative pregnancy test performed at screening visit prior to randomization and 
prior to baseline at visits 3 and 6. Women enrolled in this trial must use adequate 
birth control. 
7. Subjects with a current (within the last 3 months) DSM-IV-TR diagnosis of alcohol 
or substance use disorder or dependence (excluding nicotine) as established by 
the clinical assessment (SCID) at the screening visit will be excluded.  
8. Has tested positive for any of the following:  cannabis, opioids, cocaine, 
amphetamines, barbiturates methadone, methamphetamine and phencyclidine at 
the screening or baseline visits. If positive, the urine drug toxicology screen may 
be repeated once based on investigator judgment, but due to safety concerns, the 
result must be negative for the subject to continue in the study. 


 
 
9. Subjects at imminent risk of suicide or injury to self or others, as per the opinion of 
the investigator, or history of significant suicide attempt within the last 6 months as 
per C-SSRS. 
10. Subjects that have taken an investigational drug or taken part in a clinical trial 
within 30 days prior to screening. 
11. Any other reason that, in the opinion of the investigator, would compromise patient 
safety or integrity of the study 
 
Table 1- Exclusionary Safety Values of Potential Clinical Concern  
Hematology 
Leukocytes 
<2 or >17.5 x 103/mm3 
Platelets 
<75 or >700 x 103/mm3 
Comprehensive Metabolic Panel 
Sodium 
<1.1 times the lower limit or >1.1 times upper limit of the reference range 
Potassium 
<1.1 times the lower limit or >1.1 times upper limit of the reference range 
Chloride 
<1.1 times the lower limit or >1.1 times upper limit of the reference range 
Carbon Dioxide (Bicarbonate) 
<1.1 times the lower limit or >1.1 times upper limit of the reference range 
Glucose 
>2 times the limits of the reference range 
Blood Urea Nitrogen (BUN) 
>1.3 times upper limit of the reference range 
Creatinine 
>1.3 times upper limit of the reference range 
Calculated Glomerular Filtration  
< 60 
Total bilirubin 
>2 times the upper limit of the reference range 
Aspartate amino transferase (AST) 
>3 times upper limit of the reference range 
Alanine amino transferase (ALT) 
>3 times upper limit of the reference range 
Alkaline phosphatase (ALP) 
>3 times upper limit of the reference range 
Creatine phosphokinase (CPK) 
>3 times the upper limit of the reference range 
Creatine kinase (CK) 
>3 times the upper limit of the reference range 
Thyroid Stimulating Hormone (TSH) 
>1.5 times upper limit of the reference range 
Uric acid 
>1.5 times upper limit of the reference range 
Lipid panel (triglycerides, total 
cholesterol (C), HDL-C, calculated 
LDL-C) 
>3 times the upper limit of the reference range 
 
Pregnancy 
Serum beta human chorionic gonadotropin (Beta- hCG) 
< 6 IU/L negative 
 
Urine Screen for Drugs of Abuse  


 
 
Per Exclusionary Criteria #6, a subject is excluded from the study if they meet DSM-
IV-TR criteria for diagnosis of alcohol or substance use disorder or dependence 
(excluding nicotine) within the last 3 months as established by the SCID at the Visit 1 
(screening). Per exclusionary criterion 8, for all subsequent urine drug screens 
(performed at Visits 3 and 6) any individual testing positive for a potential drug of 
abuse without a documented prescription for that medication will be evaluated by the 
investigator who will determine if the subject should be terminated from the study due 
to concerns with respect to subject safety and/or confounding of study data. 
Rationale for the Inclusion/Exclusion Criteria 
Eligibility criteria for this study have been carefully considered to ensure the safety of the 
study subjects and to ensure that the results of the study are meaningful in support of 
the research objectives.  
Nitroprusside infusion has been widely used for decades to control profound 
hypertension and most recent reviews have concluded that it is quite safe at doses less 
than 2 μg/kg/min.  The most important adverse reactions to sodium nitroprusside are the 
avoidable ones of excessive hypotension and cyanide toxicity. (Package Insert 
http://medlibrary.org/lib/rx/meds/nitropress/ - last revised January 16, 2014). 
No adverse effects were observed in 10 schizophrenia subjects who received 
nitroprusside 0.5 μg/kg/min in the study by Hallak et al., including no cases of 
hypotension despite administering nitroprusside to two subjects treated with 
chlorpromazine (500 mg/d and 300 mg/d); chlorpromazine has the greatest propensity 
for orthostatic hypotension of any antipsychotic and subjects taking this drug will be 
excluded from the study.  Nitroprusside was also added to high-dose ziprasidone (240 
mg/d) and high dose risperidone (8 mg/d) without measurable effects on blood pressure 
or EKG.  
The potential for cyanide toxicity is greatest when more than 500 μg /kg of sodium 
nitroprusside is administered faster than 2 μg /kg/min, as cyanide is generated faster 
than the unaided patient can eliminate it. Cyanide toxicity will be avoided in this study as 
the dose administered is very low, and individuals with renal disease will be excluded. 
Also, the study treatment will be infused within 3 hours of preparation as sodium 
nitroprusside is stable in solution for 24 hours. 
Subjects will be continuously monitored for adverse effects during the infusion and blood 
pressure and heart rate will be taken and recorded 2 hours post infusion.  
Given that  subjects with renal disease, a history of orthostatic hypotension or 
medications that destabilize blood pressure will be excluded from the study, and that the 
infusion rate of SNP for subjects randomized to active drug in this study will be very low 
(0.5 μg/kg/min), the risk of excessive hypotension and cyanide toxicity is very low. 
H. 
STUDY ASSESSMENTS – PLAN AND METHODS 


 
 
Study Conduct 
Subjects will sign a HIPAA-compliant informed consent form (ICF) before any study 
related screening procedures are performed. An overview of the study objectives and a 
summary of study procedure will be explained to the subject prior to signing the ICF. At 
any point during the study, subject will be encouraged to seek answers to any questions 
they may have. 
Study Procedures 
Medical History 
A detailed medical history will be obtained by the PI or designee during Visit 1 
(screening visit).  This will include information regarding the subjects’ full history of 
medical and psychiatric conditions, diagnoses, procedures, treatments, demographic 
information, and any other noteworthy medical information, including suicidality, with 
dates of start and finish.  Any updates to medical history information that the PI or 
designee becomes aware of will be captured throughout the study. Medical records will 
also be requested from the participant’s primary care physician for confirmation of 
relevant eligibility criteria. 
Physical Examination 
The PI, or medically-qualified designee, will perform the physical examinations (PEs) at 
Visit 1 (screening) as indicated in the Schedule of Events (SOE).  A complete PE, 
including assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, 
chest/lungs, heart, abdomen, lymph nodes, extremities, and general appearance.  The 
physical examination will not include a pelvic, breast, or rectal examination.  A 
neurological examination will also be performed at Visit 1 (screening), which includes 
mental status, cranial nerves, strength, sensation, deep tendon reflexes, and 
coordination. 
If any clinically significant change is noted from screening, it will be reported as an AE 
and will be followed up to resolution or upon reaching a stable end point. 
Vital Signs 
Evaluation of vital signs will be performed by qualified site personnel after the subject 
has been supine for 5 minutes, and will include a measurement of systolic and diastolic 
blood pressure, pulse rate, oral temperature and respiratory rate. Systolic and diastolic 
blood pressure should be then measured from supine to standing to assess orthostatic 
hypotension. Vital sign measurements will be obtained at the time points indicated in the 
SOE and following the supine ECG assessments, if taken at the same time.  Blood 
pressure should be taken on the same arm throughout the study. 
If clinically significant findings, as determined by the PI or medically qualified Sub-
Investigator, occur in any vital sign measurement, that measurement should be captured 


 
 
as an adverse event and will be repeated at medically appropriate intervals until the 
value returns to an acceptable range, a specific diagnosis is established, or the condition 
is otherwise explained 
Anthropometric Measurements 
Weight (kg) (assessed in ordinary indoor clothing with shoes off) will be recorded at the 
time points indicated in the SOE.  Height (cm) will be recorded at Visit 1 (screening) 
only. Body Mass Index (BMI) will be calculated at all visits in which anthropometrics are 
collected and is defined as the subject’s weight in kilograms divided by the square of the 
subject’s height in meters (kg/m2). Waist circumference will be measured to the nearest 
0.1 cm. 
Laboratory Procedures 
Laboratory tests will be performed at the site, and each site will provide their laboratory 
reference ranges to the coordinating center. Screening blood work will be fasting and 
blood work taken as part of the study treatment monitoring process will be non-fasting as 
a precautionary measure to reduce the risk of a hypotensive episode. 
Routine laboratory panels will include: 
Hematology (absolute and percentage): White blood cell (WBC) count with differential 
(absolute neutrophil count, lymphocytes, monocytes, basophils, and eosinophils), red 
blood cell (RBC) count, hemoglobin (Hgb), hematocrit (Hct), and platelet count. 
Comprehensive Metabolic Panel:  glucose, sodium, potassium, calcium, chloride, carbon 
dioxide, blood urea nitrogen (BUN), creatinine, calculated glomerular filtration rate, uric 
acid, phosphorus, magnesium, total protein, albumin, lipid panel (triglycerides, total 
cholesterol, HDL-cholesterol, caluculated LDL-cholesterol)  aspartate amino transferase 
(AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), gamma glutamyl 
transpeptidase (GGT), total bilirubin, creatine phosphokinase (CPK), creatine kinase 
(CK) thyroid stimulating hormone (TSH) and uric Acid. 
Urinalysis:  color, appearance, specific gravity, pH, ketones, protein, glucose, nitrite, 
leukocyte esterase, and occult blood; microscopic examination of sediment will be 
performed only if the results of the urinalysis evaluation are positive (microscopic 
examination may include but is not limited to WBC count, red blood cell (RBC) count, 
casts, and crystals). 
Urine drug screen:  cannabis, opioids, cocaine, amphetamines, methadone, 
cannabinoids, barbiturates, benzodiazepines, methamphetamine, and phencyclidine. 
Urine Pregnancy Test: urine pregnancy test will be performed in female subjects of 
childbearing potential using a dipstick urine test at visits 4 and 7.  
 


 
 
Laboratory Panels assessed at Visit 1 only: 
Serum Pregnancy Test: serum beta human chorionic gonadotropin test for pregnancy in 
female subjects of childbearing potential and FSH for post-menopausal female subjects 
will be conducted. 
Other: glycosylated hemoglobin (Hb)A1c 
Study physicians should mark either “CS” for Clinically Significant or “NCS” for Not 
Clinically Significant in the margin of the laboratory result source document for items 
outside the normal range. 
 
12-Lead Electrocardiogram (EGG) 
A 12-lead ECG will be taken at following a supine rest for 5 minutes.  ECG parameters 
including the QT interval, Bazett’s corrected QT interval (QTcB), and QTcF Fridericia’s 
corrected QT interval (QTcF), pulse rate (PR), and QRS intervals, and heart rate will be 
recorded.  The ECGs will be reviewed by the PI or medically qualified Sub-Investigator 
to assess any immediate abnormalities.  The findings of the ECGs will be marked by the 
PI or medically qualified Sub-Investigator as normal, abnormal-not clinically significant, 
or abnormal-clinically significant. 
The QTcB and QTcF will be manually calculated and recorded on a worksheet that will 
serve as the source document.  All ECGs that are considered abnormal and clinically 
significant should be evaluated for a change from baseline and captured as an AE. 
If any clinically significant change is noted from screening or an ECG is considered 
abnormal and clinically significant, it will be reported as an AE and will be appropriately 
recorded in both the source documents and the eCRF. 
 
Study Instruments 
The following instruments will be administered according to the schedule in the Schedule 
of Events in Appendix 1: 
Diagnostic Instruments 
Structured Clinical Interview for DSM-IV-TR™ (SCID I/P): The SCID, administered by 
the clinician, includes modules aimed at diagnosing possible Axis I disorders (First et al, 
1996). Questions here are asked exactly as written, and each is based on the individual 
criteria from DSM-IV-TR™. 
Massachusetts General Hospital- Fast Additive Summary of Treatment (FAST) - 
This questionnaire (Appendix 2) provides an efficient, structured means of capturing 


 
 
historical treatments across mood and psychotic disorders. It allows extraction of other 
historical measures for antidepressants: ATRQ (Fava and Davidson, 1996; Fava, 2003); 
for lithium: the Alda Scale (Grof JCP 2002): The questionnaire captures treatment 
duration, response, and reason for discontinuation. In the present study, FAST is a 
means of recording number and type of prior antipsychotic trials, to define treatment 
resistance for purposes of stratification. 
SAFER Rater Assessment  
In order to confirm diagnosis and to ensure patients are appropriate for the study, 
remote diagnostic assessments (SCID-I/P Psychosis module), and disease severity 
assessments (PANSS, MGH FAST, and CGI-S) will be performed remotely by an 
independent MGH CTNI rater. The subject will be provide contact information and a 
SAFER interview will be scheduled within 27 days of Visit 1 (screening). Sites will be 
notified of the results within 24 hours of the interview. 
 
