A Proof of Concept Study of Intravenous Sodium Nitroprusside in Adults With Symptomatic Schizophrenia

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT02164981
• Collaborator: Stanley Medical Research Institute (Other)
• Enrollment: 60
• Locations: 4
• Arms: 3
• Duration (Months): 23.2
• Patients Per Site: 15
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: sodium nitroprusside; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized Double-Blind, Placebo-Controlled, Proof of Concept Study of Intravenous Sodium Nitroprusside in Adults With Symptomatic Schizophrenia
• Study Start Date: May 1, 2015
• Actual Primary Completion Date: Mar 31, 2017
• Actual Study Completion Date: Apr 5, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Drug - Drug Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside	Drug: sodium nitroprusside; intravenous; Other Names: Nitropress
Other: Placebo - Drug Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside	Drug: sodium nitroprusside; intravenous; Other Names: Nitropress
Placebo Comparator: Placebo - Placebo Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose	Other: Placebo; Placebo; Other Names: 5% dextrose

Outcome Measures

Primary Outcome Measures

1. Change in Positive and Negative Syndrome Scale (PANSS) - Total Score - Study Phases 1 and 2 [For Phase 1, timeframe is Day 0 and Day 14; Phase 2 timeframe is Day 14 and Day 28]

   The Positive and Negative Syndrome Scale (PANSS) 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. Total score minimum = 30, maximum = 210

Secondary Outcome Measures

1. PANSS - Positive Subscale - Phases 1 and 2 [Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28]

   The Positive and Negative Syndrome Scale (PANSS) 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. Positive scale: 7 Items, (minimum score = 7, maximum score = 49)

2. PANSS - Negative Subscale - Phases 1 and 2 [Phase 1 timeframe is Day 0 and Day 14; Phase 2 timeframe is Day 14 and Day 28]

   The Positive and Negative Syndrome Scale (PANSS) 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. Negative scale: 7 Items, (minimum score = 7, maximum score = 49)

3. PANSS - General Psychopathology Subscale - Phases 1 and 2 [Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28]

   The Positive and Negative Syndrome Scale (PANSS) 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. General Psychopathology Subscale: 16 Items, (minimum score = 16, maximum score = 112)

4. Average Percent Change From Baseline in the PANSS Total Score After 2 Weeks of Treatment Using SPCD [For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28]

   The Positive and Negative Syndrome Scale (PANSS) 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. Total score minimum = 30, maximum = 210.

5. Percentage of Subjects With 20% or More Reduction From Baseline in PANSS Total Score After 2 Weeks of Treatment Using SPCD [For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28]

   The Positive and Negative Syndrome Scale (PANSS) 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. Total score minimum = 30, maximum = 210.

6. Average Percent Change From Baseline in the PANSS Positive Subscale Score After 2 Weeks of Treatment Using SPCD [For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28]

   The Positive and Negative Syndrome Scale (PANSS) 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. Positive subscore scale: 7 items (minimum score = 7; maximum score = 49)

7. Average Percent Change From Baseline in the PANSS Negative Subscale Score After 2 Weeks of Treatment Using SPCD [For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28]

   The Positive and Negative Syndrome Scale (PANSS) 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. Negative subscore scale: 7 items (minimum score = 7; maximum score = 49)

8. Average Percent Change From Baseline in the PANSS General Psychopathology Subscale Score After 2 Weeks of Treatment Using SPCD [For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28]

   The Positive and Negative Syndrome Scale (PANSS) 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. General Psychopathology subscore scale: 16 items (minimum score = 16; maximum score = 112)

Other Outcome Measures

1. Change in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) - Phases 1 and 2 [Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28]

   MATRICS: The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). 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 composite score represents a global measure of cognition. MCCB composite T scores are between 40 and 60 (normal range) and < 40 (below normal range).

2. Average AIMS Total Scores (Items 1-7) by Group and Timepoint [Baseline 1 (Day -1), 7 Hours Post-Infusion 1, Baseline 2 (Day 13), 7 Hours Post-Infusion 2, Final Follow-Up, including early termination visits]

   Abnormal Involuntary Movement Scale (AIMS): The AIMS Total Dyskinesia Score was calculated by averaging the first 7 items of the AIMS. The 7 items included in the AIMS Dyskinesia Score are rated on a scale from 0 (no dyskinesia) to 4 (severe dyskinesia). Items 1 through 7 include facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). The AIMS dyskinesia total score ranges from 0 to 4; a higher score reflects increased severity.

3. Percent of Participants Rated as ≥ "Mild" or as "Yes" on AIMS Items 8-12 [Baseline (Day -1), Follow-Up = reported at any assessment thereafter, including 7 hours after Infusions #1 and #2, Baseline 2 (Day 13) and final follow-up, including early termination visits.]

   Abnormal Involuntary Movement Scale (AIMS): The AIMS is a 12-item anchored score that is clinician administered and scored. Items are scored on a 0 (none) to 4 (severe) basis; items 8-10 deal with global severity; items 11-12 are yes-no questions concerning problems with teeth and/or dentures.

4. Change in The University of California San Diego (UCSD) Performance-based Skills Assessment Brief (UPSA-B) - Phases 1 and 2 [Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28]

   The University of California San Diego (UCSD) Performance-based Skills Assessment Brief (UPSA-B) consists of two of the five original UPSA domains, finances and communication. Each subscale contributes 50 points; total scores range from 0 to 100 points with higher scores reflecting better performance.

5. Number of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS) [Screening Visit, Days 3 (Baseline 1), Days 7, 13 (Baseline 2), 21 and 28]

   The Columbia Suicide Severity Rating Scale (C-SSRS): 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 or improvement. It contains 5 rating scale questions (yes/no) for suicidal ideation increasing severity and 5 rating scale questions (yes/no) for suicidal behavior of increasing severity. The time frame is for both lifetime and the past six months for the Baseline/Screening scale and since the last visit for the Since Last Visit scale.

6. Systolic Blood Pressure Per Infusion Phase by Group [Day 0 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours]

   Infusion 1 (Day 0) - Systolic Blood Pressure at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.

7. Diastolic Blood Pressure Per Infusion Phase by Group [Day 0 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours]

   Infusion 1 (Day 0) - Diastolic Blood Pressure at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.

8. Systolic Blood Pressure Per Infusion Phase by Group [Day 14 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours]

   Infusion 2 (Day 14) - Systolic Blood Pressure at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.

9. Phase 2 - Diastolic Blood Pressure Per Infusion Phase by Group [Day 14 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours]

   Infusion 2 (Day 14) - Diastolic Blood Pressure at all time points by group

10. Heart Rate Per Infusion Phase by Group [Day 0 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours]

    Infusion 1 (Day 0) - Heart rate at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.

11. Heart Rate Per Infusion Phase by Group [Day 14 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours]

    Infusion 2 (Day 14) - Heart rate at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.

12. ECG Measures at All Time Points by Group [Day 0 - Baseline (pre-infusion), During Infusion (@30 min), Post-Infusion (@60min)]

    Infusion 1 (Day 0) - ECG measures at all time points by group

13. ECG Measures at All Time Points by Group [Day 14 - Baseline (pre-infusion), During Infusion (@30 min), Post-Infusion (@60min)]

    Infusion 2 (Day 14) - ECG measures at all time points by group

14. Incidence of Treatment-Emergent Adverse Events (TEAEs) [The period of observation for collection of treatment-emergent adverse events extends from Day 0 treatment through the final visit at Day 28.]

    Incidence of Treatment-Emergent Adverse Events (TEAE) by Treatment Group. 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.

15. Number of Subject Withdrawals Due to Treatment-Emergent Adverse Events (TEAEs) [The period of observation extends from Day 0 treatment through the final visit at Day 28]

    Incidence of Treatment-Emergent Adverse Events (TEAE) by Treatment Group. 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.

16. Systematic Assessment for Treatment Emergent Effects-Systematic Inquiry (SAFTEE-SI) - Percent of Participants Reporting Experiencing Symptoms at "Moderate" or "Severe" Level for the 10 Most Frequently Reported Symptoms Post Randomization [Baseline (Day - 1), Follow-Up = reported at any assessment thereafter, including 7 hours after Infusions #1 and #2, Baseline 2 (Day 13) and final follow-up, including early termination visits.]

    The Systematic Assessment for Treatment Emergent Effects-Systematic Inquiry (SAFTEE-SI): This is a self-rated 77-item questionnaire organized into 13 body areas assessing possible adverse events during the course of the trial.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Schizophrenia Clinical Research Program, Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	University of Massachusetts Medical School	Worcester	Massachusetts	United States	01605
3	Zucker Hillside Hospital	Glen Oaks	New York	United States	11004
4	New York University Langone Medical Center/Bellevue Hospital	New York	New York	United States	10016

Sponsors and Collaborators

• Massachusetts General Hospital
• Stanley Medical Research Institute

Investigators

• Principal Investigator: Maurizio Fava, MD, Massachusetts General Hospital
• Principal Investigator: Roy Perlis, MD MSc, Massachusetts General Hospital

Study Documents (Full-Text)

• Study Protocol - Dec 1, 2016
• Statistical Analysis Plan - Dec 1, 2016

More Information

Publications

None provided.

