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

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

Detailed Description
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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.

Official Title
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A Randomized Double-Blind, Placebo-Controlled, Proof of Concept Study of Intravenous Sodium Nitroprusside in Adults With Symptomatic Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: sodium nitroprusside
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each subject must meet all of the following criteria to be eligible for this study: Males or Females aged 18-65 years inclusive. 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. 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. 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. A score of ≥4 on the Clinical Global Impression-Severity (CGI-S) (Guy, 1976). Confirmation of both diagnosis and severity of psychosis symptoms by an independent MGH SAFER interview. Must have ongoing antipsychotic treatment for at least 8 weeks, with a stable dose for at least 4 weeks. Subjects who have failed to achieve clinically-recognized symptom reduction to at least 1 marketed antipsychotic agent, given at a Physician Desk Reference (PDR)-defined therapeutic dose for ≥ 8 weeks during the past 12 months, as assessed by the MGH FAST, will be eligible Understands and is able, willing, and (in the opinion of the investigator) likely to fully comply with the study procedures and restrictions. Exclusion Criteria Subjects who meet any of the following criteria will be excluded from the study: Subjects with a history of renal insufficiency, congestive heart failure, cardiac arrhythmias or history of myocardial infarction. 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. 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. 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. Medications which in the opinion of the PI, and in conjunction with the medical monitor, may be expected to significantly interfere with the metabolism or excretion of sodium nitroprusside, and/or may be associated with a significant drug interaction with sodium nitroprusside that may pose a significant risk to subjects' health and/or confound the study data. Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed at screening visit prior to randomization and prior to baseline at visits 3 and 6. Women enrolled in this trial must use adequate birth control. Subjects with a current (within the last 3 months) DSM-IV-TR diagnosis of alcohol or substance use disorder or dependence (excluding nicotine) as established by the clinical assessment (SCID) at the screening visit will be excluded. Has tested positive for any of the following: cannabis, opioids, cocaine, amphetamines, barbiturates methadone, methamphetamine and phencyclidine at the screening or baseline visits. If positive, the urine drug toxicology screen may be repeated once based on investigator judgment, but due to safety concerns, the result must be negative for the subject to continue in the study. Subjects at imminent risk of suicide or injury to self or others, as per the opinion of the investigator, or history of significant suicide attempt within the last 6 months as per C-SSRS. Subjects that have taken an investigational drug or taken part in a clinical trial within 30 days prior to screening. Any other reason that, in the opinion of the investigator, would compromise patient safety or integrity of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Drug - Drug<br>Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside | Drug: sodium nitroprusside<br>* intravenous<br>* Other names: Nitropress;|
| Other: Placebo - Drug<br>Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside | Drug: sodium nitroprusside<br>* intravenous<br>* Other names: Nitropress;|
| Placebo Comparator: Placebo - Placebo<br>Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose | Other: Placebo<br>* Placebo<br>* Other names: 5% dextrose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Positive and Negative Syndrome Scale (PANSS) - Total Score - Study Phases 1 and 2 | 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 | For Phase 1, timeframe is Day 0 and Day 14; Phase 2 timeframe is Day 14 and Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PANSS - Positive Subscale - Phases 1 and 2 | 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) | Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28 | 
| PANSS - Negative Subscale - Phases 1 and 2 | 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) | Phase 1 timeframe is Day 0 and Day 14; Phase 2 timeframe is Day 14 and Day 28 | 
| PANSS - General Psychopathology Subscale - Phases 1 and 2 | 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) | Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28 | 
| Average Percent Change From Baseline in the PANSS Total Score After 2 Weeks of Treatment Using SPCD | 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. | For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28 | 
| Percentage of Subjects With 20% or More Reduction From Baseline in PANSS Total Score After 2 Weeks of Treatment Using SPCD | 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. | For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28 | 
| Average Percent Change From Baseline in the PANSS Positive Subscale Score After 2 Weeks of Treatment Using SPCD | 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) | For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28 | 
| Average Percent Change From Baseline in the PANSS Negative Subscale Score After 2 Weeks of Treatment Using SPCD | 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) | For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28 | 
| Average Percent Change From Baseline in the PANSS General Psychopathology Subscale Score After 2 Weeks of Treatment Using SPCD | 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) | For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28 |