Efficacy Measures 
The Positive and Negative Syndrome Scale (PANSS) (Kay, 1987) will be used to 
measure symptom severity in this trial. PANSS is a 30-item questionnaire used to 
evaluate schizophrenia symptoms, based on the clinical interview as well as reports of 
family members or primary care hospital workers. PANSS consists of Positive scale (7 
items), Negative scale (7 items), and General Psychopathological scale (16 items) 
sections. Each item (symptom) will be scored on a 7-point scale with higher scores 
representing increasing levels of psychopathology: 1) Absent, 2) Minimal, 3) Mild, 4) 
Moderate, 5) Moderate severe, 6) Severe, and 7) Extreme. 
Each of the 30 items is accompanied by a specific definition as well as detailed 
anchoring criteria for all seven rating points. Ratings will be performed by the 
Investigator or qualified sub-Investigator. The highest applicable rating point is always 
assigned, even if the subject meets criteria for lower points as well. In judging the level 
of severity, the rater must utilize a holistic perspective in deciding which anchoring point 
best characterizes the subject’s functioning and rate accordingly, whether or not all 
elements of the description are observed. The determined results must be documented 
on the source documents and in the CRF.  
For the purpose of this study, the total PANSS score along with sub-scores for Positive 
scale, Negative scale, General Psychopathology scale, and Composite scale will be 
derived as follows: 
 
Positive Subscale Score: the total of scores for items P1 through P7. This 
score could range from a minimum of seven to a maximum of 49, with higher 
scores representing increasing levels of psychopathology.  


 
 
 
Negative Subscale Score: the total of scores for items N1 through N7. This 
score could range from a minimum of seven to a maximum of 49, with higher 
scores representing increasing levels of psychopathology. 
 
General Psychopathology Score: the total of scores for items G1 through G16. 
This score could range from a minimum of 16 to a maximum of 112, with higher 
scores representing increasing levels of psychopathology. 
 
Total PANSS Score: the total of scores for items P1 through P7, N1 through N7, 
and G1 through G16. This score could range from a minimum of 30 to a 
maximum of 210, with higher scores representing increasing levels of 
psychopathology. 
. 
Clinical Global Impressions–Severity (CGI-S) and Clinical Global Impressions–
Improvement (CGI-I) Scales (Guy, 1976): The CGI-S is an observer-rated scale that 
measures illness severity. The severity is measured using a 7 point Likert scale: 1) 
Normal, not at all ill, 2) Borderline mentally ill, 3) Mildly ill, 4) Moderately ill, 5) Markedly 
ill, 6) Severely ill, and 7) Among the most extremely ill patient. The CGI-I is an observer-
rated scale that measures illness improvement. Improvement is measured using a 7 
point Likert scale: 1) Very much improved, 2) Much improved, 3) Minimally improved, 4) 
No change 5) Minimally worse, 6) Much worse, 7) Very much worse.  
 
Safety Measures 
The Systematic Assessment for Treatment Emergent Effects–Systematic Inquiry 
(SAFTEE-SI) (Levine and Schooler, 1986): This is a self-rated questionnaire assessing 
possible adverse events during the course of the trial. The time frame is the past 7 days. 
Site personnel should also review the SAFTEE-SI before the subject has left the clinic to 
check for any symptoms which are endorsed as “moderate” or “severe.” This process is 
meant to ensure that the study physician is given the opportunity to evaluate these 
symptoms adequately for adverse event reporting.  Study physicians should mark either 
“CS” for Clinically Significant or “NCS” for Not Clinically Significant in the margin of the 
source document for items endorsed as moderate or severe. 
It is up to the study physician to determine if symptoms represent either a worsening of 
pre-existing conditions or an unfavorable/ unintended sign, symptom or disease which is 
temporally related with study participation; and to document AEs in the AE log 
accordingly. 
 
Abnormal Involuntary Movement Scale (AIMS)  (Riezen 1988) 
The AIMS is a 12-item scoring tool that is commonly used to monitor the occurrence and 
severity of tardive dyskinesia for patients receiving neuroleptic medications. In this study, 


 
 
the highest severity observed for each item on the AIMS scoring sheet will be recorded. 
For movements that occur upon activation, one severity grade less than the 
spontaneously observed movement will be selected for the item. The 12-item AIMS to be 
used in this study consists of five categories, as outlined below: 
I. 
Facial and Oral Movements (items 1 through 4) includes an item for each of the 
following: muscles of facial expression, lips and perioral area, jaw, and tongue. 
Each item will be assessed using a 5-point scale (0 = none, 1 = minimal (may be 
extreme normal), 2 = mild, 3 = moderate, and 4 = severe).  
II. 
Extremity Movements (items 5 and 6) includes an item for each of the following: 
upper extremities (including arms, wrists, hands, and fingers) and lower 
extremities (including legs, knees, ankles, and toes). Each of these items will be 
assessed using the same 5-point scale as items 1 through 4.  
III. 
Trunk Movements (item 7) includes one item for assessing the movements in 
the neck, shoulders, and hips. This item will be assessed using the same 5-point 
scale as items 1 through 4. 
IV. 
Global Judgment (items 8 through 10) includes three items. Item 8 assesses 
severity of abnormal movements overall. Item 9 assesses the severity of 
incapacitation due to the abnormal movements. These two items (i.e., items 8 
and 9) will be assessed using the same 5-point scale as items 1 through 4. Item 
10 assesses the subject’s awareness of his/her abnormal movements, as judged 
by the subject. For Item 10, the following 5-point scale will be used: 0 = no 
awareness; 1 = aware, no distress; 2 = aware, mild distress; 3 = aware, 
moderate distress; 4 = aware, severe distress.  
 
 
The Columbia Suicide Severity Rating Scale (C-SSRS) (Posner 2007): 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and 
behavior that was developed in the National Institute of Mental Health Treatment of 
Adolescent Suicide Attempters Study to assess severity and track suicidal events 
through any treatment. It is a clinical interview providing a summary of both ideation 
and behavior that can be administered during any evaluation or risk assessment to 
identify the level and type of suicidality present. The C-SSRS can also be used 
during treatment to monitor for clinical worsening. The C-SSRS will be performed to 
assess suicidal ideation and behavior.  The C-SSRS tool was first developed for a 
prospective national study of treatment for adolescent suicide attempts. C-SSRS was 
developed by reliance on evidence stemming from two decades of research.  It 
contains a 1-to-5 rating scale for suicidal ideation of increasing severity (from a “wish 
list to die” to an “active thought of killing oneself with plan and intent”). The time 
frame is the past six months for the Baseline/Screening scale and since the last visit 
for the Since Last Visit scale. 
 


 
 
Neurocognitive Measures 
MATRICS: The Measurement and Treatment Research to Improve Cognition in 
Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) (Nuechterlein 2008): 
The MATRICS Consensus Cognitive Battery is the standard tool for assessing cognitive 
change in trials of cognitive-enhancing agents in schizophrenia.  The MCCB domains 
include: Speed of Processing; Attention/Vigilance; Working Memory; Verbal Learning; 
Visual Learning; Reasoning & Problem-Solving; and Social Cognition and the battery 
takes about 80 minutes to complete. The MCCB is accepted by the US FDA as a 
primary outcome measure for registry trials for cognition in schizophrenia. The MCCB 
composite score represents a global measure of cognition and is than outcome measure 
for inclusion in the efficacy analyses. MCCB will be administered at Visits 3 (baseline), 6, 
and 9.  
The University of California San Diego (UCSD) Performance-based Skills 
Assessment Brief  (UPSA-B) (Mausbach et al., 2007) consists of two of the five original 
UPSA domains, finances and communication, and has been shown to be highly 
correlated with the long form of the UPSA and to have substantial test–retest reliability ( 
Green et al., 2011). Each subscale contributes 50 points; total scores range from 0 to 
100 points with higher scores reflecting better performance. The UPSA-Brief requires 
approximately 10–15 minutes to complete and may be administered by a suitably trained 
lay professional. The UPSA-B will be administered at Visits 3 (baseline), 6, and 9. 
 
Study Visit Assessment Schedule  
Screening 
Screening will take place from Visit 1 (Day -28 to -14) through Visit 2 (Day -13 to -3). All 
screening assessments must be completed prior to randomization.   
Visit 1 (Consent, Day -28 to -14) 
The following procedures will be conducted at Visit 1 (screening) for all subjects: 
• The signed informed consent will be obtained before any screening or other study 
related procedures are initiated. 
• Assignment of a subject ID. When a subject signs the ICF, she/he will be assigned a 
unique subject ID in numerical sequence. The subject ID will be recorded in the 
source document and eCRF. 
• The DSM-IV-TR diagnosis of Schizophrenia will be made using the Structured 
Clinical Interview (SCID) and documented by an adequately trained clinician. 
• The PANSS will be performed to assess symptoms associated with Schizophrenia.  
Subjects are required to have a total PANSS score of 70 or greater, and have a 
score of 4 on at least two of the following five items of the PANSS positive 
subscale: hallucinatory behavior, delusions, conceptual disorganization, 


 
 
suspiciousness, or unusual thought content at screening in order to be included in 
the trial. 
• The MGH FAST, a structured questionnaire for recording psychotropic treatment, will 
be used to assess prior antipsychotic and other psychotropic trials. 
• The CGI-S will be performed. 
• Recording of the subject’s comprehensive medical history, including medical and 
psychiatric conditions;  
• Subject’s demographic information and tobacco use will be obtained 
• Recording a complete history of use of central nervous system (CNS)-active 
compounds, including details (eg, drug name, dose, and frequency), as well all other 
medications, including prescription and non-prescription medications, taken within 
30 days of screening.  
 
After a minimum 5 minute rest in the seated position, vital sign measurements 
(systolic and diastolic blood pressure, pulse, respiration rate, and oral temperature). 
 
Anthropometrics (height, weight, waist circumference and body mass index (BMI)) 
 
Fasting blood samples will be collected at screening for clinical laboratory tests 
including hematology and serum chemistry (using a venous blood sample) 
 
Urine will be collected for urinalysis 
 
For female subjects of childbearing potential, a serum pregnancy test. 
 
For female subjects that are post-menopausal, an FSH test, using a venous blood 
sample. 
 
Urine drug screen (cannabis, opioids, cocaine, amphetamines, methadone, 
cannabinoids, barbiturates, benzodiazepines, methamphetamine, and 
phencyclidine). 
 
HbA1c testing using a venous blood sample. 
 
Physical examination (including a neurological examination). 
 
12-lead ECG will be performed at rest after the subject has been lying down for 
approximately 5 minutes.  ECG will be evaluated at the investigational site to 
determine the subject’s eligibility and to monitor safety.  
 
The Columbia Suicide Severity Rating Scale (C-SSRS) will be conducted and 
together with the clinical opinion of the investigator will be used to assess risk for 
suicide. 
 
AEs will be monitored starting at the time the informed consent is signed. 
 
Review of the inclusion/exclusion criteria. 
 
A blood sample will be collected at Visit 1 (screening) to obtain DNA to enable 
pharmacogenetic studies. Samples will be sent to The Stanley Center for Psychiatric 
Research at the Broad Institute at Massachusetts Institute of Technology in Cambridge, 
Massachusetts for banking and future extraction/genotyping. The MGH CTNI will ensure 
that appropriate informed consent process and privacy and de-identification procedures 
are in place for the collection of biomaterials. 
 


 
 
Visit 2 (Day -13 to -3) 
The following procedures will be conducted at Visit 2 for all subjects: 
 
MGH SAFER Interview 
 
MGH-FAST 
 
PANSS 
 
CGI-S 
 
Randomization 
Randomization: When all of the screening  assessments,  including the SAFER 
assessment, have been completed and entered into the CTMS, the subject’s status will 
be moved to eligible and the CTMS will generate a randomization ID for the subject. This 
ID will be accessible to the site pharmacy and will be used to prepare the corresponding 
study treatment. Once a subject has been assigned a Randomization ID, they will be 
identified in the CRF by this Randomization ID for the duration of their study 
participation. The subject ID should no longer be used.  
 
Phase 1 
Visit 3 (Baseline, Day -2 to -1) 
The following procedures will be conducted at Visit 3 for all subjects: 
 
Concomitant Medications 
 
Vital Signs 
 
Anthropometrics (height, weight, waist circumference, BMI) 
 
12-Lead ECG 
 
Urine Drug Screen 
 
PANSS 
 
CGI-S 
 
CGI-I 
 
MATRICS 
 
UPSA-B 
 
AE/SAE Assessment 
 
AIMS 
 
SAFTEE-SI 
 
C-SSRS 
 
Visit 4 (Phase 1 Study Treatment, Day 0) 
Anthropometrics, vital signs, urinalysis, and concomitant medications will be collected for 
all subjects at the start of Visit 4 (Hours -1 to 0) prior to initiating the infusion.  Subjects 


 
 
will also have blood sample drawn for chemistry and electrolytes. Female subjects of 
childbearing potential will have a pregnancy test prior to the infusion. If pregnancy test is 
positive, subject will not continue with the infusion. Subjects who use tobacco will be 
provided transdermal nicotine in order to prevent withdrawal symptoms. The nicotine 
replacement will be based on the number of cigarettes per day (cpd) or tobacco 
equivalent collected at screening.  
 
≥15 cpd: 21 mg patch 
 
 8-15 cpd: 14 mg patch  
 
5-8  cpd: 7 mg patch   
 
<5 cpd: as needed nicotine gum or 2mg lozenges (1 piece every 3-4 
hours) 
Intravenous sodium nitroprusside or Placebo infusion will take place during Hours 0-4.  
Cardio-pulmonary monitoring will take place throughout intravenous infusion (see 
Infusion Monitoring and Discharge Procedures).   
Following completion of infusion, the subject will have a post-infusion debrief. The 
following measurements will also be collected for all subjects between hours 4 and 7: 
 
Vital Signs 
 
12-Lead ECG 
 
AE/SAE Assessment  
 
AIMS 
 
SAFTEE-SI 
 
PANSS 
 
CGI-S 
 
CGI-I 
Following the completion of all study assessments, a study psychiatrist or nurse 
practitioner will perform discharge procedures in order release the subject at the end of 
the visit.  
 