• Responsible Party: Maurizio Fava, MD, Director, Clinical Research Program, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02164981
• Other Study ID Numbers: 2014P001204; NCT02695589
• First Posted: Jun 17, 2014
• Last Update Posted: Oct 2, 2018
• Last Verified: Sep 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Schizophrenia; Nitroprusside

Study Results

Participant Flow

Pre-assignment Detail	Per the Sequential Parallel Comparison Design, the 18 subjects in the SNP-SNP group were excluded from Phase 2 analyses. There were no Phase 1 placebo responders, so no exclusions were made based on this SPCD criterion. Ph 1 (N=52): all groups; Ph 2 (N=34): (Placebo)-Placebo (N=18), (SNP)-Placebo (N=16). All subjects were followed for 28 days.

Arm/Group Title	Drug - Drug	Placebo - Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium Nitroprusside (Drug) Phase 2 - intravenous sodium Nitroprusside (Drug) Subjects will receive i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at Day 0 (Phase 1) and Day 14 (Phase 2)	Phase 1 - intravenous dextrose (Placebo) Phase 2 - intravenous sodium Nitroprusside (Drug) Subjects will receive i.v. placebo (intravenous dextrose) at Day 0 (Phase 1) and i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at Day 14 (Phase 2)	Phase 1 - intravenous dextrose (Placebo) Phase 2 - intravenous dextrose (Placebo) Subjects will receive i.v. placebo (intravenous dextrose) at Day 0 (Phase 1) and again at Day 14 (Phase 2).
Period Title: Started
STARTED	23	19	18
COMPLETED	18	16	18
NOT COMPLETED	5	3	0
Period Title: Started
STARTED	18	16	18
COMPLETED	18	14	18
NOT COMPLETED	0	2	0
Period Title: Started
STARTED	18	14	18
COMPLETED	16	12	18
NOT COMPLETED	2	2	0

Baseline Characteristics

Arm/Group Title	Drug - Drug	Placebo - Drug	Placebo - Placebo	Total
Arm/Group Description	Phase 1 - intravenous sodium Nitroprusside (Drug) Phase 2 - intravenous sodium Nitroprusside (Drug) Subjects will receive i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at Day 0 (Phase 1) and Day 14 (Phase 2)	Phase 1 - intravenous dextrose (Placebo) Phase 2 - intravenous sodium Nitroprusside (Drug) Subjects will receive i.v. placebo (intravenous dextrose) at Day 0 (Phase 1) and i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at Day 14 (Phase 2)	Phase 1 - intravenous dextrose (Placebo) Phase 2 - intravenous dextrose (Placebo) Subjects will receive i.v. placebo (intravenous dextrose) at Day 0 (Phase 1) and again at Day 14 (Phase 2).	Total of all reporting groups
Overall Participants	18	16	18	52
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.1 (10.5)	45.9 (12.3)	40.4 (11.0)	44.5 (11.3)
Sex: Female, Male (Count of Participants)
Female	4 22.2%	4 25%	4 22.2%	12 23.1%
Male	14 77.8%	12 75%	14 77.8%	40 76.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5.6%	1 6.3%	2 11.1%	4 7.7%
Not Hispanic or Latino	17 94.4%	15 93.8%	16 88.9%	48 92.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	10 55.6%	9 56.3%	6 33.3%	25 48.1%
Black	6 33.3%	5 31.3%	11 61.1%	22 42.3%
Asian	1 5.6%	2 12.5%	1 5.6%	4 7.7%
Other	1 5.6%	0 0%	0 0%	1 1.9%
Region of Enrollment (Count of Participants)
United States	18 100%	16 100%	18 100%	52 100%
The Positive and Negative Syndrome Scale (PANSS) at Baseline (Day 3) (units on a scale) [Mean (Standard Deviation) ]
PANSS -total	83.6 (10.0)	77.6 (8.8)	81.7 (8.8)	80.9 (9.2)
PANSS - positive	24.9 (3.5)	22.3 (3.4)	22.6 (3.1)	23.26 (3.3)
PANSS - negative	20.9 (5.5)	20.3 (5.0)	21.4 (4.6)	20.8 (15.1)

Outcome Measures

1. Primary Outcome

Title	Change in Positive and Negative Syndrome Scale (PANSS) - Total Score - Study Phases 1 and 2
Description	The Positive and Negative Syndrome Scale (PANSS) 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. Total score minimum = 30, maximum = 210
Time Frame	For Phase 1, timeframe is Day 0 and Day 14; Phase 2 timeframe is Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Ph 1 analysis includes 34 subjects with Baseline PANSS data in the Placebo-Placebo (N=18) and Placebo-Drug (N=16) groups and 18 Drug-Drug group subjects. Per SPCD, the Ph 2 data excludes 18 Drug-Drug group subjects and includes the 14 subjects in the Placebo-Drug group and 18 subjects in the Placebo-Placebo group with PANSS Baseline data.

Arm/Group Title	Drug	Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	32	34
Phase 1 - Total Score - Baseline	83.6 (10.0)	79.8 (8.9)
Phase 1 - Total Score - Day 14	77.6 (12.2)	76.7 (11.0)
Phase 1 - Total Score - Change	-6.0 (11.3)	-2.5 (7.1)
Phase 2 - Total Score - Day 14	74.0 (12.0)	78.8 (10.1)
Phase 2 - Total Score - Day 28	71.8 (10.6)	74.7 (9.0)
Phase 2 - Total Score - Change	-1.8 (8.2)	-4.2 (6.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Drug, Placebo
	Comments	Given the sequential parallel comparison design (SPCD), we used a two-stage test (weighted z-test, Tamura approach: CHANGE_score = BASELINE_value + GROUP (i.e., SNP vs. placebo)) to combine the data on treatment effects from phases 1 and 2 (weighted equally). Assessments were on Day -1 (phase 1 baseline), Day 13 (phase 1 outcome, phase 2 baseline) and Day 28 (phase 2 outcome). Only participants who at least started the infusion were included in analysis (i.e., modified intent to treat).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments	No adjustment for multiple comparisons, as there was only one primary outcome variable.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.04
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Drug, Placebo
	Comments	The same analysis as in Analysis 1 was conducted, except that CLOZAPINE (i.e., patient used clozapine vs. other antipsychotic) was added as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.54
	Comments	No adjustment for multiple comparisons, as there was only one primary outcome variable.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.09
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	PANSS - Positive Subscale - Phases 1 and 2
Description	The Positive and Negative Syndrome Scale (PANSS) 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. Positive scale: 7 Items, (minimum score = 7, maximum score = 49)
Time Frame	Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Ph 1 analysis includes the 34 subjects with Baseline PANSS data in the Placebo-Placebo (N=18) and Placebo-Drug (N=16) groups and 22 Drug-Drug group subjects. Per SPCD, the Ph 2 data excludes the 18 Drug-Drug group subjects and includes the 14 subjects in the Placebo-Drug group and 18 subjects in the Placebo-Placebo group with PANSS Baseline data.

Arm/Group Title	Drug	Placebo
Arm/Group Description	Phase 1 - intravenous sodium Nitroprusside or placebo Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	32	34
Phase 1 - Positive Score - Baseline	24.5 (3.5)	22.3 (3.1)
Phase 1 - Positive Score - Day 14	23.1 (4.6)	21.3 (3.6)
Phase 1 - Positive Score - Change	-1.8 (1.8)	-0.81 (2.7)
Phase 2 - Positive Score - Day 14	20.7 (3.6)	21.8 (3.6)
Phase 2 - Positive Score - Day 28	21.3 (4.6)	22.3 (3.4)
Phase 2 - Positive Score - Change	0.5 (3.8)	0.5 (2.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Drug, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.35
	Comments	Exploratory efficacy outcome, hence no adjustment for multiple comparison.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Drug, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments	Exploratory efficacy outcome, hence no adjustment for multiple comparisons
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	PANSS - Negative Subscale - Phases 1 and 2
Description	The Positive and Negative Syndrome Scale (PANSS) 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. Negative scale: 7 Items, (minimum score = 7, maximum score = 49)
Time Frame	Phase 1 timeframe is Day 0 and Day 14; Phase 2 timeframe is Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Ph 1 analysis includes the 34 subjects with Baseline PANSS data in the Placebo-Placebo (N=18) and Placebo-Drug (N=16) groups and 18 Drug-Drug group subjects. Per SPCD, the Ph 2 data excludes the 18 Drug-Drug group subjects and includes the 14 subjects in the Placebo-Drug group and 18 subjects in the Placebo-Placebo group with PANSS Baseline data.

Arm/Group Title	Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	32	34
Phase 1 - Negative Score - Baseline	20.8 (5.8)	20.6 (4.8)
Phase 1 - Negative Score - Day 14	19.0 (4.6)	19.7 (5.1)
Phase 1 - Negative Score - Change	-1.8 (4.1)	-1.0 (2.8)
Phase 2 - Negative Score - Day 14	18.5 (5.8)	20.7 (4.4)
Phase 2 - Negative Score - Day 28	18.0 (6.2)	19.8 (4.7)
Phase 2 - Negative Score - Change	-0.1 (0.9)	-0.9 (2.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Drug, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.85
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Drug, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	PANSS - General Psychopathology Subscale - Phases 1 and 2
Description	The Positive and Negative Syndrome Scale (PANSS) 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. General Psychopathology Subscale: 16 Items, (minimum score = 16, maximum score = 112)
Time Frame	Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Ph 1 analysis includes the 34 subjects with Baseline PANSS data in the Placebo-Placebo (N=18) and Placebo-Drug (N=16) groups and 18 Drug-Drug group subjects. Per SPCD, the Ph 2 data excludes the 18 Drug-Drug group subjects and includes the 14 subjects in the Placebo-Drug group and 18 subjects in the Placebo-Placebo group with PANSS Baseline data.