Visit 5 (Phase 1 Follow Up, Day 7) 
The following procedures will be conducted at Visit 5 for all subjects: 
 
Concomitant Medications 
 
Vital Signs 
 
Anthropometrics (weight, height, waist circumference, BMI) 
 
12-Lead ECG 
 
PANSS 
 
CGI-S 
 
CGI-I 


 
 
 
AE/SAE Assessment 
 
C-SSRS 
 
Phase 2 
Visit 6 (Phase 2 Baseline, Day 13) 
The following procedures will be conducted at Visit 6 for all subjects: 
 
Concomitant Medications 
 
Vital Signs 
 
Anthropometrics (weight, height, waist circumference, BMI) 
 
12-Lead ECG 
 
Urine Drug Screen 
 
PANSS 
 
CGI-S 
 
CGI-I 
 
MATRICS 
 
UPSA-B 
 
AE/SAE Assessment 
 
AIMS 
 
SAFTEE-SI 
 
C-SSRS 
 
Visit 7 (Phase 2 Infusion, Day 14) 
Anthropometrics, vital signs urinalysis, and concomitant medications will be collected for 
all subjects at the start of Visit 7 (Hours -1 to 0) prior to initiating the infusion. Subjects 
will also have blood sample drawn for chemistry and electrolytes. Female subjects of 
childbearing potential will have a pregnancy test prior to the infusion. If pregnancy test is 
positive, subject will not continue with the infusion. Subjects who use tobacco will be 
provided transdermal nicotine in order to prevent withdrawal symptoms. The nicotine 
replacement will be based on the number of cigarettes per day (cpd) or tobacco 
equivalent collected at screening.  
 
≥15 cpd: 21 mg patch 
 
 8-15 cpd: 14 mg patch  
 
5-8  cpd: 7 mg patch   
 
<5 cpd: PRN nicotine gum or lozenges 2 mg (1 piece every 3-4 hours) 
Intravenous sodium nitroprusside or Placebo infusion will take place during hours 0-4.  
Cardio-pulmonary monitoring will take place throughout intravenous infusion (see 
Infusion Monitoring and Discharge Procedures).   


 
 
 
Following completion of infusion, the subject will have a post-infusion debrief. The 
following measurements will be collected for all subjects between hours 4 and 7: 
 
 
Vital Signs 
 
12-Lead ECG 
 
AE/SAE Assessment  
 
AIMS 
 
SAFTEE-SI 
 
PANSS 
 
CGI-S 
 
CGI-I 
Following the completion of all study assessments, a study psychiatrist or nurse 
practitioner will perform discharge procedures in order release the subject at the end of 
the visit.  
 
 
Visit 8 (Phase 2 Follow Up, Day 21) 
The following procedures will be conducted at Visit 8 for all subjects: 
 
Concomitant Medications 
 
Vital Signs 
 
Anthropometrics (weight, height, waist circumference, BMI) 
 
12-Lead ECG 
 
PANSS 
 
CGI-S 
 
CGI-I 
 
AE/SAE Assessment 
 
C-SSRS 
 
Visit 9 (Phase 2 Final Follow Up/Study Completion, Day 28) 
The following procedures will be conducted at Visit 9 for all subjects: 
 
Concomitant Medications 
 
Vital Signs 
 
Anthropometrics (weight, height, waist circumference, BMI) 
 
12-Lead ECG 
 
CBC with differential and electrolytes 
 
PANSS 


 
 
 
CGI-S 
 
CGI-I 
 
MATRICS 
 
UPSA-B 
 
AE/SAE Assessment 
 
AIMS 
 
SAFTEE 
 
C-SSRS 
 
 
Safety Profile of Sodium Nitroprusside  
 
We recognize that acceptability of risk may differ across various treatment populations. 
However, we believe the risk-benefit ratio to be similar for sodium nitroprusside’s current 
indication and the proposed use in this study. In fact, as the dose being tested in this 
study is very low, we anticipate the risk to be modest at most. 
Recent reviews have concluded that sodium nitroprusside has an excellent safety profile 
at doses less than 2 μg/kg/min.  The most important adverse reactions are the avoidable 
ones 
of 
excessive 
hypotension 
and 
cyanide 
toxicity. 
(Package 
Insert 
http://medlibrary.org/lib/rx/meds/nitropress/ - last revised January 16, 2014). No adverse 
effects were observed in 10 schizophrenia subjects who received nitroprusside 0.5 
μg/kg/min in the study by Hallak et al., including no cases of hypotension despite 
administering nitroprusside to two subjects treated with chlorpromazine (500 mg/d and 
300 mg/d); chlorpromazine has the greatest propensity for orthostatic hypotension of any 
antipsychotic and subjects taking this drug will be excluded from the study.  
Nitroprusside was also added to high-dose ziprasidone (240 mg/d) and high dose 
risperidone (8 mg/d) without measurable effects on blood pressure or EKG.  
The potential for cyanide toxicity is greatest when more than 500 μg /kg of sodium 
nitroprusside is administered faster than 2 μg /kg/min, as cyanide is generated faster 
than the unaided patient can eliminate it. Cyanide toxicity will be avoided in this study as 
the dose administered is very low, and individuals with renal impairment will be 
excluded. Also, the study treatment will be infused within 3-12 hours of preparation as 
sodium nitroprusside is only stable in solution for 24 hours. Subjects will be continuously 
monitored for adverse effects during the infusion and blood pressure and heart rate will 
be taken and recorded hourly for 2 hours post infusion.  
Given that  subjects with renal disease, cardiac disease, hypotension or medications that 
destabilize blood pressure will be excluded from the study, and that the infusion rate of 
SNP for subjects randomized to active drug in this study will be low (0.5 μg/kg/min), the 
risk of excessive hypotension and cyanide toxicity is low. 


 
 
Sodium nitroprusside does have some potential for drug-drug interactions. The 
hypotensive effect of sodium nitroprusside is augmented by that of most other 
hypotensive drugs, including ganglionic blocking agents, negative inotropic agents, and 
inhaled anesthetics. Subjects taking any of these drugs will be excluded from the study. 
Patients will also be advised not to take these medications during the course of the 
study. 
 
Infusion Monitoring and Discharge Procedures 
The study treatment will be infused with a volumetric infusion pump and the blood 
pressure of a subject will be continuously monitored by a cardiologist, anesthesiologist, 
or medically qualified designate as per institutional guidelines. A study physician will be 
available for consultation on any participant safety issues that arise during the infusion. 
Each participant will be allowed to rest in a semi-recumbent position. Each subject will 
receive an intravenous line. The study treatment will be infused with a volumetric 
infusion pump and the blood pressure of a subject will be continuously monitored by a 
cardiologist, anesthesiologist, or medically qualified designate as per institutional 
guidelines. To maintain the double blind, each subject will receive an infusion for 4 
hours. Nitroprusside or placebo will be administered at the dose specified in the 
randomization scheme. Subjects will have one-to-one nursing care during the infusion of 
the study treatment. 
The assigned nurse or medically qualified designate will perform the following monitoring 
procedures, as developed by the consulting cardiologist: 
 
Pre-Infusion: 12-Lead ECG (Time -1 to Time 0, baseline)  
 
During Infusion: 
o   12-Lead ECG @ 30 min  
 
Post-Infusion:  
o 12-Lead ECG @ 60 min post-infusion  
 
Vital Signs: BP, HR and O2 sat (same arm, non-IV arm)  
  
Pre-Infusion (baseline) 
During Infusion:  
o Q5 min Xs 30 minutes then Q10 min Xs 3.5 Hrs (210 min)  
Post-Infusion:  
o  Q5 min Xs 30 minutes then Q10 min Xs 1.5 Hrs (90 min)  
 
A 10-minute run-in period (“Phase I”) has been added to ensure that the patient tolerates 
the drug.  As determined by consulting cardiologist, this will include the administration of 
the drug at half of the rate (0.25 mcg/kg/min).  The following Safety parameters will be 
followed for Phase I: 
 
Safety Parameters 
Safety Parameters Phase I dose: 
-If SBP < 89 STOP infusion.  Lie flat, feet up, call N.P. & P.I. 
-If HR > 120 bpm or >20 bpm over baseline HR, abort study 
-If SpO2 <92%, stop infusion 
-If patient reports headache, ask: “do you feel this headache is tolerable?” 
 
-If patient says “yes,” continue dose 
 
-If patient says “no,” STOP dose 


 
 
-If patient experiences symptomatic hypotension (nausea, dizziness) STOP infusion. 
  
If Phase I is tolerated per the above guidelines after the 10 minute run-in period, the 
drug will be administered at the rate of 0.5 mcg/kg/min (“Phase II”) with the following 
parameters: 
 
Safety Parameters for Phase II dose:  
- If SBP between 81 and 89, lower dose to Phase I dose for 15 min.  Monitor with CRC 
NP.  
- If SBP rises to > 89mm Hg continue Phase I dose 
- If SBP remains between 81 and 89mm Hg abort and call P.I.  
- If SBP < 80, STOP infusion, lie flat, feet up & call P.I.  
- If HR > 120 bpm or > 20 bpm over baseline HR, lower dose to Phase I dose for 15 min  
- If SpO2 < 92% Stop infusion  
- If patient reports headache, ask, “Do you feel this headache is tolerable?”  
- If patient says “yes”, continue dose 
- If patient says “no”, lower dose to Phase I dose for 15 min  
- If better, continue Phase I dose  
- If still intolerable, STOP dose  
- If patient experiences symptomatic hypotension (nausea, dizziness) lower dose to 
Phase I dose for 15 min  
- If better, continue Phase I dose  
- If not, Stop infusion, call P.I. 
 
Should the patient require PRN rescue medications, the following procedures will take 
place: 
 
PRN Rescue medications:  
In consultation with CRC N.P.  
For SBP < 80 mmHg, may give 250 ml 0.9% NS 
IV bolus via Sigma pump @999 ml/hr over 15 min X 2  
For rash may give 
Diphenhydramine 25 mg by mouth X 1   
 
The IV line will be left in place for at least 1 hour following the infusion to allow for 
additional medications to control emergent side effects. If additional IV medication is 
necessary, an anesthesiologist, cardiologist, or medically qualified designate will start 
the infusion and a medical team will be present during the entire infusion period.   
A study psychiatrist or medically qualified designate will release the subject at the 
conclusion of the testing period at the end of the visit. A trained research assistant along 
with a research nurse will be present during the entire infusion and monitoring period. 
The psychiatry research staff member will administer rating scales. All side effects and 
vital parameters will be recorded during the infusion and 2 hours following. Any 
abnormal, clinically significant vital signs will be recorded as adverse events. 
Discharge Procedure: Gross motor and cognitive function, ataxia, reflexes/clonus will be 
evaluated and documented by a study psychiatrist or medically qualified designate prior 


 
 
to discharge. Before being discharged patients should be awake and alert, feeling well, 
with no nausea, vertigo, or dizziness. There should be no significant change in vital 
signs from prior to infusion. They will be given a small meal before discharge. 
Patients will be instructed not to drive. If necessary, the study nurse will release them to 
the care of an adult family member or caregiver, who will accompany the patient home. 
 
 
Reliability Training 
All physicians/raters involved in the assessment of study subjects will use standardized 
clinician-rated measures such as the SCID I/P, the PANSS, and CGI-S. Training in the 
use of these instruments occurs through videotaped and live interviews of mock patients. 
Both intra-individual and inter-individual reliability measures will be reported. 
 
Patient Adherence to Protocol 
Every effort will be made to encourage patients to comply with the procedures and the 
assessments involved in study. Patients will be compensated for their time at each visit, 
at a rate determined appropriate by each individual IRB (estimated compensation: 
$20.00/hour). This level of subject compensation, while non-coercive, facilitates 
adherence to assessments and procedures that require weekly visits.  
Subjects and clinicians will be asked to guess which arm of the study the subjects were 
in at the end of the study to assess if blinding was successful. 
 
Evaluation of Adverse Events (AEs) 
Definition  
In accordance with International Conference on Harmonization (ICH) and Food and Drug 
Administration (FDA) guidance, any study related event incurred by a subject that occurs 
after the first study-related procedure to the completion of the protocol-defined safety 
surveillance period, that represents a change (positive or negative) in frequency or 
severity from a baseline (pre-study) event (if any), regardless of the presence of causal 
relationship or medical significance, is a reportable AE. 
Abnormal results of diagnostic procedures, including laboratory test abnormalities, are 
considered AEs if they: 
• Result in discontinuation from the study, 
• Require treatment or any other therapeutic intervention, 


 
 
• Require further diagnostic evaluation (excluding a repetition of the same 
procedure to confirm the abnormality), or 
• Are associated with clinical signs or symptoms that would have a significant 
clinical impact, as determined by the PI. 
 