Arm/Group Title	Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	32	34
Phase 1 - General Score - Baseline	37.6 (6.0)	36.4 (5.1)
Phase 1 - General Score - Day 14	35.3 (7.1)	35.5 (6.4)
Phase 1 - General Score - Change	-2.2 (7.0)	-0.6 (3.9)
Phase 2 - General Score - Day 14	34.7 (6.4)	36.2 (6.6)
Phase 2 - General Score - Day 28	32.4 (5.6)	32.4 (5.3)
Phase 2 - General Score - Change	-2.1 (5.2)	-3.7 (4.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Drug, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.86
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Drug, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.83
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Average Percent Change From Baseline in the PANSS Total Score After 2 Weeks of Treatment Using SPCD
Description	The Positive and Negative Syndrome Scale (PANSS) 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. Total score minimum = 30, maximum = 210.
Time Frame	For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Ph 1 analysis includes 34 subjects with Baseline PANSS data in the Placebo-Placebo (N=18) and Placebo-Drug (N=16) groups and 18 Drug-Drug group subjects. Per SPCD, the Ph 2 data excludes 18 subjects in the Drug-Drug group and includes the 14 subjects in the Placebo-Drug group and 18 subjects in the Placebo-Placebo group with PANSS Baseline data.

Arm/Group Title	Drug	Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	32	34
Phase 1 Average Percent Change from Baseline	-6.7 (12.8)	-3.2 (9.0)
Phase 2 Average Percentage Change from Day 14	-3.0 (10.5)	-3.3 (8.1)

6. Secondary Outcome

Title	Percentage of Subjects With 20% or More Reduction From Baseline in PANSS Total Score After 2 Weeks of Treatment Using SPCD
Description	The Positive and Negative Syndrome Scale (PANSS) 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. Total score minimum = 30, maximum = 210.
Time Frame	For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Phase 1 analysis combines the 34 subjects assigned to Placebo-Placebo (N=18) and Placebo-Drug (N=16) groups and the 18 subjects assigned to the Drug-Drug group with complete data at all visits. Per SPCD, the Phase 2 data includes the 14 subjects in the Placebo-Drug group and 18 subjects in the Placebo-Placebo group with complete data at all visits.

Arm/Group Title	Drug	Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	32	34
Phase 1 % of subjects with >=20% reduction	16.67	0
Phase 2 % of subjects with >=20% reduction	0	5.56

7. Secondary Outcome

Title	Average Percent Change From Baseline in the PANSS Positive Subscale Score After 2 Weeks of Treatment Using SPCD
Description	The Positive and Negative Syndrome Scale (PANSS) 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. Positive subscore scale: 7 items (minimum score = 7; maximum score = 49)
Time Frame	For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Ph 1 analysis includes 34 subjects with Baseline PANSS data in the Placebo-Placebo (N=18) and Placebo-Drug (N=16) groups and 18 Drug-Drug group subjects. Per SPCD, the Ph 2 data excludes 18 subjects in the Drug-Drug group and includes the 14 subjects in the Placebo-Drug group and 18 subjects in the Placebo-Placebo group with PANSS Baseline data.

Arm/Group Title	Drug	Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	32	34
Phase 1 Average Percent Change from Baseline	-7.9 (8.1)	-3.2 (13.6)
Phase 2 Average Percentage Change from Day 14	-3.5 (15.4)	-2.9 (12.5)

8. Secondary Outcome

Title	Average Percent Change From Baseline in the PANSS Negative Subscale Score After 2 Weeks of Treatment Using SPCD
Description	The Positive and Negative Syndrome Scale (PANSS) 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. Negative subscore scale: 7 items (minimum score = 7; maximum score = 49)
Time Frame	For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Phase 1 analysis combines the 34 subjects assigned to Placebo-Placebo (N=18) and Placebo-Drug (N=16) groups and the 18 subjects assigned to the Drug-Drug group with complete data at all visits. Per SPCD, the Phase 2 data includes the 14 subjects in the Placebo-Drug group and 18 subjects in the Placebo-Placebo group with complete data at all visits.

Arm/Group Title	Drug	Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	32	34
Phase 1 Average Percent Change from Baseline	-7.1 (17.6)	-4.6 (14.9)
Phase 2 Average Percentage Change from Day 14	-7.9 (12.3)	-2.1 (16.5)

9. Secondary Outcome

Title	Average Percent Change From Baseline in the PANSS General Psychopathology Subscale Score After 2 Weeks of Treatment Using SPCD
Description	The Positive and Negative Syndrome Scale (PANSS) 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. General Psychopathology subscore scale: 16 items (minimum score = 16; maximum score = 112)
Time Frame	For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Ph 1 analysis includes 34 subjects with Baseline PANSS data in the Placebo-Placebo (N=18) and Placebo-Drug (N=16) groups and 18 Drug-Drug group subjects. Per SPCD, the Ph 2 data excludes 18 subjects in the Drug-Drug group and includes the 14 subjects in the Placebo-Drug group and 18 subjects in the Placebo-Placebo group with PANSS Baseline data.

Arm/Group Title	Drug	Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	32	34
Phase 1 Average Percent Change from Baseline	-4.8 (18.3)	-1.8 (10.9)
Phase 2 Average Percentage Change from Day 14	0.47 (13.3)	-3.7 (8.7)

10. Other Pre-specified Outcome

Title	Change in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) - Phases 1 and 2
Description	MATRICS: The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). 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 composite score represents a global measure of cognition. MCCB composite T scores are between 40 and 60 (normal range) and < 40 (below normal range).
Time Frame	Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Ph1 analysis includes 34 subjects with Baseline MATRICS data in the Placebo-Placebo (N=18) and Placebo-Drug (N=16) groups and 18 subjects the Drug-Drug group. Per SPCD, Ph 2 excludes the 18 subjects in the Drug-Drug group and includes the 14 subjects in the Placebo-Drug group and 18 subjects in the Placebo-Placebo group with Baseline MATRICS data.

Arm/Group Title	Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	32	34
Phase 1 - Baseline	26.2 (14.3)	26.5 (14.5)
Phase 1 - Day 14	29.3 (12.9)	28.6 (16.2)
Phase 1 - Change	3.1 (3.9)	1.4 (5.1)
Phase 2 - Day 14	28.8 (12.8)	28.4 (18.8)
Phase 2 - Day 28	30.3 (13.6)	31.0 (18.0)
Phase 2 - Change	3.3 (4.2)	2.6 (5.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Drug, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Drug, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Other Pre-specified Outcome

Title	Average AIMS Total Scores (Items 1-7) by Group and Timepoint
Description	Abnormal Involuntary Movement Scale (AIMS): The AIMS Total Dyskinesia Score was calculated by averaging the first 7 items of the AIMS. The 7 items included in the AIMS Dyskinesia Score are rated on a scale from 0 (no dyskinesia) to 4 (severe dyskinesia). Items 1 through 7 include facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). The AIMS dyskinesia total score ranges from 0 to 4; a higher score reflects increased severity.
Time Frame	Baseline 1 (Day -1), 7 Hours Post-Infusion 1, Baseline 2 (Day 13), 7 Hours Post-Infusion 2, Final Follow-Up, including early termination visits

Outcome Measure Data

Analysis Population Description

Includes all subjects with AIMS data at Phases 1 and 2

Arm/Group Title	Drug - Drug	Placebo - Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo: Placebo
Measure Participants	18	16	18
Baseline 1	0.72 (1.41)	0.56 (0.96)	0.56 (0.96)
7 Hours Post-Infusion 1	0.56 (1.10)	0.31 (0.48)	0.31 (0.48)
Baseline 2	0.44 (0.92)	1.00 (1.47)	1.00 (1.47)
7 Hours Post-Infusion 2	0.47 (0.87)	0.54 (0.88)	0.54 (0.88)
Final follow-up	1.00 (2.09)	0.93 (1.67)	0.93 (1.67)

12. Other Pre-specified Outcome

Title	Percent of Participants Rated as ≥ "Mild" or as "Yes" on AIMS Items 8-12
Description	Abnormal Involuntary Movement Scale (AIMS): The AIMS is a 12-item anchored score that is clinician administered and scored. Items are scored on a 0 (none) to 4 (severe) basis; items 8-10 deal with global severity; items 11-12 are yes-no questions concerning problems with teeth and/or dentures.
Time Frame	Baseline (Day -1), Follow-Up = reported at any assessment thereafter, including 7 hours after Infusions #1 and #2, Baseline 2 (Day 13) and final follow-up, including early termination visits.

Outcome Measure Data

Analysis Population Description

For each item, percentages of participants rated as exhibiting behaviors at the "mild" level or higher, or for items 11 and 12, as being present versus not (yes/no rated) are provided per treatment group.

Arm/Group Title	Drug - Drug	Placebo - Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo: Placebo
Measure Participants	18	16	18
Baseline - Overall Severity Index (Item 8)	5.6 31.1%	6.3 39.4%	11.1 61.7%
Follow-Up - Overall Severity Index (Item 8)	16.7 92.8%	18.8 117.5%	16.7 92.8%
Baseline - Incapacitation (Item 9)	0.0 0%	0.0 0%	5.6 31.1%
Follow-Up - Incapacitation (Item 9)	0.0 0%	6.3 39.4%	0.0 0%
Baseline - Awareness (Item 10)	11.1 61.7%	6.3 39.4%	5.6 31.1%
Follow-Up - Awareness (Item 10)	5.6 31.1%	18.8 117.5%	5.6 31.1%
Baseline - Dental Problem (Item 11; % yes)	22.2 123.3%	31.3 195.6%	16.7 92.8%
Follow-Up - Dental Problem (Item 11; % yes)	27.8 154.4%	37.5 234.4%	22.2 123.3%
Baseline - Dentures (Item 12; % yes)	5.6 31.1%	18.8 117.5%	16.7 92.8%
Follow-Up - Dentures (Item 12; % yes)	11.1 61.7%	31.3 195.6%	22.2 123.3%

13. Other Pre-specified Outcome

Title	Change in The University of California San Diego (UCSD) Performance-based Skills Assessment Brief (UPSA-B) - Phases 1 and 2
Description	The University of California San Diego (UCSD) Performance-based Skills Assessment Brief (UPSA-B) consists of two of the five original UPSA domains, finances and communication. Each subscale contributes 50 points; total scores range from 0 to 100 points with higher scores reflecting better performance.
Time Frame	Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Ph1 analysis includes 34 subjects with Baseline UPSA-B data in the Placebo-Placebo (N=18) and Placebo-Drug (N=16) groups and 18 subjects the Drug-Drug group. Per SPCD, Ph 2 excludes the 18 subjects in the Drug-Drug group and includes the 14 subjects in the Placebo-Drug group and 18 subjects in the Placebo-Placebo group with Baseline UPSA-B data.

Arm/Group Title	Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	32	34
Phase 1 - Baseline	74.0 (17.2)	71.8 (17.1)
Phase 1 - Day 14	76.7 (17.4)	77.9 (14.6)
Phase 1 - Change	2.7 (7.6)	6.2 (9.9)
Phase 2 - Day 14	80.2 (13.1)	76.0 (15.9)
Phase 2 - Day 28	85.4 (11.2)	74.5 (20.9)
Phase 2 - Change	5.5 (7.7)	-1.5 (10.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Drug, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Drug, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.05
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Other Pre-specified Outcome

Title	Number of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS)
Description	The Columbia Suicide Severity Rating Scale (C-SSRS): 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 or improvement. It contains 5 rating scale questions (yes/no) for suicidal ideation increasing severity and 5 rating scale questions (yes/no) for suicidal behavior of increasing severity. The time frame is for both lifetime and the past six months for the Baseline/Screening scale and since the last visit for the Since Last Visit scale.
Time Frame	Screening Visit, Days 3 (Baseline 1), Days 7, 13 (Baseline 2), 21 and 28

Outcome Measure Data

Analysis Population Description

All subjects with C-SSRS data reporting suicidal ideation/behavior

Arm/Group Title	Drug - Drug	Placebo - Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo: Placebo
Measure Participants	23	19	18
Suicidal ideation (SI) (% any of the following)	2 11.1%	1 6.3%	2 11.1%
Wish to be dead	1 5.6%	1 6.3%	1 5.6%
Non-specific active suicidal thoughts	2 11.1%	1 6.3%	1 5.6%
Active SI w/any method (no plan) W/O intent to act	0 0%	0 0%	0 0%
Active SI w/some intent to act, W/O specific plan	0 0%	0 0%	0 0%
Active SI with specific plan & intent	0 0%	0 0%	0 0%
Suicidal behavior (% any of the following)	0 0%	0 0%	0 0%
Prepatory acts or behavior	0 0%	0 0%	0 0%
Aborted attempt	0 0%	0 0%	0 0%
Interrupted attempt	0 0%	0 0%	0 0%
Non-fatal suicide attempt	0 0%	0 0%	0 0%
Self-injurious behavior W/O suicidal intent	0 0%	0 0%	0 0%

15. Other Pre-specified Outcome

Title	Systolic Blood Pressure Per Infusion Phase by Group
Description	Infusion 1 (Day 0) - Systolic Blood Pressure at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.
Time Frame	Day 0 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours

Outcome Measure Data

Analysis Population Description

Includes all subjects during Phase 1 (i.e., infusion 1)

Arm/Group Title	Drug-Drug	Placebo-Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	18	16	18
Phase 1 - min000s1	121.79 (14.46)	121.50 (10.65)	123.78 (11.46)
Phase 1 - min005s1	116.95 (12.78)	126.13 (13.01)	121.94 (14.39)
Phase 2 - min000	114.89 (13.13)	125.13 (11.04)	121.00 (12.86)
Phase 2 - min005	111.32 (11.51)	124.38 (10.29)	121.00 (14.12)
Phase 2 - min010	112.72 (12.84)	127.06 (8.93)	122.33 (11.56)
Phase 2 - min015	111.28 (9.48)	125.75 (10.51)	121.94 (11.58)
Phase 2 - min020	108.28 (10.21)	124.63 (9.94)	121.11 (10.81)
Phase 2 - min025	109.83 (10.70)	126.63 (11.89)	121.11 (11.80)
Phase 2 - min030	108.61 (10.01)	125.13 (9.84)	119.67 (13.77)
Phase 2 - min040	111.82 (9.80)	125.63 (11.86)	122.56 (11.46)
Phase 2 - min050	111.00 (8.89)	125.73 (9.32)	122.56 (11.46)
Phase 2 - min060	112.53 (11.99)	126.87 (9.69)	120.17 (12.91)
Phase 2 - min070	114.82 (12.83)	126.27 (8.86)	120.11 (10.76)
Phase 2 - min080	110.00 (9.98)	125.53 (9.62)	120.83 (13.90)
Phase 2 - min090	111.94 (9.83)	125.00 (11.14)	121.33 (12.88)
Phase 2 - min100	111.00 (12.97)	123.87 (11.75)	122.11 (12.39)
Phase 2 - min110	112.29 (7.83)	128.33 (10.60)	122.83 (12.32)
Phase 2 - min120	111.76 (10.56)	124.93 (12.57)	119.06 (15.30)
Phase 2 - min130	109.82 (9.19)	125.20 (8.99)	119.17 (10.63)
Phase 2 - min140	109.47 (7.34)	127.67 (9.76)	119.72 (11.20)
Phase 2 - min150	110.12 (9.62)	126.93 (10.75)	123.39 (12.95)
Phase 2 - min160	107.88 (9.97)	126.00 (9.56)	121.72 (15.23)
Phase 2 - min170	109.35 (11.89)	124.33 (9.51)	122.72 (15.14)
Phase 2 - min180	110.06 (9.85)	127.07 (12.63)	123.22 (13.01)
Phase 2 - min190	110.12 (11.60)	125.13 (13.10)	121.94 (12.46)
Phase 2 - min200	107.41 (12.57)	125.40 (13.00)	122.67 (14.63)
Phase 2 - min210	109.71 (8.08)	131.87 (13.79)	122.94 (11.34)
Phase 2 - min220	109.82 (9.57)	125.73 (13.24)	125.89 (14.58)
Phase 2 - min230	109.35 (9.57)	126.00 (13.80)	124.61 (13.75)
Phase 2 - min240	109.53 (9.13)	128.67 (14.01)	124.44 (14.16)
Post Infusion - min000	107.50 (11.53)	128.38 (13.87)	125.22 (13.80)
Post Infusion - min005	114.44 (11.01)	126.13 (13.84)	123.12 (10.01)
Post Infusion - min010	116.28 (11.74)	127.33 (12.80)	122.06 (11.62)
Post Infusion - min015	117.22 (11.07)	128.40 (16.79)	124.67 (11.96)
Post Infusion - min020	117.39 (9.12)	128.80 (13.04)	124.50 (12.08)
Post Infusion - min025	116.33 (12.58)	129.53 (14.94)	126.72 (14.74)
Post Infusion - min030	118.56 (11.93)	129.81 (13.96)	124.00 (14.12)
Post Infusion - min040	119.67 (12.03)	128.33 (14.99)	123.33 (14.48)
Post Infusion - min050	117.33 (13.91)	128.47 (11.86)	123.11 (13.78)
Post Infusion - min060	122.22 (12.35)	129.93 (12.21)	124.61 (14.97)
Post Infusion - min070	122.33 (13.78)	130.27 (11.51)	122.72 (15.86)
Post Infusion - min080	118.83 (12.78)	128.47 (11.86)	122.94 (14.49)
Post Infusion - min090	117.67 (12.56)	129.20 (13.03)	124.06 (10.94)
Post Infusion - min100	120.44 (11.87)	125.67 (11.63)	121.72 (10.65)
Post Infusion - min110	122.61 (13.42)	129.27 (11.49)	125.06 (14.58)
Post Infusion - min120	122.22 (13.41)	128.67 (10.99)	124.44 (12.34)

16. Other Pre-specified Outcome

Title	Diastolic Blood Pressure Per Infusion Phase by Group
Description	Infusion 1 (Day 0) - Diastolic Blood Pressure at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.
Time Frame	Day 0 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours

Outcome Measure Data

Analysis Population Description

Includes all subjects during Phase 1 (i.e., infusion 1)