Performing Adverse Events Assessments 
The PI is ultimately responsible for assessing and reporting all adverse events as 
outlined in the protocol.  The assessment of AEs may be delegated to a medically 
qualified Sub-Investigator, trained on this study protocol, who is listed on the FDA Form 
1572 or equivalent document, and on the delegation of authority form. 
AEs should be volunteered by the subject, or solicited from the subjects using a 
standard statement, from examination of the subject at a clinic visit, or from observations 
of clinically significant lab values or special exam abnormal values.  AEs will not be 
solicited by the use of a specific list of anticipated events. 
All AEs are to be assessed and recorded in a timely manner and followed to resolution 
or until the Investigator determines that there is not an anticipated resolution. Each AE is 
to be documented with reference to severity, date of occurrence, duration, treatment, 
and outcome. Furthermore, each AE is to be classified as being serious or non-serious 
(as per definitions). In addition, the PI or delegated medically qualified Sub-Investigator 
must assess whether the AE is drug-related or not. Changes in severity of AEs and 
resolution dates should be documented as separate events. 
Timing 
AEs will be captured from the first study-related procedure through to the completion of 
the protocol defined safety surveillance period. For the purposes of this study, the period 
of observation for collection of AEs extends from the time the subject gives informed 
consent until the final visit.  
Surgical procedures, planned before enrollment of the subject in the study, are not 
considered AEs if the condition was known before study inclusion. In this case the 
medical condition should be reported in the subject’s medical history.  Intermittent 
adverse events will not be reported as multiple adverse events.  The definition of an 
intermittent adverse event is “a recurring event of consistent severity, frequency, and 
causality.” 
Severity 
Each AE is to be documented with reference to severity.  Changes in severity of AEs 
and resolution dates should be documented as separate events.  Any event that 
ameliorates over more than one assessment time point may be considered for listing as 
a single event at the highest severity. 
Table 2. Definition of Intensity of Adverse Events 


 
 
Intensity 
Definition 
Mild 
Causes transient or mild discomfort; no limitation of usual activities; no 
medical intervention required. 
Moderate 
Causes mild to moderate limitation in activity; some limitation of usual 
activities: no or minimal medical intervention or therapy is required. 
Severe 
Causes marked limitation in activity; some assistance is usually required; 
medical intervention or therapy is required; hospitalization is probable. 
 
The term “severe” is often used to describe the intensity (severity) of a specific event (as 
in mild, moderate, or severe); the event itself, however, may be of relatively minor 
medical significance (such as a severe headache).  This is not the same as “serious,” 
which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject’s life or functioning. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
 
 
Relationship 
The PI or a medically qualified Sub-Investigator, trained on this study protocol, listed on 
the 1572 or equivalent document and on the delegation of authority form, is responsible 
for determining the adverse event relationship to the investigational product.  
The following categories will be used to define the relationship of an AE to the 
administration of the IMP: 
• Not Related:  Data are available to identify a clear alternative cause for the AE 
other than the investigational product. 
• Related:  The cause of the AE is related to the investigational product and cannot 
be reasonably explained by other factors (e.g., the subject’s clinical state, 
concomitant therapy, and/or other interventions). 
 
 
 
Expectedness 
An unexpected AE is any AE, the nature and severity of which is not consistent with the 
applicable product information (e.g., Package Insert of product characteristics for an 
approved product). 
Clinical Significance 


 
 
The PI or a medically qualified Sub-Investigator, trained on this study protocol who is 
listed on the 1572 or equivalent document and on the delegation of authority form, is 
responsible for determining the clinical significance of abnormal results (e.g., labs, ECG 
results) for the subject. 
Clinical Laboratory Adverse Events 
Changes in laboratory values or vital signs, or other safety parameters (e.g., ECG, study 
assessments) as noted in the protocol, are a subset of AEs and are reportable only if 
considered to be clinically significant by the PI or medically qualified Sub-Investigator.  
Screening assessment exams are differentiated from adverse events/symptoms that are 
incurred post informed consent.  Pre-dose abnormal results without clinical symptoms 
will not be reported as adverse events. 
 
Pregnancy 
If a subject (or subject’s partner) becomes pregnant during the study, it must be reported 
in within 24 hours of the time the investigator becomes aware of the event and in 
accordance with the procedures described on the Pregnancy Report Form. Pregnancy in 
itself is not regarded as an AE unless there is a suspicion that a study drug may have 
interfered with the effectiveness of a contraceptive medication. Any pregnancy that 
occurs from Day 1 to 30 days following the last dose given will be followed for Serious 
Adverse Events (SAEs). 
 
Evaluation of Serious Adverse Events (SAEs) 
Definition 
An SAE is defined by federal regulation as any AE occurring at any dose that results in 
any of the following outcomes:  
- 
Death 
- 
Life-threatening event 
- 
Hospitalization or prolongation of hospitalization 
- 
Persistent or significant disability/incapacity 
- 
Congenital anomaly/birth defect 
Reporting Serious Adverse Events 
All SAEs will be reported to MGH-CTNI by the PI through telephone or email within 
24 hours of discovery, using the form provided by the CTNI. 
In the event of a SAE, the PI or designate will notify the MGH-CTNI Medical Monitor by 
phone or email within 24 hours of the event and will email supporting documentation 


 
 
within 48 hours of the event and then as relevant data is available within the following 
week. 
The PI must inform the IRB immediately regarding any AE (does not have to be causally 
related) that is both serious and unexpected; or that represents a series of AEs that, on 
analysis, is unanticipated, or occurs at an unanticipated frequency, or otherwise 
represents an unanticipated safety risk to the study subject.  The IRB may subsequently 
choose to modify the informed consent or request changes to the protocol. 
Treatment-Emergent Adverse Events 
A treatment emergent adverse event (TEAE) is an AE that either began following 
initiation of study treatment or was present prior to the initiation of the treatment, but 
increased in frequency or severity following initiation treatment, regardless of causality. 
All TEAEs (post infusion) will be captured on the subject source documents for all 
required assessments and data transferred to the eCRF.  The reporting PI or medically 
qualified Sub-Investigator will sign and date the source document and eCRF. 
 
Procedures and follow-up of Subjects Experiencing AEs after Completion of or 
Withdrawal from the Study 
If a subject experiences the onset of a SAE within a period of 30 days following study 
completion and, in the opinion of the PI or medically qualified Sub-Investigator, it is 
associated with the study, it will be followed up and reported as described above. 
 
Protocol Waivers and Violations 
Protocol Waivers 
Protocol waivers will be assessed on a case by case basis by the medical monitor and 
the principle investigator for this study. 
Procedure for Non-Compliant Subjects  
Subjects who miss a study visit will be allowed (at the discretion of the PI) to make up 
that visit the next day. Subjects who miss more than one visit will be discontinued from 
the study.  Subjects who withdraw consent will no longer have data collected for the 
study.  Every effort will be made to maintain contact with patients who are discontinued, 
but who do not withdraw consent, according to the study schedule for 30 days post-
treatment in order to collect safety data. 
Protocol Deviation and Violation Definitions 


 
 
Protocol violations as defined in the table below will be reported as described in the 
Manual of Operations. 
Table 3. Major and Minor Protocol Violations 
 
Major Protocol Violation 
Minor Protocol Violation 
The list of examples is intended as a guide and is not all-inclusive. 
Definition 
A violation that may: 
Impact subject safety, 
Affect the integrity of study data, and/ 
or 
Affect the subject’s willingness to 
participate in the study. 
A violation that does not: 
Impact subject safety, 
Compromise the integrity of study 
data, and/ or 
Affect the subject’s willingness to 
participate in the study. 
Examples  
(not all-
inclusive) 
Failure to obtain informed consent 
Informed consent obtained by an 
unauthorized individual 
Enrollment of a subject who did not 
meet eligibility criteria for whom a 
protocol exception was not obtained 
Performing a study procedure that is 
not approved by the IRB and/or is not 
in the protocol 
Failure to perform a required lab test 
that, in the opinion of the Site 
Investigator, may affect subject safety 
or data integrity 
Failure to perform or follow a study 
procedure that, in the opinion of the 
Site Investigator, may affect subject 
safety or data integrity 
Failure to follow safety (AE) 
management plan 
Failure to report a SAE to the IRB 
and/or Coordination Center 
Implementation of unapproved 
recruitment procedures 
Only a photocopy of the signed/ dated 
consent form is available (the original 
is missing) 
Pages are missing from the signed/ 
dated informed consent form 
Use of invalid consent form (i.e. 
without IRB approval or 
outdated/expired form) 
Failure to perform or follow an 
approved study procedure that, in the 
opinion of the Site Investigator, does 
not affect subject safety or data 
integrity 
Study procedure conducted out of 
sequence 
Failure to perform a required lab test 
Missing lab results 
Study Visit out of approved window 
Over-enrollment 
Enrollment of subjects after IRB 
approval of the study has expired 


 
 
Failure to submit a continuing review 
application to the IRB before study 
expiration  
Reporting 
Requirements 
Record the date discovered, date 
occurred, description of event in the 
Protocol Deviation Log. 
Notify the Coordinating Center within 
24 hours. 
Record the date discovered, date 
occurred, description of event in the 
Protocol Deviation Log. 
Notify the Coordinating Center  
 
I. 
TREATMENT 
Dosing 
Subjects will receive either sodium nitroprusside diluted with 5% dextrose and infused at 
a rate 0.5 μg/kg/min for 4 hours, or a placebo solution of 5% dextrose infused over 4 
hours. The study treatment will not be exposed to light prior to and during the infusion as 
exposure of SNP to light has the potential to form cyanide ions.  Subjects will be 
recumbent and blood pressure, heart rate, blood oxygen saturation, and ECG will be 
continuously monitored during infusion of the study treatment. 
 
Study Product Supplies and Administration 
The Institutional Pharmacy will issue either undiluted sodium nitroprusside in sterile 5% 
dextrose or sterile 5% dextrose only. For subjects randomized to sodium nitroprusside, 
an unblinded pharmacist will dilute the SNP with 5% dextrose to achieve a concentration 
allowing infusion of 0.5 μg/kg/min over the course of 4 hours. 
 Packaging and Labeling  
Sodium nitroprusside or placebo will be prepared within 12 hours from the scheduled 
delivery time and once prepared in solution will be protected from UV light by covering 
the iv bag with an aluminum foil bag. The intravenous drip chamber will also be covered 
for blinding purposes but the tubing does not need to be covered. 
A study label that includes the subject ID and randomization ID will be pasted to the foil 
bag so that it is clearly visible. The dextrose solution will also be covered with an 
identical foil bag and study label so that medical personal administering the i.v. will be 
blinded to the study treatment.  
Dose Modification during Treatment  
As previously stated, the subject’s blood pressure will be monitored continuously during 
the study treatment. If the subject’s systolic blood pressure falls below 90 mm Hg the 


 
 
infusion rate will be reduced by 50% and a drop below 80 mm Hg will terminate the 
infusion.  Nitroprusside has a circulating half-life of 2 minutes and blood pressure is 
usually restored within 1-5 minutes of stopping the infusion.  Trendelenburg position and 
IV fluids will be used if subjects experience symptomatic hypotension.  The medical 
monitor will receive all safety data within 24 hours after each infusion and will inform the 
PI who will inform the IRB of any safety concerns. 
Possible Drug Interactions 
The hypotensive effect of sodium nitroprusside is augmented by that of most other 
hypotensive drugs, including ganglionic blocking agents, negative inotropic agents, and 
inhaled anesthetics. Subjects taking any of these drugs will be excluded from the study. 
Concomitant Therapy 
The subject may not have adjustment of psychotropic medications except for 
benzodiazepines or anticholinergic agents if deemed absolutely necessary by the 
Investigator for relief of transient symptoms. (See Appendix 3: Medications Allowed and 
Not Allowed as Concomitant Medications). Subjects must be questioned at each study 
visit concerning any new medications or changes in current medications including over-
the-counter medication and topical medication. All medications and therapies 
administered or taken by the subject beginning 30 days prior to signing the ICF and 
throughout the study will be recorded. The subjects’ antipsychotic medication type 
should have remained unchanged for at least eight (8) weeks prior to screening into the 
study, at constant dose for at least 4 weeks, and should be expected to remain 
unchanged during the study. 
For each medication and non-study treatment, the following will be documented: 
 
Medication/treatment name (generic name may be used if trade name is unknown) 
 
If an anti-psychotic medication, whether typical or atypical. 
 
Dose, unit, and frequency of dosing (individual dosages, not total daily dose). Note: 
Each new dose of medication should be recorded as a separate entry, with the 
exception of medications that are given on a sliding scale. For these, it is acceptable 
to enter the range of the dosage, including the start and stop dates for which the 
specified dosage range was used. 
 
Route of dosing 
 
Indication for use 
 
The start date  
 
The stop date (if medication/therapy is not ongoing) 
 
Discontinuation from Study Treatment 


 
 
Every effort will be made to keep the patient in the study for the full study period 
consisting of two phases of treatment with follow-up assessments. Acceptable reasons 
for early discontinuation include the following: 1) request of patient, 2) decision of 
physician, 3) serious adverse event, and 4) protocol violation. 
Medical Reasons for Discontinuation:  
Treatment (infusion) discontinuation will be determined by the criteria outlined in the 
Infusion Monitoring and Discharge Procedures section of this Protocol.  A study 
physician will be available for consultation on any participant safety issues that arise 
during the infusion. 
A patient who decides to discontinue participation in the study will always be asked 
about the reason(s) and the presence of any AEs. If possible, they will be seen and 
assessed by an investigator. AEs will be followed up until resolution. 
Procedures for Discontinuation from Study: 
If a patient discontinues from the study before randomization, then no further follow-up 
will be expected. However, if the patient discontinues after randomization, but before 
receiving any study treatment, the patient will be asked to return for a final study visit, 
during which the procedures outlined in the Visit 9 Final Visit/Early Termination Visit 
procedures will be completed, including AEs and concomitant medication assessments. 
If a patient discontinues from the study before completion and has received the dose of 
study drug, the patient will be asked to return for a final study visit, at which the 
procedures outlined in the Early Termination Visit will be completed. Every effort should 
be made to follow up with patients who discontinue from the study prior to Visit 9 (Day 
28). If patients refuse to return to the clinic for the study-related assessments, a modified 
follow-up through, for example, regular telephone contact or a contact at study closure 
should be arranged, if agreed to by the patient and in compliance with local data privacy 
laws/practices. If the patient refuses follow-up, the reason for the refusal and last contact 
date should be documented in the eCRF and source documents. 
Patients who discontinue from the study will not be replaced. 
If an Early Termination Visit is warranted, the following procedures will be performed: 
 
Concomitant medications 
 
Vital Signs 
 
12-lead ECG 
 
Anthropometrics (weight, height, waist circumference, BMI) 
 
CBC with differential and Comprehensive Metabolic Panel (CMP) 
 
Urinalysis 
 
Serum Pregnancy test 
 
PANSS 
 
CGI-S 


 
 
 
CGI-I 
 
AE/SAE assessment 
 
AIMS 
 
SAFTEE 
 
C-SSRS 
 
MATRICS 
 
UPSA-B 
 
Unblinding Procedure 
Methods for Ensuring Blinding 
The investigator, subject, and study staff will be blinded. The preparation and labeling of 
the study drugs will be performed by the site pharmacy in a way to ensure blinding 
throughout the study. 
No members of the study team at study sites, will have access to the randomization 
scheme during the conduct of the study, with the exception of the Site’s unblinded 
pharmacist or nurse as designated by the PI. 
The randomization schedule for blinding of randomized treatment will be maintained by 
MGH CTNI or representative and will not be disclosed until after database lock. 
During the infusion visits, the study staff conducting the clinical efficacy assessments 
must not be able to view the bag containing the infusion solution to ensure that they 
remain blinded. The bag must be protected from view with an opaque covering. 
 
Methods for Unblinding the Study 
Individual treatment codes, indicating the treatment randomization for each randomized 
patient, will be available to the investigator(s) or pharmacists from MGH CTNI or its 
designee. 
The treatment code must not be broken except in medical emergencies when the 
appropriate management of the patient necessitates knowledge of the treatment 
randomization. The investigator documents and reports the action to MGH CTNI or 
representative, without revealing the treatment given to the patient to MGH CTNI or 
representative’s staff. 
MGH CTNI retains the right to break the code for serious adverse events (SAEs) that are 
unexpected and are suspected to be causally related to a study drug and that potentially 
require expedited reporting to regulatory authorities.  Treatment codes will not be broken 


 
 
for the planned analyses of data until all decisions on the evaluability of the data from 
each individual patient have been made and documented. 
J. 
ETHICAL CONSIDERATIONS 
Risk/Benefit Assessment 
The clinical use of nitroprusside has been restricted due to concerns about cyanide 
toxicity at high doses.  In particular, the FDA established a black box warning for doses 
greater than 2 μg/kg/min.  Upon review of the literature the threshold for safety with 
nitroprusside is probably substantially higher than a dose of 5 μg/kg/min  (Kristiansen 
2010).    Recent work has suggested that neurotoxicity associated with high-dose 
nitroprusside is mediated by iron-related free radicals and can be prevented by the anti-
oxidant, glutathione (Nong 2003) or by hydroxocobalamine (vitamin B12) (Burgdorf 
2011). However, Hallak et al reported no adverse events (including hypotension) in 
association with an infusion rate of 0.5 μg/kg/min for 4 hours of nitroprusside, and the 
efficacy of the treatment was evident within 4 hours of treatment and persisted for 4 
weeks post infusion. Thus, this study will potentially help provide a novel treatment for 
individuals with Schizophrenia. If this intervention is effective, these results will lead to a 
full clinical development program of nitroprusside as a treatment for Schizophrenia. 
The treatment has been selected with consideration of safety in mind. Additionally, 
exposure to the intervention will be brief and carefully monitored. The risks of 
participation in the study are therefore judged to be small, and adequate protections are 
in place to monitor the medical wellbeing of participants.  
The aforementioned data suggest that risks to subjects are minimal. The benefit to 
society from the development of efficacious interventions for schizophrenia would be a 
substantial public health benefit. 
Informed Consent 
The Investigator must ensure that patients are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical trials in which they 
volunteer to participate. Preparation of the consent form is the responsibility of the 
Investigator and must include all elements required by CFR 21 Part 50.25 and the local 
IRB or Ethics Committee.  
All subjects will receive the consent form for the study. Any questions, concerns, or 
ambiguities will be clarified by the site’s PI or another study clinician prior to the patient 
signing consent. Subjects will sign informed consent and only then will begin 
participation in the study. 
IRB or Ethics Committee Review 


 
 
Before study initiation, the Investigator must have written and dated approval/favorable 
opinion from the IRB for the protocol, consent form, patient recruitment materials and 
process (e.g., advertisements), and any other written information to be provided to 
subjects. 
The Investigator should provide the IRB with reports, updates, and other information 
(e.g., Safety Updates, Amendments, and Administrative Letters) according to regulatory 
requirements and Institution procedures. 
A detailed list of required regulatory documents also to be submitted to MGH CTNI will 
be sent upon final approval of the protocol. 
 
K. 
DATA HANDLING AND RECORD KEEPING 
 
A  Clinical Trials Management Software (CTMS) package with a Microsoft SQL server 
database and internet browser interface will be implemented for data management. The 
system will be HIPAA compliant with transmission security, 21 CFR Part 11 compliance, 
audit trails, electronic signatures, user authentication, study site and role–base security 
and datasets can be extracted as de-identified data sets. The system uses electronic 
data capture (EDC) allowing data assessments to be entered directly into the browser 
interface. It supports multi-site projects with separate security for each site including 
Serious Adverse Event (SAE) Reporting. 
Study specific data that has been outlined in the protocol will be entered into the clinical 
database via the EDC system by designated site staff in accordance with the eCRF 
Completion Guidelines. Data is verified electronically using a series of on-line 
programmed edit checks that have been created by the clinical data manager and 
programmed by the clinical data programmer or designee. Data discrepancies will be 
brought to the attention of the site staff and investigated by the clinical monitor and site 
study coordinator. The clinical monitor(s) will review and verify all eCRF data against 
acceptable source documentation during scheduled monitoring visits. The clinical 
monitor will work closely with the site study coordinator to address any discrepancies 
which have been found so that resolutions can be made and documented into the 
clinical database.  An audit trail within the system will track all changes made to the 
data. 
 
DATABASE Quality Assurance 
The clinical database will be reviewed and checked for omissions, apparent errors, and 
values requiring further clarification using computerized and manual procedures. Data 
queries requiring clarification will be generated and addressed by the investigational site. 


 
 
Only authorized personnel will make corrections to the clinical database, and all 
corrections will be documented in an audit trail. 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines. Site visit 
audits will be made periodically by a contract research organization’s qualified 
compliance auditing team, which is an independent function from the study conduct 
team. 
Record Retention 
All documents pertaining to the study, including all versions of the approved study 
protocol, copy of the informed consent document and Health Insurance Portability and 
Accountability Act (HIPAA) documents, eCRFs, source documents (i.e., subject records, 
hospital records, laboratory records, medication records, etc.), and other study-related 
documents will be retained at the study site for 5 years after the study ends. 
The PI must notify and obtain approval in writing from the CTNI prior to destruction of 
any study records or provide an opportunity for the CTNI to collect such records.  If the 
Investigator withdraws from the study (e.g., relocation, retirement) all study-related 
records should be transferred, in a written agreement with the CTNI, to a mutually 
agreed upon designee and specified timeframe. 
Data Confidentiality 
Potential risks to data confidentiality will be mitigated by requirements for the de-
identification of all study data and by security protocols for all data capture systems. All 
users of the EDC system will be tracked and provided access in a secure fashion 
following established SOPs for this process.  
As with all research data, information gathered by the study will be used only for 
aggregate analysis; it will not be released with any information that identifies research 
participants.  Pharmacogenetic information, in particular, will be coded and unlinked to 
individual respondent identifiers. The data manager, statistician, Investigator, and 
sponsor do not have access to the identities of patients. That information is retained only 
at the clinical centers. Uses and risks related to data collection will be outlined in the 
informed consent and reviewed with the subjects.  
L. 
MONITORING AND OVERSIGHT 
Evaluation of Study Sites 
Study sites selected by MGH CTNI will provide facility details and site capabilities, past 
performance in similar studies, investigator, and staff experience, ongoing studies at the 
site, projected enrollment in this study, and FDA or other agency audit findings. Study 
sites may be asked to complete a study-specific Site Selection Questionnaire and other 


 
 
documents for consideration for participation and MGH CTNI or clinical study monitors 
will complete a remote Site Qualification Visit prior to completing the evaluation. 
Initiation of Study Sites 
Prior to subject enrollment, a study initiation visit or evaluation will be completed at each 
investigational site to ensure the following: IRB approval has been obtained and 
documented prior to subject screening, the Investigators and study personnel are 
appropriately trained and clearly understand the protocol, the Investigators and study 
personnel accept the obligations incurred in undertaking this clinical investigation. 
Periodic Monitoring Visits  
Qualified clinical monitors representing MGH CTNI will conduct investigational site 
monitoring visits to ensure that all Investigators conduct the study in compliance with the 
protocol and applicable regulations. The site will receive notification prior to each 
monitoring visit during the course of the study. It is expected that the Investigator and/or 
sub-Investigator and other appropriately trained study staff are available on the day of 
the visit in the event any questions arise.  
Periodic monitoring visits will be made in accordance with the approved monitoring plan 
at all active study sites throughout the clinical study to assure that the Investigator 
obligations are fulfilled and all applicable regulations and guidelines are being followed. 
These visits will assure that the facilities are still acceptable, the protocol and 
investigational plan are being followed, the IRB has been notified of approved protocol 
changes as required, complete records are being maintained, appropriate and timely 
reports have been made to the Sponsor and the IRB, and the Investigator is executing 
all agreed activities. 
MGH CTNI retains the right to remove either the investigator or the investigational site 
from the study for issues of non-compliance with the protocol or regulatory requirements.  
On one or more occasions, the study site may be inspected or audited by a MGH CTNI 
or a representative. The Investigator will be informed in advance of this visit. 
Study Closeout Visit 
Upon completion of the clinical study (when all subjects at the site have completed follow 
up visits, all data has been entered in the EDC system and cleaned, all queries resolved, 
and final electronic signatures have been obtained), a study closeout procedure will be 
performed. Any unused study materials and equipment will be collected and returned to 
MGH CTNI. The Monitor will ensure that the Investigator’s regulatory files are up to date 
and complete and that any outstanding issues from previous visits have been resolved. 
Other issues which will be reviewed at this visit include: discussing retention of study 
files, possibility of site audits, publication policy, and ensuring that the Investigator will 
notify the local IRB regarding study closeout. 
 


 
 
Medical Monitoring 
The medical monitor for this trial will be a board certified psychiatrist designated by MGH 
CTNI. The MGH CTNI Medical Monitor will review all adverse events, review issues 
related to subject eligibility, assess the benefits and risks of protocols on an ongoing 
basis, and work in collaboration with the IRB to identify safety signals and trends. 
 
M. 
DATA ANALYSIS 
This section presents general information about statistical considerations and concepts 
such as randomization, stratification, statistical power, sample size, and a brief 
discussion on analysis methodology.  
 
Treatment Groups  
The following treatment groups will be assessed: 
Table 4. Study Treatments 
Group 
Description 
Test Treatment  
Sodium Nitroprusside (0.5 μg/kg/min  for 4 hours) 
Control Treatment  
Placebo (5% dextrose for 4 hours) 
 
Description of Study Endpoints  
Primary Efficacy Endpoint 
 Mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total 
score after 2 weeks of randomized treatment using SPCD. 
 
Secondary Efficacy Endpoints 
 Percent change from baseline in the PANSS total score after 2 weeks of treatment 
using SPCD 
 Percentage of subjects with 20% or more reduction from baseline in PANSS total 
score after 2 weeks of treatment using SPCD 
 Percent change in PANSS subscales using SPCD 
 


 
 
Additional Efficacy Endpoints 
 Percent change in Clinical Global Impression-Severity (CGI-S) using SPCD 
 Percent change in MATRICS Consensus Cognitive Battery (MCCB) using SPCD 
 
Safety Assessments 
 Incidence of Treatment-Emergent Adverse Events (TEAE) 
 Incidence of withdrawals from the study due to TEAEs 
 Percent change in Abnormal Involuntary Movement Scale (AIMS) 
 Percent change in Systematic Assessment for Treatment Emergent Effects–
Systematic Inquiry (SAFTEE-SI) 
 Assessment of suicidality per the Columbia-Suicide Severity Rating Scale (C-SSRS) 
 Changes in blood pressure and heart rate  
 Changes in electrocardiogram (ECG) parameters  
 
Sample Size Determination and Rationale 
Sixty (60) subjects will be randomized in an effort to assure that 48 subjects complete 
the study. 
The 
RCT 
Logic 
Calculator 
(by 
Schoenfeld, 
D 
and 
Ivanova,A; 
http://www.rctlogic.com/calculator/calculator-continuous.aspx) was used for this sample 
size calculation. This sample size will provide “sufficient” statistical power for the 
selected primary endpoint. The sample size calculation is based on the assumption that 
there is a clinically meaningful weighted (50%) average difference of 10 points (9 points 
in Stage 1 and 11 points in Stage 2) between sodium nitroprusside and placebo group 
accordingly, (with standard deviation of 14) in PANSS total scores after 2 weeks of 
treatment between the two treatment groups. This power calculation is based on a 20% 
attrition by Week 4 and 30% placebo response at the end of Stage 1. Under the above 
assumptions, 60 subjects will be required to meet the Type I error rate of 0.05 and an 
81% power.  
Randomization 
This is a double-blind, placebo-controlled, multi-center, randomized clinical trial. 
Subjects who have provided written informed consent and have met all the inclusion 
criteria and have met none of the exclusion criteria will be randomized to one of the 
three treatment sequences.  