Arm/Group Title	Drug-Drug	Placebo-Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	18	16	18
Phase 1 - min000s1	71.63 (19.03)	75.13 (10.44)	75.11 (10.12)
Phase 1 - min005s1	68.79 (10.12)	75.38 (6.30)	74.94 (9.91)
Phase 2 - min000	67.58 (10.18)	74.44 (7.28)	74.72 (11.88)
Phase 2 - min005	66.37 (12.88)	74.31 (7.01)	74.39 (8.42)
Phase 2 - min010	65.72 (14.70)	75.50 (8.09)	73.72 (9.50)
Phase 2 - min015	62.67 (9.94)	74.75 (8.38)	72.78 (8.61)
Phase 2 - min020	62.06 (9.33)	75.19 (8.29)	74.33 (12.25)
Phase 2 - min025	62.33 (8.61)	74.31 (6.02)	72.83 (11.20)
Phase 2 - min030	60.78 (8.93)	75.50 (8.09)	72.06 (11.67)
Phase 2 - min040	61.29 (7.46)	75.06 (9.76)	72.67 (11.66)
Phase 2 - min050	60.65 (7.52)	76.47 (10.23)	71.28 (10.06)
Phase 2 - min060	61.88 (9.50)	75.80 (9.30)	71.94 (11.11)
Phase 2 - min070	64.53 (11.21)	75.27 (9.62)	71.11 (12.74)
Phase 2 - min080	62.41 (10.89)	76.73 (9.80)	71.61 (11.69)
Phase 2 - min090	64.18 (11.48)	74.53 (9.81)	73.11 (14.06)
Phase 2 - min100	62.29 (8.96)	74.87 (7.74)	73.94 (11.50)
Phase 2 - min110	63.94 (6.97)	77.07 (12.02)	72.06 (12.98)
Phase 2 - min120	66.94 (12.02)	74.20 (8.94)	72.28 (14.71)
Phase 2 - min130	62.47 (8.87)	76.27 (8.44)	69.72 (13.47)
Phase 2 - min140	61.94 (8.75)	78.27 (8.96)	71.06 (10.98)
Phase 2 - min150	64.53 (6.38)	75.60 (8.10)	73.83 (11.74)
Phase 2 - min160	61.88 (8.99)	75.53 (17.01)	72.22 (10.50)
Phase 2 - min170	62.29 (6.28)	74.40 (9.30)	72.83 (11.74)
Phase 2 - min180	62.06 (9.05)	74.20 (9.67)	72.22 (12.74)
Phase 2 - min190	63.47 (9.41)	74.67 (7.48)	73.56 (11.93)
Phase 2 - min200	64.18 (7.57)	78.60 (9.83)	74.33 (11.63)
Phase 2 - min210	63.82 (9.51)	76.20 (8.83)	75.56 (11.22)
Phase 2 - min220	63.47 (10.40)	76.00 (9.06)	75.17 (12.94)
Phase 2 - min230	60.82 (9.13)	76.40 (7.95)	74.17 (9.82)
Phase 2 - min240	63.47 (8.46)	76.53 (7.79)	74.00 (10.19)
Post Infusion - min000	62.56 (8.69)	77.50 (8.40)	74.67 (11.11)
Post Infusion - min005	67.17 (9.67)	76.40 (8.49)	76.18 (9.19)
Post Infusion - min010	66.78 (9.90)	78.07 (9.03)	75.56 (13.17)
Post Infusion - min015	69.00 (10.84)	76.20 (9.65)	75.78 (11.33)
Post Infusion - min020	71.72 (11.10)	77.80 (12.25)	75.61 (12.53)
Post Infusion - min025	66.72 (11.40)	78.87 (10.80)	77.06 (10.80)
Post Infusion - min030	69.67 (9.00)	78.81 (9.70)	75.33 (11.75)
Post Infusion - min040	68.06 (11.43)	77.53 (10.85)	75.89 (11.84)
Post Infusion - min050	69.56 (10.78)	78.40 (7.27)	75.17 (11.81)
Post Infusion - min060	68.83 (10.44)	79.33 (11.17)	74.61 (10.87)
Post Infusion - min070	70.22 (10.33)	78.13 (7.49)	75.28 (9.37)
Post Infusion - min080	71.89 (10.02)	76.60 (7.49)	75.06 (13.17)
Post Infusion - min090	69.89 (7.08)	79.07 (9.06)	74.44 (10.07)
Post Infusion - min100	69.50 (9.24)	76.80 (10.75)	73.56 (10.61)
Post Infusion - min110	71.61 (8.13)	76.53 (10.64)	74.22 (9.74)
Post Infusion - min120	70.61 (9.86)	78.27 (8.40)	75.89 (8.53)

17. Other Pre-specified Outcome

Title	Systolic Blood Pressure Per Infusion Phase by Group
Description	Infusion 2 (Day 14) - Systolic Blood Pressure at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.
Time Frame	Day 14 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours

Outcome Measure Data

Analysis Population Description

Includes all subjects during Phase 2 (i.e., infusion 2)

Arm/Group Title	Drug-Drug	Placebo-Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	18	14	18
Phase 1 - min000s1	120.69 (11.84)	121.92 (9.66)	122.61 (10.22)
Phase 1 - min005s1	112.69 (12.38)	120.77 (12.38)	119.39 (10.67)
Phase 2 - min000	110.88 (11.61)	120.92 (14.20)	120.78 (12.08)
Phase 2 - min005	107.50 (11.36)	116.31 (9.96)	120.39 (12.22)
Phase 2 - min010	108.50 (9.39)	113.38 (12.53)	120.41 (12.62)
Phase 2 - min015	108.88 (9.06)	113.46 (10.32)	117.28 (13.35)
Phase 2 - min020	108.19 (8.93)	112.62 (10.66)	117.94 (12.65)
Phase 2 - min025	110.81 (11.11)	115.62 (13.88)	118.22 (14.40)
Phase 2 - min030	109.88 (8.43)	113.69 (16.09)	116.44 (13.40)
Phase 2 - min040	108.06 (8.46)	117.54 (16.58)	118.94 (11.57)
Phase 2 - min050	109.00 (10.22)	112.77 (13.91)	118.56 (15.60)
Phase 2 - min060	109.63 (13.20)	113.31 (14.12)	116.94 (12.75)
Phase 2 - min070	108.56 (10.46)	113.15 (12.15)	118.50 (14.20)
Phase 2 - min080	108.50 (10.98)	113.08 (15.34)	118.50 (13.57)
Phase 2 - min090	109.06 (10.59)	109.00 (11.63)	118.06 (12.49)
Phase 2 - min100	106.94 (11.58)	111.50 (16.10)	119.00 (14.98)
Phase 2 - min110	105.67 (7.80)	112.46 (16.04)	120.39 (11.95)
Phase 2 - min120	105.87 (9.19)	106.33 (10.87)	118.83 (15.25)
Phase 2 - min130	108.53 (10.70)	110.17 (11.75)	120.06 (13.58)
Phase 2 - min140	111.27 (10.50)	110.54 (11.23)	120.33 (15.11)
Phase 2 - min150	112.13 (11.42)	110.83 (18.52)	117.67 (12.76)
Phase 2 - min160	109.87 (11.11)	116.17 (13.07)	121.17 (13.79)
Phase 2 - min170	114.33 (12.61)	113.33 (12.04)	120.61 (12.65)
Phase 2 - min180	111.27 (9.38)	113.92 (11.77)	117.67 (11.44)
Phase 2 - min190	110.47 (9.82)	114.83 (16.46)	120.72 (11.74)
Phase 2 - min200	110.40 (13.47)	115.08 (16.76)	120.94 (14.24)
Phase 2 - min210	113.13 (14.71)	114.33 (17.85)	121.17 (11.75)
Phase 2 - min220	109.20 (15.18)	112.33 (11.54)	120.06 (11.44)
Phase 2 - min230	110.27 (12.79)	113.58 (12.92)	118.83 (12.64)
Phase 2 - min240	108.53 (9.48)	111.83 (12.58)	119.00 (12.29)
Post Infusion - min000	107.75 (9.94)	113.25 (13.51)	118.22 (120.28)
Post Infusion - min005	111.06 (12.41)	118.25 (18.23)	120.28 (11.93)
Post Infusion - min010	116.88 (16.70)	122.83 (16.03)	122.94 (10.91)
Post Infusion - min015	114.75 (15.07)	124.58 (16.14)	122.78 (11.70)
Post Infusion - min020	115.00 (11.55)	122.92 (13.24)	121.56 (12.60)
Post Infusion - min025	116.00 (12.41)	125.83 (16.94)	126.67 (15.06)
Post Infusion - min030	117.50 (12.56)	123.67 (16.54)	126.06 (14.86)
Post Infusion - min040	118.44 (11.40)	123.92 (11.24)	122.11 (13.75)
Post Infusion - min050	122.75 (22.66)	124.17 (13.19)	122.72 (14.82)
Post Infusion - min060	125.31 (14.93)	121.08 (12.45)	123.17 (15.00)
Post Infusion - min070	122.44 (19.68)	120.33 (10.46)	124.78 (14.82)
Post Infusion - min080	122.38 (15.21)	121.83 (14.65)	123.17 (13.34)
Post Infusion - min090	122.25 (14.19)	125.08 (13.73)	126.28 (14.52)
Post Infusion - min100	121.94 (21.68)	123.92 (10.99)	122.94 (16.25)
Post Infusion - min110	123.50 (13.57)	125.17 (16.51)	125.06 (11.88)
Post Infusion - min120	122.31 (16.41)	125.75 (12.26)	125.00 (12.29)

18. Other Pre-specified Outcome

Title	Phase 2 - Diastolic Blood Pressure Per Infusion Phase by Group
Description	Infusion 2 (Day 14) - Diastolic Blood Pressure at all time points by group
Time Frame	Day 14 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours

Outcome Measure Data

Analysis Population Description

Includes all subjects during Phase 1 (i.e., infusion 1)

Arm/Group Title	Drug-Drug	Placebo-Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	18	14	18
Phase 1 - min000s1	69.38 (7.80)	74.50 (8.89)	74.50 (8.89)
Phase 1 - min005s1	63.56 (8.78)	73.89 (8.70)	73.89 (8.70)
Phase 2 - min000	63.94 (8.46)	72.72 (8.84)	72.72 (8.84)
Phase 2 - min005	61.00 (6.23)	71.28 (7.28)	71.28 (7.28)
Phase 2 - min010	61.63 (7.57)	74.65 (9.03)	74.65 (9.03)
Phase 2 - min015	61.44 (9.06)	73.50 (7.15)	73.50 (7.15)
Phase 2 - min020	63.19 (8.72)	70.94 (7.07)	70.94 (7.07)
Phase 2 - min025	59.25 (8.29)	71.56 (9.10)	71.56 (9.10)
Phase 2 - min030	61.75 (7.87)	71.11 (7.23)	71.11 (7.23)
Phase 2 - min040	59.94 (8.82)	73.17 (9.07)	73.17 (9.07)
Phase 2 - min050	60.25 (8.42)	71.89 (12.07)	71.89 (12.07)
Phase 2 - min060	60.38 (11.97)	71.44 (12.23)	71.44 (12.23)
Phase 2 - min070	59.19 (10.78)	71.00 (10.77)	71.00 (10.77)
Phase 2 - min080	59.00 (7.38)	70.72 (12.81)	70.72 (12.81)
Phase 2 - min090	57.13 (7.83)	70.22 (12.34)	70.22 (12.34)
Phase 2 - min100	58.13 (8.37)	71.00 (12.39)	71.00 (12.39)
Phase 2 - min110	59.73 (5.97)	71.89 (11.54)	71.89 (11.54)
Phase 2 - min120	59.47 (8.59)	68.28 (10.65)	68.28 (10.65)
Phase 2 - min130	60.33 (8.16)	73.44 (11.94)	73.44 (11.94)
Phase 2 - min140	58.73 (10.23)	71.56 (10.87)	71.56 (10.87)
Phase 2 - min150	61.87 (10.10)	74.06 (12.80)	74.06 (12.80)
Phase 2 - min160	60.53 (7.68)	73.94 (10.41)	73.94 (10.41)
Phase 2 - min170	61.87 (11.60)	74.61 (8.43)	74.61 (8.43)
Phase 2 - min180	60.27 (9.00)	72.28 (8.17)	72.28 (8.17)
Phase 2 - min190	59.73 (10.23)	73.00 (10.99)	73.00 (10.99)
Phase 2 - min200	58.40 (7.03)	73.56 (10.35)	73.56 (10.35)
Phase 2 - min210	60.27 (9.00)	74.11 (11.53)	74.11 (11.53)
Phase 2 - min220	59.13 (8.60)	72.22 (9.62)	72.22 (9.62)
Phase 2 - min230	62.00 (8.12)	72.33 (10.48)	72.33 (10.48)
Phase 2 - min240	59.60 (8.58)	70.11 (8.05)	70.11 (8.05)
Post Infusion - min000	59.81 (8.42)	70.39 (8.10)	70.39 (8.10)
Post Infusion - min005	63.31 (7.87)	71.94 (9.14)	71.94 (9.14)
Post Infusion - min010	67.06 (9.26)	73.39 (9.76)	73.39 (9.76)
Post Infusion - min015	65.13 (10.20)	75.67 (10.79)	75.67 (10.79)
Post Infusion - min020	69.44 (12.44)	74.89 (9.62)	74.89 (8.66)
Post Infusion - min025	66.88 (12.94)	76.89 (8.66)	76.89 (8.66)
Post Infusion - min030	68.81 (12.45)	76.89 (14.57)	76.89 (14.57)
Post Infusion - min040	70.31 (14.89)	72.39 (11.32)	72.39 (11.32)
Post Infusion - min050	70.25 (10.79)	74.72 (12.56)	74.72 (12.56)
Post Infusion - min060	67.69 (7.88)	74.11 (11.90)	74.11 (11.90)
Post Infusion - min070	68.81 (9.72)	76.78 (10.28)	76.78 (10.28)
Post Infusion - min080	68.88 (7.87)	74.61 (11.25)	74.61 (11.25)
Post Infusion - min090	69.88 (8.87)	73.83 (11.40)	73.83 (11.40)
Post Infusion - min100	69.38 (8.61)	74.28 (12.15)	74.28 (12.15)
Post Infusion - min110	70.81 (9.09)	77.11 (10.78)	77.11 (10.78)
Post Infusion - min120	70.56 (7.69)	78.00 (9.15)	78.00 (9.15)

19. Other Pre-specified Outcome

Title	Heart Rate Per Infusion Phase by Group
Description	Infusion 1 (Day 0) - Heart rate at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.
Time Frame	Day 0 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours

Outcome Measure Data

Analysis Population Description

Includes all subjects during Phase 1 (i.e., infusion 1)

Arm/Group Title	Drug-Drug	Placebo-Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	18	16	18
Phase 1 - min000s1	78.47 (13.11)	79.00 (15.84)	79.94 (17.67)
Phase 1 - min005s1	81.21 (15.79)	77.81 (14.39)	79.44 (16.33)
Phase 2 - min000	84.00 (13.81)	76.94 (15.05)	79.94 (16.86)
Phase 2 - min005	85.47 (13.49)	77.88 (15.13)	78.00 (17.19)
Phase 2 - min010	85.17 (13.44)	77.25 (14.75)	79.61 (16.75)
Phase 2 - min015	84.33 (13.97)	78.00 (14.01)	77.89 (17.33)
Phase 2 - min020	83.00 (13.84)	76.44 (14.77)	79.28 (17.28)
Phase 2 - min025	83.83 (14.61)	77.13 (13.61)	77.06 (17.12)
Phase 2 - min030	83.94 (14.21)	76.69 (14.38)	78.83 (17.57)
Phase 2 - min040	83.06 (13.98)	77.88 (14.42)	77.56 (18.10)
Phase 2 - min050	83.65 (14.28)	76.67 (13.28)	79.50 (18.06)
Phase 2 - min060	83.59 (13.86)	78.13 (12.88)	78.56 (17.12)
Phase 2 - min070	82.53 (13.73)	77.07 (12.66)	77.11 (17.27)
Phase 2 - min080	84.76 (13.37)	76.47 (15.08)	76.89 (17.83)
Phase 2 - min090	83.82 (12.73)	77.80 (14.36)	76.22 (17.13)
Phase 2 - min100	84.29 (12.46)	78.53 (12.82)	75.94 (16.31)
Phase 2 - min110	85.18 (12.54)	76.73 (11.66)	75.44 (16.76)
Phase 2 - min120	83.71 (11.97)	78.47 (13.52)	78.39 (20.37)
Phase 2 - min130	83.59 (12.50)	77.33 (12.66)	75.94 (15.69)
Phase 2 - min140	81.76 (11.99)	77.60 (12.79)	75.28 (16.35)
Phase 2 - min150	82.06 (13.38)	79.67 (11.79)	76.06 (15.42)
Phase 2 - min160	83.41 (11.49)	78.73 (11.81)	79.33 (16.11)
Phase 2 - min170	83.88 (11.19)	79.07 (13.57)	76.44 (18.07)
Phase 2 - min180	82.12 (10.34)	77.53 (13.72)	78.56 (16.76)
Phase 2 - min190	83.24 (12.40)	79.40 (15.08)	76.89 (16.36)
Phase 2 - min200	83.41 (11.37)	79.27 (13.42)	80.00 (15.98)
Phase 2 - min210	81.24 (11.68)	80.27 (14.39)	77.50 (15.57)
Phase 2 - min220	82.94 (12.29)	79.93 (14.10)	77.33 (16.83)
Phase 2 - min230	84.47 (12.96)	79.87 (15.06)	78.78 (16.75)
Phase 2 - min240	85.29 (12.01)	79.40 (13.74)	78.56 (16.85)
Post Infusion - min000	86.28 (11.96)	82.44 (14.81)	78.11 (16.91)
Post Infusion - min005	80.39 (12.46)	80.80 (15.81)	80.29 (16.13)
Post Infusion - min010	80.78 (12.74)	78.67 (1317)	78.83 (14.77)
Post Infusion - min015	80.67 (10.32)	79.93 (13.34)	79.39 (15.79)
Post Infusion - min020	82.06 (10.78)	82.13 (13.91)	80.33 (16.94)
Post Infusion - min025	79.78 (11.83)	81.60 (13.83)	78.22 (17.13)
Post Infusion - min030	79.39 (13.56)	82.13 (13.07)	79.72 (16.44)
Post Infusion - min040	79.72 (12.55)	81.47 (13.41)	78.72 (15.97)
Post Infusion - min050	79.06 (12.32)	78.47 (13.45)	81.28 (15.18)
Post Infusion - min060	79.17 (11.93)	79.40 (12.40)	78.83 (15.96)
Post Infusion - min070	79.83 (10.74)	81.87 (15.81)	79.94 (14.49)
Post Infusion - min080	78.44 (10.92)	83.87 (11.54)	80.33 (16.22)
Post Infusion - min090	79.11 (12.36)	82.33 (12.82)	79.22 (17.16)
Post Infusion - min100	79.17 (12.66)	84.67 (12.58)	80.00 (16.95)
Post Infusion - min110	79.67 (11.74)	82.80 (13.61)	80.61 (16.55)
Post Infusion - min120	79.56 (11.98)	83.47 (13.44)	80.00 (16.37)