 
 
The study design contains two double-blind treatment phases (i.e. Phase 1 and Phase 
2) of the same duration of two weeks. Subjects will be randomly assigned using stratified 
block randomization. The randomization scheme will be programmed in to the CTMS 
software and will generate a randomization code for each subject upon enrollment into 
the study. Subjects will be stratified by primary treatment status (clozapine, versus 
antipsychotic other than clozapine) and by site. The number of subjects taking clozapine 
will be restricted to 20 study wide. 
Blinding and prevention of Bias 
All subjects, Investigators and their staff involved in the management of the study will be 
blinded to treatment assignments.  
Treatment unblinding for the study will occur after all clinical data have been received, 
data inconsistencies have been resolved, and the database is locked, except for safety 
reasons on a case by case basis (i.e., emergency unblinding).  
Interim Analysis  
There will be no interim analysis for this trial.  
General Statistical Considerations  
All collected study data will be presented in subject data listings. Statistical analyses will 
be performed using SAS® for Windows, version 9.3 or later. Descriptive statistics (n, 
mean, standard deviation, median, minimum and maximum) will be calculated by 
treatment group for continuous variables. Frequencies and percentages will be 
presented by treatment group for categorical variables. 
 
Analysis Populations  
The details of the analysis population to be used for the study are described in the below 
sections. All the subjects who were randomized in the study will be considered for 
analysis. For the primary and secondary endpoint analyses the following set of subject 
will be accounted:  
 
All subjects randomized to the sodium nitroprusside group in Phase 1 of the 
study (~ 20 subjects) 
 
All subjects randomized to the Placebo group in Phase 1 of the study (~ 40 
subjects) 


 
 
 
All subjects who did not respond to placebo in Phase 1 and were pre-randomized 
to the sodium nitroprusside  group in Phase 2 of the study (~11 subjects) 
 
All subjects who did not respond to placebo in Phase 1 and were pre-randomized 
to the placebo  group in Phase 2 of the study (~11 subjects) 
 
 
Intent-to-Treat (ITT) population 
The Intent-to-Treat (ITT) population is defined as all randomized subjects. The ITT 
population will be the primary population for the analysis of the primary, secondary, and 
additional efficacy endpoints.  
Per Protocol (PP) Population  
The Per Protocol (PP) population is defined as all randomized subjects who were not 
associated with a major protocol violation. This population will be identified before the 
database lock. The PP analysis of primary, secondary and additional endpoints will be 
considered supportive. 
Safety Population 
The Safety population is defined as any subject receiving the treatment after 
randomization. This population will be used for the analysis of safety parameters.  
Covariates  
For efficacy analyses, baseline values will be used as covariates in the analysis models. 
Missing data  
For efficacy evaluation data points missing data will be imputed per the method that will 
be detailed in the SAP for the study.  
Multiple Comparisons and Multiplicity 
This is a two phase Sequential Parallel Comparison Design (SPCD) study.   
A two-stage test (Weighted Z-test approach with fixed weight of 0.5 for each part of the 
study) will be used to combine the data on treatment effects from the two stages of the 
study. This method will address the Type I error rate adjustment to protect the trial wise 
Type I error at the final analysis.  


 
 
For the primary endpoint there will be only one hypothesis testing and there will be no 
Type I error adjustment for testing this endpoint.   
There will also be no Type I error adjustment on the hypotheses testing of the secondary 
endpoints, other than using the Closed Test procedure. 
 
Statistical Methods  
A Statistical Analysis Plan (SAP) will be developed and approved before the database is 
locked. The SAP will present the detailed statistical methodology to be used in analyzing 
the efficacy and safety data from this trial.  Inferential statistics for all inferential statistical 
analysis will be based on a 2 sided test with Type I Error rate of 0.05. 
All the efficacy endpoints presented here will be conducted using both the evaluable and 
ITT populations. All safety analysis will be conducted using the safety population.  
All data collected will be summarized according to the variable type:  
 
Continuous data summaries will include:  
o Number of observations, mean, standard deviation, median, and minimum 
and maximum values.   
o Analysis of Covariance using the stratification factor for inferential statistics.  
 
Categorical data summaries will include: 
o Frequency counts and percentages.  
o Logit model will be used for inferential statistics using the stratification factors 
referenced. 
 
Subject Disposition  
The disposition of all subjects who sign an ICF will be provided. The numbers of subjects 
screened, randomized, re-randomized, completed, and discontinued during the study, as 
well as the reasons for all post-randomization discontinuations will be summarized by 
treatment group.  Disposition and reason for study discontinuation will also be provided 
as a by-subject listing.   
 Demographics and baseline characteristics analysis  


 
 
Demographics and baseline characteristics will be summarized by treatment group using 
appropriate descriptive statistics. 
Concomitant Medications 
Concomitant medications will be summarized separately for the Safety population.  All 
prior and concomitant medications recorded in the case report form will be coded to all 
matching Anatomic Therapeutic Classification codes using the most recent version of 
WHO Drug version.  Descriptive summaries, by treatment group and stage of the study, 
will be prepared using the coded term.  All concomitant medications recorded in the case 
report form will be listed.   
Efficacy Analyses 
Primary Efficacy Analyses 
Primary Analysis of the primary, secondary and additional efficacy endpoints will be 
conducted on the ITT population using SPCD.  
 
Primary Endpoint: Mixed Model Repeated Measures analysis (MMRM)/non-
parametric methods will be used to compare using SPCD the difference between 
the two treatment groups on the primary endpoint depending on the distribution 
of the data. A weight of 50% will be used in pooling the data from Stages 1 and 
2. 
 
Secondary Endpoints: To maintain the trial-wise Type I error rate at 0.05, a 
closed test procedure will be used for the secondary endpoints. The order of the 
endpoints will be pre-specified in the statistical analysis plan prior to database 
lock. A weight of 50% will be used in pooling the data from Stages 1 and 2, using 
SPCD. 
o Continuous data comparisons will be based on Mixed Model Repeated 
Measures (MMRM), if the Normality assumption is met, or a rank –
ANCOVA analysis i.e., an ANCOVA analysis on rank-transformed data 
will be used if the data is not normally distributed.   
o Categorical data comparisons will be based on Logit model.    
 
Additional Efficacy Endpoints: These endpoints are considered exploratory 
endpoints. These additional Efficacy Endpoints will be analyzed using the similar 
methods outlined for the primary and secondary endpoints or additional 


 
 
appropriate methods, if needed. The statistical methods will be detailed in the 
SAP. 
Supportive Analysis  
To assess the consistency of the Primary Analysis results, supportive analysis will be 
conducted using the PP population. Statistical methodology for the supportive analyses 
will be the same as that of the primary analysis, with the exception of the analysis 
population used. The PP population will be used for the supportive analysis while the ITT 
population will be used for the primary analysis.   
Safety Analyses  
Adverse Events  
Adverse events will be coded using MedDRA. Treatment Emergent AE’s (TEAE) are 
defined as events with an onset on or after the first randomized treatment. TEAEs will be 
summarized by treatment group and by stage of the study, System Organ Class, and 
preferred term. The following TEAE summaries will be provided: 
 
TEAEs by severity grade 
 
TEAEs by relationship to study treatment. 
In addition, separate summaries of serious adverse events, and adverse events resulting 
in discontinuation of study treatment will be presented. 
Abnormal Involuntary Movement Scale (AIMS) 
All the data from the AIMS will be listed and the percent change in the total score will 
also be presented.  
Systematic Assessment for Treatment Emergent Effects–Systematic Inquiry 
(SAFTEE-SI)  
All the data from the SAFTEE-SI will be listed and the percent change in the total score 
will also be presented.  
Columbia-Suicide Severity Rating Scale (C-SSRS) 
All the data from C-SSRS will be listed and descriptive summaries will be presented for 
each of the subscales (i.e. Suicidal Ideation and Suicidal Behavior). 
Clinical Laboratory Data 


 
 
All laboratory values will be listed. Laboratory measurements will also be summarized as 
continuous variables and presented by treatment group and time point.  
In addition, changes in vital signs, weight and ECG will be summarized over time. 
 
N. 
PUBLICATION POLICY 
A publication committee will be established by the Principal Investigator, with the 
assistance of the Stanley Center Scientific Advisory Board. The Publication Committee 
will develop a list of publication topics which will be assigned to site investigators for 
writing and analysis. In addition, investigators may submit topics for review by the 
Publication Committee. All publications will be reviewed by the Publication Committee 
for accuracy before submission to peer reviewed journals or scientific meetings. All 
manuscripts should be submitted to the SAB at least 30 days before submission to peer 
reviewed journals. Abstracts should be submitted for review at least 10. 
 
 
 


 
 
O. 
PROTOCOL SIGNATURE PAGE 
 
I have read this protocol and agree to adhere to the requirements. I will provide copies of 
this protocol and all pertinent information to the study personnel under my supervision. I 
will discuss this material with them and ensure they are fully informed regarding the 
conduct of the study according to 21 CFR parts 50, 54, 56 and 812, 45 CFR 46, to GCP 
as described in ICH guideline E6 and to hospital Institutional Review Boards/Ethics 
Committees. 
 
 
 
 
_____________________________ 
 
Clinical Site 
 
 
 
 
_____________________________ 
 
 
_____________________ 
Principal Investigator Signature  
 
 
Date 
 
 
 
_____________________________ 
Principal Investigator  
Printed Name 
 
 
 
 


 
 
P. 
APPENDICES 
APPENDIX 1: SCHEDULE OF EVENTS   
 
 
 
 
 
 
 
 


 
 
 
APPENDIX 2: MGH- FAST ADDITIVE SUMMARY OF TREATMENT 
OF ANTIPSYCHOTIC MEDICATIONS 
 


 
 
 
 
 


 
 
Atypical Antipsychotic Drugs  
Aripiprazole (marketed as Abilify) 
Asenapine Maleate (marketed as Saphris) 
Clozapine (marketed as Clozaril) 
Iloperidone (marketed as Fanapt) 
Lurasidone (marketed as Latuda) 
Olanzapine (marketed as Zyprexa) 
Olanzapine/Fluoxetine (marketed as Symbyax) 
Paliperidone (marketed as Invega) 
Quetiapine (marketed as Seroquel) 
Risperidone (marketed as Risperdal) 
Ziprasidone (marketed as Geodon)  
 
 
Source: http://www.fda.gov/drugs/drugsafety/ucm243903.htm#list 
 
 


 
 
APPENDIX 3: CONCOMITANT MEDICATIONS ALLOWED 
Drug Name or Class 
Episodic 
Use (prn) 
Chronic 
Use 
Restrictions/Comment 
Analgesics 
Y 
Y 
Non-narcotic analgesics are allowed. Medically 
appropriate episodic use of narcotic analgesics is 
allowed for acute medical indications but is limited to 
no more than 3 days for each episode. Chronic NSAID 
use is allowed; tramadol is not allowed. 
Anesthetics, general 
Y 
— 
If procedures requiring general anesthesia are to 
occur/have occurred, please contact MGH CTNI to 
report the medical condition(s). 
Anesthetics, local 
Y 
N 
— 
Anorexics 
N 
N 
— 
Antacids 
Y 
Y 
— 
Antiacne 
Y 
Y 
Topical agents only, including topical antibiotics. 
Isotretinoin (Accutane) is not allowed. 
Antianginal agents 
N 
N 
— 
Antiarrhythmics 
N 
N 
— 
Antiasthma agents 
Y 
Y 
— 
Antibiotics 
Y 
Y 
Chronic use of topical or oral antibiotics for acne is 
allowed, with the exception of the MAOI linezolid 
(Zyvox) and isoniazid, which are not allowed. 
Erythromycin, clarithromycin, rifampin are excluded. 
Anticoagulants 
N 
N 
Warfarin (Coumadin) is not allowed. Antiplatelet 
agents are allowed (see “Antiplatelets”). 
Anticholinergics 
Y 
Y 
Except for scopolamine. 
Anticonvulsants 
N 
YY 
Gabapentin and pregabalin are allowed. Other 
anticonvulsants are not allowed, including lamotrigine 
and carbamazepine. 
Antidepressants 
N 
Y 
Stable (for at least 4 weeks prior to screening), 
ongoing antidepressant therapy is required during the 
course of the study. No dose changes are allowed 
during the study. Monoamine oxidase inhibitors (which 
may have unknown drug-drug interactions) are 
excluded. Concomitant use of trazodone (up to 200mg 
daily) is allowed. Nefazodone is excluded. 


 
 
Antidiarrheal 
preparations 
Y 
N 
Only loperamide HCl (Imodium), bismuth subsalicylate 
(Pepto-Bismol), and kaolin preparations are allowed. 
Antifungals, systemic 
N 
Y 
— 
Antifungals, topical 
Y 
Y 
Ketoconazole and itraconzole are excluded 
Antihistamines 
Y 
Y 
The use of combinations containing pseudoephedrine 
or phenylephrine is not allowed. Combination products 
containing the word nighttime or some synonym 
routinely include a sedating antihistamine and are not 
allowed. Combination products ending in “-D” routinely 
contain a stimulant such as phenylephrine, and the 
appropriate limits above apply to them.  
Anti-hypertensives 
N 
Y 
Diltiazem, verapamil are excluded 
Anti-impotence 
medications 
N 
N 
— 
Anti-inflammatory drugs Y 
Ya 
Indomethacin (Indocin) and systemic corticosteroids 
are not allowed.  
Antifungal 
Y 
Y 
Itraconazole is excluded 
Antimigraine 
Y 
Y 
Triptans are not allowed 
Antinauseants/Antiemeti
cs 
Y 
N 
Phosphoric acid preparations (Emetrol, Emecheck), 
bismuth subsalicylate (Pepto-Bismol), cola syrup, 5-
HT3 receptor antagonists (e.g., ondansetron), and 
prokinetic agents (metoclopramide) are allowed. 
Scopolamine is not allowed (see section on 
antihistamines). 
Antineoplastics/ 
Immunosuppressant 
agents 
N 
Yc 
Interferons, methotrexate, and other 
immunosuppressant agents are not allowed. Call MGH 
CTNI for approval for certain cases in cancer 
remission maintaining therapy. 
Antiobesity/Appetite 
suppressants 
N 
N 
OTC Alli (Xenical), sibutramine (Meridia), and 
phentermine (Adipex-P and others) are not allowed. 
Antiplatelet agents 
N 
Yb 
Aspirin (maximum 325 mg/day) and clopidogrel 
(Plavix) are allowed.  
Antipsoriatic treatments Y 
Y 
Only topical agents are allowed. Acitretin (Soriatane) is 
not allowed. 
Antipsychotics 
N 
Y 
Stable in dosing at least 8 weeks prior to 
randomization is allowed. 