20. Other Pre-specified Outcome

Title	Heart Rate Per Infusion Phase by Group
Description	Infusion 2 (Day 14) - Heart rate at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.
Time Frame	Day 14 - Phase 1 - Baseline = min000s1 and @5 min; Phase 2 - Baseline = min000 then every 10 minutes for 4 hours; Post Infusion - Baseline = min000, then every 10 minutes for 2 hours

Outcome Measure Data

Analysis Population Description

Includes all subjects during Phase 1 (i.e., infusion 1)

Arm/Group Title	Drug-Drug	Placebo-Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo:
Measure Participants	18	14	18
Phase 1 - min000s1	77.38 (11.77)	75.08 (13.94)	76.94 (18.50)
Phase 1 - min005s1	79.69 (12.43)	76.77 (14.86)	78.67 (17.85)
Phase 2 - min000	81.06 (11.25)	77.77 (15.24)	78.72 (17.75)
Phase 2 - min005	82.31 (12.88)	81.38 (15.32)	76.39 (17.77)
Phase 2 - min010	81.50 (13.46)	80.62 (16.44)	77.12 (17.19)
Phase 2 - min015	81.38 (12.99)	80.92 (15.40)	76.06 (17.11)
Phase 2 - min020	82.06 (12.13)	79.69 (16.73)	74.89 (16.97)
Phase 2 - min025	82.31 (12.35)	80.69 (18.08)	76.22 (16.81)
Phase 2 - min030	81.50 (10.22)	81.15 (16.32)	76.17 (15.73)
Phase 2 - min040	79.88 (13.61)	81.69 (15.50)	76.72 (15.35)
Phase 2 - min050	80.25 (12.23)	78.85 (15.42)	75.00 (16.30)
Phase 2 - min060	79.69 (15.12)	79.69 (14.63)	75.50 (15.75)
Phase 2 - min070	81.69 (13.85)	81.31 (13.53)	75.06 (16.28)
Phase 2 - min080	79.44 (13.93)	80.23 (14.11)	75.39 (14.61)
Phase 2 - min090	78.00 (14.58)	79.58 (14.71)	73.78 (15.56)
Phase 2 - min100	79.94 (14.29)	78.17 (14.66)	76.11 (15.15)
Phase 2 - min110	83.33 (11.58)	80.15 (15.51)	75.17 (15.52)
Phase 2 - min120	82.47 (12.97)	81.25 (16.16)	74.56 (14.27)
Phase 2 - min130	82.13 (13.03)	78.75 (15.24)	75.11 (13.60)
Phase 2 - min140	81.73 (13.95)	80.69 (14.92)	75.89 (15.87)
Phase 2 - min150	81.40 (12.57)	78.75 (13.59)	75.78 (14.53)
Phase 2 - min160	81.53 (13.20)	80.00 (11.26)	75.33 (13.75)
Phase 2 - min170	81.60 (14.46)	78.75 (12.55)	75.06 (14.43)
Phase 2 - min180	80.00 (12.91)	81.25 (12.81)	74.78 (14.10)
Phase 2 - min190	80.93 (12.91)	80.58 (16.37)	73.94 (14.18)
Phase 2 - min200	81.60 (14.39)	80.33 (14.27)	75.00 (12.63)
Phase 2 - min210	84.73 (11.93)	80.75 (17.12)	75.33 (15.04)
Phase 2 - min220	84.07 (12.55)	79.92 (13.92)	74.61 (14.46)
Phase 2 - min230	85.07 (11.78)	78.00 (14.59)	77.56 (14.61)
Phase 2 - min240	82.53 (13.73)	80.42 (12.55)	76.72 (15.69)
Post Infusion - min000	81.50 (13.85)	79.25 (14.77)	76.22 (16.13)
Post Infusion - min005	77.44 (12.19)	73.25 (13.97)	79.06 (16.00)
Post Infusion - min010	77.38 (13.64)	73.75 (13.60)	77.78 (15.38)
Post Infusion - min015	75.13 (13.59)	75.17 (12.71)	78.83 (14.50)
Post Infusion - min020	78.88 (13.72)	76.92 (11.24)	78.39 (14.74)
Post Infusion - min025	79.25 (12.46)	75.75 (14.14)	77.44 (12.87)
Post Infusion - min030	80.31 (11.16)	74.83 (11.76)	78.33 (13.92)
Post Infusion - min040	80.63 (16.66)	74.92 (10.42)	78.39 (13.85)
Post Infusion - min050	79.00 (11.89)	75.67 (12.20)	78.33 (14.58)
Post Infusion - min060	78.00 (11.35)	77.08 (13.21)	79.11 (13.64)
Post Infusion - min070	78.81 (11.12)	77.75 (13.92)	77.50 (13.95)
Post Infusion - min080	80.69 (10.87)	75.92 (14.85)	78.06 (14.94)
Post Infusion - min090	80.25 (10.07)	78.42 (16.55)	78.89 (14.29)
Post Infusion - min100	80.06 (10.51)	79.75 (16.80)	80.17 (14.29)
Post Infusion - min110	79.88 (10.25)	77.50 (16.94)	80.22 (14.72)
Post Infusion - min120	80.19 (11.73)	80.83 (17.02)	78.44 (14.30)

21. Other Pre-specified Outcome

Title	ECG Measures at All Time Points by Group
Description	Infusion 1 (Day 0) - ECG measures at all time points by group
Time Frame	Day 0 - Baseline (pre-infusion), During Infusion (@30 min), Post-Infusion (@60min)

Outcome Measure Data

Analysis Population Description

All subjects receiving a complete or partial Phase 1 infusion

Arm/Group Title	Drug - Drug	Placebo - Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium Nitroprusside (Drug) Phase 2 - intravenous sodium Nitroprusside (Drug) Subjects will receive i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at Day 0 (Phase 1) and Day 14 (Phase 2)	Phase 1 - intravenous dextrose (Placebo) Phase 2 - intravenous sodium Nitroprusside (Drug) Subjects will receive i.v. placebo (intravenous dextrose) at Day 0 (Phase 1) and i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at Day 14 (Phase 2)	Phase 1 - intravenous dextrose (Placebo) Phase 2 - intravenous dextrose (Placebo) Subjects will receive i.v. placebo (intravenous dextrose) at Day 0 (Phase 1) and again at Day 14 (Phase 2).
Measure Participants	18	16	18
Baseline_PR Interval	162.84 (30.09)	149.11 (11.52)	164.56 (19.61)
Baseline_QRS Interval	91.37 (11.37)	86.89 (8.76)	88.11 (10.12)
Baseline_QT Interval	380.16 (26.60)	384.28 (31.47)	381.94 (36.50)
Baseline_RR Interval	0.81 (0.19)	0.82 (0.15)	0.81 (0.19)
30min_PR Interval	159.63 (34.81)	152.40 (12.44)	167.59 (21.30)
30min_QRS Interval	89.79 (11.22)	88.00 (10.39)	89.12 (9.97)
30min_QT Interval	385.11 (25.55)	385.27 (29.72)	385.53 (42.92)
30min_RR Interval	0.76 (0.12)	0.81 (0.16)	0.81 (0.20)
End_PR Interval	165.94 (38.63)	149.43 (11.33)	165.63 (25.23)
End_QRS Interval	91.67 (13.43)	87.50 (9.63)	89.00 (10.09)
End_QT Interval	371.94 (41.97)	377.00 (25.33)	391.13 (43.35)
End_RR Interval	0.79 (0.12)	0.80 (0.11)	0.82 (0.20)

22. Other Pre-specified Outcome

Title	ECG Measures at All Time Points by Group
Description	Infusion 2 (Day 14) - ECG measures at all time points by group
Time Frame	Day 14 - Baseline (pre-infusion), During Infusion (@30 min), Post-Infusion (@60min)

Outcome Measure Data

Analysis Population Description

All subjects receiving a complete or partial Phase 2 infusion

Arm/Group Title	Drug - Drug	Placebo - Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium Nitroprusside (Drug) Phase 2 - intravenous sodium Nitroprusside (Drug) Subjects will receive i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at Day 0 (Phase 1) and Day 14 (Phase 2)	Phase 1 - intravenous dextrose (Placebo) Phase 2 - intravenous sodium Nitroprusside (Drug) Subjects will receive i.v. placebo (intravenous dextrose) at Day 0 (Phase 1) and i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at Day 14 (Phase 2)	Phase 1 - intravenous dextrose (Placebo) Phase 2 - intravenous dextrose (Placebo) Subjects will receive i.v. placebo (intravenous dextrose) at Day 0 (Phase 1) and again at Day 14 (Phase 2).
Measure Participants	18	14	18
Baseline_PR Interval	155.47 (23.46)	149.46 (15.61)	167.61 (20.02)
Baseline_QRS Interval	92.82 (11.29)	86.46 (10.05)	91.33 (12.45)
Baseline_QT Interval	379.35 (29.59)	385.69 (35.84)	387.33 (38.27)
Baseline_RR Interval	0.80 (0.17)	0.86 (0.16)	0.84 (0.19)
30min_PR Interval	156.18 (21.95)	146.69 (14.85)	172.00 (19.76)
30min_QRS Interval	90.18 (11.95)	87.00 (7.98)	88.44 (10.76)
30min_QT Interval	389.18 (25.33)	360.08 (46.52)	380.44 (33.30)
30min_RR Interval	0.75 (0.11)	0.77 (0.18)	0.82 (0.18)
End_PR Interval	160.41 (26.48)	153.55 (19.87)	165.63 (21.08)
End_QRS Interval	95.41 (9.90)	86.64 (9.90)	89.50 (9.97)
End_QT Interval	387.06 (38.89)	384.91 (29.89)	383.25 (31.60)
End_RR Interval	0.80 (0.16)	0.86 (0.11)	0.81 (0.16)

23. Other Pre-specified Outcome

Title	Incidence of Treatment-Emergent Adverse Events (TEAEs)
Description	Incidence of Treatment-Emergent Adverse Events (TEAE) by Treatment Group. 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.
Time Frame	The period of observation for collection of treatment-emergent adverse events extends from Day 0 treatment through the final visit at Day 28.