 
 
Antismoking medications N 
Yc 
Varenicline (Chantix) is not allowed. Chronic nicotine 
replacement may be allowed in certain cases after 
review with MGH CTNI. 
Antiviral agents 
Y 
Y 
Only oral or topical agents are allowed. Only acyclovir, 
famciclovir, valacyclovir, penciclovir, docosanal, 
trifluridine, and vidarabine are allowed. 
Amantadine,rimantadine, indinavir, nelfinavir, ritonavir, 
saquinavir are not allowed. Tamiflu (oseltamivir 
phosphate), and Relenza (zanamivir) inhalants are 
permitted for influenza prophylaxis but use is limited to 
a 7- to 14-day course in accordance with prescribing 
information.  Interferons are not allowed.  
Anxiolytics 
Y 
Y 
Chronic, stable treatment with benzodiazepines for 
reasons other than sleep is allowed. Stable dosing at 
least four weeks prior to randomization is required for 
sleep agents. Up to 1mg of benzodiazepine in a 24h 
period can be utilized as needed during the study 
period. 
Benign prostatic 
hyperplasia treatments 
N 
Yb 
Male patients who have symptoms of obstructed 
voiding should not be included in the study. Surgically 
or medically treated patients must be asymptomatic 
and receiving a stable dosage of allowed medications 
(α-1 blockers, finasteride, or dutasteride) for 1 month 
before screening. 
Buspirone 
N 
Y 
Stable in dosing at least four weeks prior to 
randomization is allowed. 
Cough/cold preparations Y 
N 
Use of cough and cold preparations containing 
pseudoephedrine or dextromethorphan is not allowed, 
as are those containing phenylephrine. Combination 
products ending in “-D” routinely contain a stimulant 
such as phenylephrine, and the appropriate limits 
apply to them. (See “Antihistamines”.) 
Diuretics 
Y 
Yb 
Episodic use of diuretics is restricted to treatment of 
premenstrual symptoms. For chronic use, medication 
and dosage should be stable for 1 month before 
screening. 
Dopaminergics 
N 
Y 
Dopamine agonists for restless leg syndrome are 
allowed. Stable in dosing at least four weeks prior to 
randomization is allowed.  


 
 
Gastrointestinal: 
 
H2-blockers/ 
 
proton pump 
inhibitors/ 
 
prokinetic agents 
Y 
Y 
Cimetidine (Tagamet) is not allowed. Metoclopramide 
is not allowed. 
Hormonal 
(noncontraceptive) 
therapies 
N 
Y 
See below. 
Hormone suppressants N 
Yb 
Only finasteride (Proscar) and dutasteride (Avodart) 
are allowed. 
Hormones: reproductive N 
Y 
Systemic hormonal contraceptives (oral contraceptives 
of estrogen and progestin combinations, depot 
injections such as Depo-Provera, the contraceptive 
implant Implanon, or transdermally delivered 
contraceptives such as Ortho Evra) are allowed 
Hormones: thyroid 
N 
Y 
Thyroid hormone replacement is allowed (dosage of 
thyroid medication should be stable for 3 months 
before screening). Therapeutic use for psychiatric 
disorders (e.g., T3 augmentation) is not allowed  
Hypoglycemic agents 
N 
Y 
Oral hypoglycemic agents are allowed. Insulin is not 
allowed 
Hypolipidemics 
N 
Yb 
Ezetimibe (Zetia) is allowed 
Hypolipidemics: 
bile acid sequestrants 
N 
N 
— 
Hypolipidemics: fibrates N 
Yb 
Gemfibrozil and fenofibrate are allowed 
Hypolipidemics: niacin 
N 
N 
Niacin and niacinamide are not allowed 
Hypolipidemics: statins 
N 
Yb 
Lovastatin, simvastatin, pravastatin, atorvastatin, 
fluvastatin, and rosuvastatin are allowed 
Laxatives 
Y 
Ya 
Only fiber-based products and docusate sodium 
(Colace) are allowed 
Lithium 
N 
Y 
Stable dosing at least four weeks prior to 
randomization is allowed. 


 
 
Medications that are 
primarily metabolized by 
CYP2C8 (e.g., 
cerivastatin, paclitaxel, 
repaglinide, sorafenib, 
and torsemide) 
N 
N 
— 
Muscle relaxants 
N 
N 
— 
NMDA receptor 
antagonist 
N 
N 
Memantine is excluded. 
Opioid 
agonists/analgesics 
(e.g., codeine, 
hydrocodone, 
methadone, morphine, 
maperidine, 
propoxyphene) and 
antagonists (e.g., 
naltrexone, naloxone, 
nalmefene) 
N* 
N* 
See section on analgesics for exceptions 
Proton pump inhibitors or 
H2 receptor blockers 
Y 
Y 
— 
Sedatives/hypnotics 
N 
Y 
Ongoing, stable hypnotic therapy (e.g., zolpidem, 
zaleplon, benzodiazepine hypnotics, and low-dose 
trazodone 50-200mg) will be allowed during the course 
of the study. Eszopiclone is not allowed. 
Steroids/systemic 
Y 
N 
Systemic steroid treatment will be allowed only for 
medical emergencies, such as severe allergic 
reactions 
Steroids/topical and 
inhalant 
Y 
Y 
— 
Steroids/intra-articular 
Y 
NA 
— 
Stimulants 
N 
N 
Oral or transdermal methylphenidate, amphetamine 
products or prodrugs, pseudoephedrine, modafinil 
(Provigil), and other medications of same category are 
not allowed 
Vaccines 
Y 
NA 
— 


 
 
a 
If being taken prior to enrolling in the study. 
b 
If being taken for at least 3 months prior to enrolling in the study and the dose has 
been stable for at least 1 month. 
c      If approved by MGH CTNI Medical Monitor5-HT3 = 5-hydroxytryptomine receptor type 3; 
5-HTP = 5-hydroxytryptophan; ACE = angiotensin-converting enzyme; CR = controlled 
release; DHEA = dehydroepiandrosterone; N = no; NA = not applicable; OTC = over the 
counter; PRN = as needed (prorenataT3prorenataT3=triiodothyronine; Y = yes. 
 
 


 
 
APPENDIX 4: LITERATURE CITED 
 
Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kayvoura FK, Khoury MJ, et al. 
Systematic meta-analyses and field synopsis of genetic association studies in 
schizophrenia: the SzGene database. Nature genetics. 2008;40(7):827-34. 
Aronson S1, Dyke CM, Stierer KA, Levy JH, Cheung AT, Lumb PD, Kereiakes DJ, 
Newman MF.  The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, 
sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac 
surgery patients.. Anesth Analg. 2008 Oct;107(4):1110-21. doi: 
10.1213/ane.0b013e31818240db. 
 
Burgdorf J, Zhang XL, Weiss C, Matthews E, Disterhoft JF, Stanton PK, et al. The N-
methyl-D-aspartate receptor modulator GLYX-13 enhances learning and memory, in 
young adult and learning impaired aging rats.  Neurobiology of aging. 2011;32(4):698-
706. 
Carlson MD1, Eckman PM..Review of vasodilators in acute decompensated heart 
failure: the old and the new) J Card Fail. 2013 Jul;19(7):478-93.  
doi: 10.1016 j.cardfail.2013.05.007 
 
Fava M and Davidson KG .Definition and epidemiology of treatment-resistant 
depression.Psychiatr.  Clin North Am 1996. 19:179–200. 
Fava M, Evins AE, Dorer DJ, Schoenfeld DA. The problem of the placebo response in 
clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study 
design approach. PsychotherPsychosom. 2003 May-Jun;72(3):115-27. Review. Erratum 
in: PsychotherPsychosom. 2003 Mar-Apr;73(2):123.  
FDA Drug Safety Communication: Antipsychotic drug labels updated on use during 
pregnancy and risk of abnormal muscle movements and withdrawal symptoms in 
newborns.  Retrieved from 
http://www.fda.gov/drugs/drugsafety/ucm243903.htm#list. 
 
First BM, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV 
Axis I Disorders - Patient Edition (SCID I/P). Biometrics Research Department, New 
York State Psychiatric Institute, 1996. 
Green MF1, Schooler NR, Kern RS, Frese FJ, Granberry W, Harvey PD, Karson CN, 
Peters N, Stewart M, Seidman LJ, Sonnenberg J, Stone WS, Walling D, Stover E, 
Marder SR. Evaluation of functionally meaningful measures for clinical trials of cognition 
enhancement in schizophrenia. Am J Psychiatry. 2011 Apr;168(4):400-7 
Grof P, Duffy A, Cavazzoni P, Grof E, Garnham J, MacDougall M, et al. Is response to 
prophylactic lithium a familial trait? The Journal of Clinical Psychiatry. 2002;63(10):942-
7. 


 
 
Guy W. Clinical Global Impression (CGI) ECDEU Assessment manual for 
Psychopharmacology. Rockville, MD: U.S. Dept Health Education and Welfare 1976. 
Hallak JE, Maia-de-Oliveira JP, Abrao J, Evora PR, Zuardi AW, Crippa JA, Belmonte-de-
Abreu P, Baker GB, Dursun SM Rapid Improvement of Acute Schizophrenia Symptoms 
After Intravenous Sodium Nitroprusside:  A Randomized, Double-blind, Placebo-
Controlled Trial JAMA Psychiatry. 2013;70(7):668-676.  
doi:10.1001 jamapsychiatry.2013.1292 
 
Kay SR, Fiszbein A, Opler LA (1987).  The positive and negative syndrome scale 
(PANSS) for schizophrenia.  Schizophr Bull.  13(2):261-276. 
Kristiansen LV, Patel SA, Haroutunian V, Meador-Woodruff JH. Expression of the NR2B-
NMDA receptor subunit and its Tbr-1/CINAP regulatory proteins in postmortem brain 
suggest altered receptor processing in schizophrenia. Synapse. 2010;64(7):495-502. 
Lahti, AC, Holcomb HH, Medoff DR, Tamminga CA. Ketamine activastes psychosis and 
alters limibic blood flow in schizophrenia. Neuroreport. 1995;6:869-72. 
Levine J and Schooler NR. SAFTEE: a technique for the systematic assessment of side 
effects in clinical trials. Psychopharmacol Bull 1986. 22(2):343-81.  
Liu et al. On efficiency of constrained longitudinal data analysis versus longitudinal 
analysis of covariance.   Biometrics 2010 Sep;66(3):891-6.  
Machado-Vieira, R., Salvadore, G., DiazGranados, N., & Zarate Jr, C. A. (2009). 
Ketamine and the next generation of antidepressants with a rapid onset of action. 
Pharmacology & therapeutics, 123(2), 143-150. 
 
Mausbach BT, Harvey PD, Goldman SR, Jeste DV, Patterson TL. Development of a 
Brief Scale of Everyday Functioning in Persons with Serious Mental Illness Schizophr 
Bull. 2007 November; 33(6): 1364–1372. Published online 2007 March 6 
Mohn A, Gainetdinov P, Caron M, Koller B. Mice with reduced NMDA receptor 
expression display behaviors related to schizophrenia. Cell. 1999;98:427-36. 
Nitropress Package Insert. (16 January 2014), from 
http://medlibrary.org/lib/rx/meds/nitropress/ 
 
Nong Y, Huang YG, Ju W, Kalia LV, Ahmadian G, Wang YT, et al. Glycine binding 
primes NMDA receptor internalization.  Nature. 2003;422(6929):302-7. 
Nuechterlein KH, Green MF, Kern RS, et al. The MATRICS Consensus Cognitive 
Battery, Part 1: Test Selection, Reliability, and Validity Am J Psychiatry 2008;165:203-
213. doi:10.1176/appi.ajp.2007.07010042 
 


 
 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M (2007).  Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's 
pediatric suicidal risk analysis of antidepressants.  Am J Psychiatry.  164(7):1035-1043. 
Riezen HV, Segal M Comparative evaluation of rating scales for clinical 
psychopharmacology. Amsterdam; New York: Elsevier. 1988: 123-334; 483-458. 
Roitberg BZ1, Hardman J, Urbaniak K, Merchant A, Mangubat EZ, Alaraj A, Mlinarevich 
N, Watson KS, Ruland S.  Retrospective randomized comparison of safety and efficacy 
of nicardipine and nitroprusside drip for control of hypertension in the neurosurgical 
intensive care unit.. Neurosurgery. 2008 Jul;63(1):115-20; discussion 120-1. doi: 
10.1227/01.NEU.0000335078.62599.14. 
 
Rudzinski W1, Waller AH, Rusovici A, Dehnee A, Nasur A, Benz M, Sanchez S, 
Klapholz M, Kaluski E. Comparison of efficacy and safety of intracoronary sodium 
nitroprusside and intravenous adenosine for assessing fractional flow reserve. Catheter 
Cardiovasc Interv. 2013 Feb;81(3):540-4. doi: 10.1002/ccd.24652. Epub 2012 Oct 15. 
 