Outcome Measure Data

Analysis Population Description

Number of Treatment-Emergent Adverse Events (TEAEs) in Each Treatment Group

Arm/Group Title	Drug - Drug	Placebo - Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo: Placebo
Measure Participants	18	16	18
Number [# of TEAEs]	13	8	10

24. Other Pre-specified Outcome

Title	Number of Subject Withdrawals Due to Treatment-Emergent Adverse Events (TEAEs)
Description	Incidence of Treatment-Emergent Adverse Events (TEAE) by Treatment Group. 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.
Time Frame	The period of observation extends from Day 0 treatment through the final visit at Day 28

Outcome Measure Data

Analysis Population Description

All subjects withdrawn from the study due to TEAEs

Arm/Group Title	Drug - Drug	Placebo - Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium Nitroprusside (SNP) Phase 2 - intravenous sodium Nitroprusside (SNP) Subjects will receive i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at Day 0 and Day 14	Phase 1 - intravenous dextrose (Placebo) Phase 2 - intravenous sodium Nitroprusside (SNP) Subjects will receive i.v. placebo (intravenous dextrose) at Day 0 and i.v. sodium nitroprusside (0.5 μg/kg/min for 4 hours) at Day 14	Phase 1 - intravenous dextrose (Placebo) Phase 2 - intravenous dextrose (Placebo) Subjects will receive i.v. placebo (intravenous dextrose) at Day 0 and again at Day 14.
Measure Participants	18	16	18
Number [participants]	3 16.7%	4 25%	0 0%

25. Other Pre-specified Outcome

Title	Systematic Assessment for Treatment Emergent Effects-Systematic Inquiry (SAFTEE-SI) - Percent of Participants Reporting Experiencing Symptoms at "Moderate" or "Severe" Level for the 10 Most Frequently Reported Symptoms Post Randomization
Description	The Systematic Assessment for Treatment Emergent Effects-Systematic Inquiry (SAFTEE-SI): This is a self-rated 77-item questionnaire organized into 13 body areas assessing possible adverse events during the course of the trial.
Time Frame	Baseline (Day - 1), Follow-Up = reported at any assessment thereafter, including 7 hours after Infusions #1 and #2, Baseline 2 (Day 13) and final follow-up, including early termination visits.

Outcome Measure Data

Analysis Population Description

Includes all subjects with SAFTEE data

Arm/Group Title	Drug - Drug	Placebo - Drug	Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous	Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo: Placebo
Measure Participants	18	16	18
10. Baseline - Hearing or seeing things	22.2 123.3%	25.0 156.3%	22.2 123.3%
10. Follow-Up - Hearing or seeing things	33.3 185%	31.3 195.6%	16.7 92.8%
3. Baseline - Feeling drowsy or sleepy	16.7 92.8%	0.0 0%	22.2 123.3%
3. Follow-Up - Feeling drowsy or sleepy	22.2 123.3%	25.0 156.3%	22.2 123.3%
8. Baseline - Trouble concentrating	16.7 92.8%	6.3 39.4%	22.2 123.3%
8. Follow-Up - Trouble concentrating	11.1 61.7%	18.8 117.5%	27.8 154.4%
7. Baseline - Poor memory	11.1 61.7%	6.3 39.4%	27.8 154.4%
7. Follow-Up - Poor memory	5.6 31.1%	25.0 156.3%	22.2 123.3%
1. Baseline - Trouble Sleeping	16.7 92.8%	6.3 39.4%	27.8 154.4%
1. Follow-Up - Trouble Sleeping	11.1 61.7%	12.5 78.1%	22.2 123.3%
4. Baseline - Feeling nervous or hyper	5.6 31.1%	18.8 117.5%	33.3 185%
4. Follow-Up - Feeling nervous or hyper	5.6 31.1%	18.8 117.5%	22.2 123.3%
18. Baseline - Dry mouth	5.6 31.1%	12.5 78.1%	11.1 61.7%
18. Follow-Up - Dry mouth	5.6 31.1%	25.0 156.3%	16.7 92.8%
34. Baseline - Frequent need to urinate	0.0 0%	6.3 39.4%	11.1 61.7%
34. Follow-Up - Frequent need to urinate	5.6 31.1%	18.8 117.5%	16.7 92.8%
17. Baseline - Stuffy nose	5.6 31.1%	6.3 39.4%	16.7 92.8%
17. Follow-Up - Stuffy nose	5.6 31.1%	18.8 117.5%	11.1 61.7%
52. Baseline - Hot flashes	0.0 0%	6.3 39.4%	5.6 31.1%
52. Follow-Up - Hot flashes	11.1 61.7%	6.3 39.4%	16.7 92.8%

Adverse Events

Time Frame	The period of observation for collection of adverse events extends from the time the subject gave informed consent until the final visit at Day 28.
Arm/Group Title	Drug - Drug		Placebo - Drug		Placebo - Placebo
Arm/Group Description	Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous		Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside sodium nitroprusside: intravenous		Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose Placebo: Placebo
All Cause Mortality
	Drug - Drug		Placebo - Drug		Placebo - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/19 (0%)		0/18 (0%)
Serious Adverse Events
	Drug - Drug		Placebo - Drug		Placebo - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/19 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Drug - Drug		Placebo - Drug		Placebo - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/23 (47.8%)		9/19 (47.4%)		9/18 (50%)
Cardiac disorders
Hypotension	5/23 (21.7%)		1/19 (5.3%)		1/18 (5.6%)
Chest Pain	0/23 (0%)		1/19 (5.3%)		2/18 (11.1%)
Abnormal ECG	1/23 (4.3%)		1/19 (5.3%)		0/18 (0%)
Palpitations	0/23 (0%)		0/19 (0%)		2/18 (11.1%)
Irregular Heart Activity	0/23 (0%)		1/19 (5.3%)		0/18 (0%)
Increased Heart Rate	1/23 (4.3%)		0/19 (0%)		0/18 (0%)
Hypertension	1/23 (4.3%)		0/19 (0%)		0/18 (0%)
Eye disorders
Blurred Vision	0/23 (0%)		1/19 (5.3%)		0/18 (0%)
Gastrointestinal disorders
Nausea	0/23 (0%)		3/19 (15.8%)		2/18 (11.1%)
Nausea/Vomiting	0/23 (0%)		2/19 (10.5%)		0/18 (0%)
Abdominal Pain	0/23 (0%)		0/19 (0%)		1/18 (5.6%)
Increased Appetite	1/23 (4.3%)		0/19 (0%)		0/18 (0%)
Constipation	0/23 (0%)		1/19 (5.3%)		0/18 (0%)
General disorders
Lightheadedness	1/23 (4.3%)		0/19 (0%)		1/18 (5.6%)
Drowsiness	1/23 (4.3%)		0/19 (0%)		0/18 (0%)
Dry Mouth	0/23 (0%)		0/19 (0%)		1/18 (5.6%)
Pelvic Pain	0/23 (0%)		0/19 (0%)		1/18 (5.6%)
Heat Exhaustion	0/23 (0%)		1/19 (5.3%)		0/18 (0%)
Hepatobiliary disorders
Elevated ALT Levels	0/23 (0%)		0/19 (0%)		1/18 (5.6%)
Immune system disorders
White Blood Cell Decrease	1/23 (4.3%)		0/19 (0%)		0/18 (0%)
Nervous system disorders
Headache	3/23 (13%)		2/19 (10.5%)		0/18 (0%)
Tingling	1/23 (4.3%)		0/19 (0%)		1/18 (5.6%)
Psychiatric disorders
Anxiety	0/23 (0%)		1/19 (5.3%)		0/18 (0%)
Feeling Nervous or Hyperactive	0/23 (0%)		0/19 (0%)		1/18 (5.6%)
Hypersomnia	0/23 (0%)		1/19 (5.3%)		0/18 (0%)
Reproductive system and breast disorders
Decreased Libido	1/23 (4.3%)		0/19 (0%)		1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Low O2 Saturation Rate	1/23 (4.3%)		2/19 (10.5%)		0/18 (0%)
Congestion	1/23 (4.3%)		0/19 (0%)		0/18 (0%)
Skin and subcutaneous tissue disorders
Rash	2/23 (8.7%)		1/19 (5.3%)		0/18 (0%)
Folliculitis	0/23 (0%)		0/19 (0%)		1/18 (5.6%)
Vascular disorders
Dizziness	0/23 (0%)		1/19 (5.3%)		1/18 (5.6%)
Flushing	2/23 (8.7%)		0/19 (0%)		0/18 (0%)
Hot Flashes	1/23 (4.3%)		0/19 (0%)		0/18 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.