Schoenfeld, D., & Ivanova, A. RCT Logic Calculator, from 
http://www.rctlogic.com/calculator/calculator-continuous.aspx 
 
Targum SD, Pollack MH, Fava M.  Redefining affective disorders: relevance for drug 
development. CNS Neurosci Ther. 2008 Spring;14(1):2-9. 
 
Thirlet, N., Aunis, D., & Zwiller, J. (2002). The Nitric Oxide Releasing Agent Sodium 
Nitroprusside Modulates Cocaine‐Induced Immediate Early Gene Expression in 
Rat Brain. Annals of the New York Academy of Sciences, 965(1), 47-54.  
 
Thomas, C., Svehla, L., & Moffett, B. S. (2009). Sodium nitroprusside induced cyanide 
toxicity in pediatric patients.  
 
Wang CC, Held RG, Chang SC, Yang L, Delpire E, Ghosh A, et al. A critical role for 
GluN2B-containing NMDA receptors in cortical development and function. Neuron. 
2011;72(5):789-805. 
 
 
 


 
 
APPENDIX 5: STUDY SCALES 
 
The Positive and Negative Syndrome Scale (PANSS) 
Link: http://www.emotionalwellbeing.southcentral.npanss-positive-and-negative-
syndrome-scale-pdf-document. 
 
Clinical 
Global 
Impressions–Severity 
(CGI-S) 
and 
Clinical 
Global 
Impressions–Improvement (CGI-I) Scales 
Link: http://miksa.ils.unc.edu/unc-hit/media/CGI.pdf 
 
Abnormal Involuntary Movement Scale (AIMS) 
Link: http://www.atlantapsychiatry.com/forms/AIMS.pdf 
 
Systematic Assessment for Treatment Emergent Effects–Systematic 
Inquiry (SAFTEE-SI)  
Link: https://www.cognitiongroup.com/pdf/aims.pdf 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Link: http://cssrs.columbia.edu/docs/C-SSRS_1_14_09_Baseline.pdf 
 
The Measurement and Treatment Research to Improve Cognition in 
Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) 
Link:  MATRICS Consensus Cognitive Battery (MCCB) 
 
The University of California San Diego (UCSD) Performance-based Skills 
Assessment Brief  (UPSA-B) 
http://www.researchgate.net/UPSA_B 

SAP_001.pdf: 
 
 
 
A Randomized Double-Blind, Placebo-Controlled, Proof of 
Concept Study of Intravenous Sodium Nitroprusside in 
Adults with Symptomatic Schizophrenia 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
PRINCIPAL INVESTIGATORS, Coordinating Center: Maurizio Fava, MD 
 
Roy Perlis, MD, MSc 
 
 
 
 
 
Funding Provided by: 
Stanley Medical Research Institute 
 
 
 
 
This protocol is the confidential property of MGH CTNI and is intended solely for 
the guidance of this clinical investigation. This protocol may not be disclosed to 
parties not associated with the clinical investigation or used for any other 
purpose without the prior written consent of MGH CTNI. 
 
Clinical Trials.gov registry: NCT02164981 
 
 


 
 
DATA ANALYSIS 
This section presents general information about statistical considerations and concepts such as 
randomization, stratification, statistical power, sample size, and a brief discussion on analysis 
methodology.  
 
Treatment Groups  
The following treatment groups will be assessed: 
Table 4. Study Treatments 
Group 
Description 
Test Treatment  
Sodium Nitroprusside (0.5 μg/kg/min  for 4 hours) 
Control Treatment  
Placebo (5% dextrose for 4 hours) 
 
Description of Study Endpoints  
Primary Efficacy Endpoint 
 Mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total score 
after 2 weeks of randomized treatment using SPCD. 
 
Secondary Efficacy Endpoints 
 Percent change from baseline in the PANSS total score after 2 weeks of treatment using 
SPCD 
 Percentage of subjects with 20% or more reduction from baseline in PANSS total score after 
2 weeks of treatment using SPCD 
 Percent change in PANSS subscales using SPCD 
 
Additional Efficacy Endpoints 
 Percent change in Clinical Global Impression-Severity (CGI-S) using SPCD 
 Percent change in MATRICS Consensus Cognitive Battery (MCCB) using SPCD 
 
Safety Assessments 
 Incidence of Treatment-Emergent Adverse Events (TEAE) 


 
 
 Incidence of withdrawals from the study due to TEAEs 
 Percent change in Abnormal Involuntary Movement Scale (AIMS) 
 Percent change in Systematic Assessment for Treatment Emergent Effects–Systematic 
Inquiry (SAFTEE-SI) 
 Assessment of suicidality per the Columbia-Suicide Severity Rating Scale (C-SSRS) 
 Changes in blood pressure and heart rate  
 Changes in electrocardiogram (ECG) parameters  
 
Sample Size Determination and Rationale 
Sixty (60) subjects will be randomized in an effort to assure that 48 subjects complete the study. 
The 
RCT 
Logic 
Calculator 
(by 
Schoenfeld, 
D 
and 
Ivanova,A; 
http://www.rctlogic.com/calculator/calculator-continuous.aspx) was used for this sample size 
calculation. This sample size will provide “sufficient” statistical power for the selected primary 
endpoint. The sample size calculation is based on the assumption that there is a clinically 
meaningful weighted (50%) average difference of 10 points (9 points in Stage 1 and 11 points in 
Stage 2) between sodium nitroprusside and placebo group accordingly, (with standard deviation 
of 14) in PANSS total scores after 2 weeks of treatment between the two treatment groups. This 
power calculation is based on a 20% attrition by Week 4 and 30% placebo response at the end 
of Stage 1. Under the above assumptions, 60 subjects will be required to meet the Type I error 
rate of 0.05 and an 81% power.  
Randomization 
This is a double-blind, placebo-controlled, multi-center, randomized clinical trial. Subjects who 
have provided written informed consent and have met all the inclusion criteria and have met none 
of the exclusion criteria will be randomized to one of the three treatment sequences.  
The study design contains two double-blind treatment phases (i.e. Phase 1 and Phase 2) of the 
same duration of two weeks. Subjects will be randomly assigned using stratified block 
randomization. The randomization scheme will be programmed in to the CTMS software and will 
generate a randomization code for each subject upon enrollment into the study. Subjects will be 
stratified by primary treatment status (clozapine, versus antipsychotic other than clozapine) and 
by site. The number of subjects taking clozapine will be restricted to 20 study wide. 
Blinding and prevention of Bias 
All subjects, Investigators and their staff involved in the management of the study will be blinded 
to treatment assignments.  


 
 
Treatment unblinding for the study will occur after all clinical data have been received, data 
inconsistencies have been resolved, and the database is locked, except for safety reasons on a 
case by case basis (i.e., emergency unblinding).  
Interim Analysis  
There will be no interim analysis for this trial.  
General Statistical Considerations  
All collected study data will be presented in subject data listings. Statistical analyses will be 
performed using SAS® for Windows, version 9.3 or later. Descriptive statistics (n, mean, standard 
deviation, median, minimum and maximum) will be calculated by treatment group for continuous 
variables. Frequencies and percentages will be presented by treatment group for categorical 
variables. 
 
Analysis Populations  
The details of the analysis population to be used for the study are described in the below sections. 
All the subjects who were randomized in the study will be considered for analysis. For the primary 
and secondary endpoint analyses the following set of subject will be accounted:  
 
All subjects randomized to the sodium nitroprusside group in Phase 1 of the study (~ 20 
subjects) 
 
All subjects randomized to the Placebo group in Phase 1 of the study (~ 40 subjects) 
 
All subjects who did not respond to placebo in Phase 1 and were pre-randomized to the 
sodium nitroprusside  group in Phase 2 of the study (~11 subjects) 
 
All subjects who did not respond to placebo in Phase 1 and were pre-randomized to the 
placebo  group in Phase 2 of the study (~11 subjects) 
 
 
Intent-to-Treat (ITT) population 
The Intent-to-Treat (ITT) population is defined as all randomized subjects. The ITT population will 
be the primary population for the analysis of the primary, secondary, and additional efficacy 
endpoints.  


 
 
Per Protocol (PP) Population  
The Per Protocol (PP) population is defined as all randomized subjects who were not associated 
with a major protocol violation. This population will be identified before the database lock. The PP 
analysis of primary, secondary and additional endpoints will be considered supportive. 
Safety Population 
The Safety population is defined as any subject receiving the treatment after randomization. This 
population will be used for the analysis of safety parameters.  
Covariates  
For efficacy analyses, baseline values will be used as covariates in the analysis models. 
Missing data  
For efficacy evaluation data points missing data will be imputed per the method that will be 
detailed in the SAP for the study.  
Multiple Comparisons and Multiplicity 
This is a two phase Sequential Parallel Comparison Design (SPCD) study.   
A two-stage test (Weighted Z-test approach with fixed weight of 0.5 for each part of the study) will 
be used to combine the data on treatment effects from the two stages of the study. This method 
will address the Type I error rate adjustment to protect the trial wise Type I error at the final 
analysis.  
For the primary endpoint there will be only one hypothesis testing and there will be no Type I error 
adjustment for testing this endpoint.   
There will also be no Type I error adjustment on the hypotheses testing of the secondary 
endpoints, other than using the Closed Test procedure. 
 
Statistical Methods  
A Statistical Analysis Plan (SAP) will be developed and approved before the database is locked. 
The SAP will present the detailed statistical methodology to be used in analyzing the efficacy and 
safety data from this trial.  Inferential statistics for all inferential statistical analysis will be based 
on a 2 sided test with Type I Error rate of 0.05. 


 
 
All the efficacy endpoints presented here will be conducted using both the evaluable and ITT 
populations. All safety analysis will be conducted using the safety population.  
All data collected will be summarized according to the variable type:  
 
Continuous data summaries will include:  
o Number of observations, mean, standard deviation, median, and minimum and 
maximum values.   
o Analysis of Covariance using the stratification factor for inferential statistics.  
 
Categorical data summaries will include: 
o Frequency counts and percentages.  
o Logit model will be used for inferential statistics using the stratification factors 
referenced. 
 
Subject Disposition  
The disposition of all subjects who sign an ICF will be provided. The numbers of subjects 
screened, randomized, re-randomized, completed, and discontinued during the study, as well as 
the reasons for all post-randomization discontinuations will be summarized by treatment group.  
Disposition and reason for study discontinuation will also be provided as a by-subject listing.   
 Demographics and baseline characteristics analysis  
Demographics and baseline characteristics will be summarized by treatment group using 
appropriate descriptive statistics. 
Concomitant Medications 
Concomitant medications will be summarized separately for the Safety population.  All prior and 
concomitant medications recorded in the case report form will be coded to all matching Anatomic 
Therapeutic Classification codes using the most recent version of WHO Drug version.  Descriptive 
summaries, by treatment group and stage of the study, will be prepared using the coded term.  All 
concomitant medications recorded in the case report form will be listed.   
 
Efficacy Analyses 
Primary Efficacy Analyses 


 
 
Primary Analysis of the primary, secondary and additional efficacy endpoints will be conducted 
on the ITT population using SPCD.  
 
Primary Endpoint: Mixed Model Repeated Measures analysis (MMRM)/non-parametric 
methods will be used to compare using SPCD the difference between the two treatment 
groups on the primary endpoint depending on the distribution of the data. A weight of 50% 
will be used in pooling the data from Stages 1 and 2. 
 
Secondary Endpoints: To maintain the trial-wise Type I error rate at 0.05, a closed test 
procedure will be used for the secondary endpoints. The order of the endpoints will be 
pre-specified in the statistical analysis plan prior to database lock. A weight of 50% will be 
used in pooling the data from Stages 1 and 2, using SPCD. 
o Continuous data comparisons will be based on Mixed Model Repeated Measures 
(MMRM), if the Normality assumption is met, or a rank –ANCOVA analysis i.e., an 
ANCOVA analysis on rank-transformed data will be used if the data is not normally 
distributed.   
o Categorical data comparisons will be based on Logit model.    
 
Additional Efficacy Endpoints: These endpoints are considered exploratory endpoints. 
These additional Efficacy Endpoints will be analyzed using the similar methods outlined 
for the primary and secondary endpoints or additional appropriate methods, if needed. 
The statistical methods will be detailed in the SAP. 
Supportive Analysis  
To assess the consistency of the Primary Analysis results, supportive analysis will be conducted 
using the PP population. Statistical methodology for the supportive analyses will be the same as 
that of the primary analysis, with the exception of the analysis population used. The PP population 
will be used for the supportive analysis while the ITT population will be used for the primary 
analysis.   
Safety Analyses  
Adverse Events  
Adverse events will be coded using MedDRA. Treatment Emergent AE’s (TEAE) are defined as 
events with an onset on or after the first randomized treatment. TEAEs will be summarized by 
treatment group and by stage of the study, System Organ Class, and preferred term. The following 
TEAE summaries will be provided: 


 
 
 
TEAEs by severity grade 
 
TEAEs by relationship to study treatment. 
In addition, separate summaries of serious adverse events, and adverse events resulting in 
discontinuation of study treatment will be presented. 
Abnormal Involuntary Movement Scale (AIMS) 
All the data from the AIMS will be listed and the percent change in the total score will also be 
presented.  
Systematic Assessment for Treatment Emergent Effects–Systematic Inquiry (SAFTEE-
SI)  
All the data from the SAFTEE-SI will be listed and the percent change in the total score will also 
be presented.  
Columbia-Suicide Severity Rating Scale (C-SSRS) 
All the data from C-SSRS will be listed and descriptive summaries will be presented for each of 
the subscales (i.e. Suicidal Ideation and Suicidal Behavior). 
Clinical Laboratory Data 
All laboratory values will be listed. Laboratory measurements will also be summarized as 
continuous variables and presented by treatment group and time point.  
In addition, changes in vital signs, weight and ECG will be summarized over time.