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

NCT02164981 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 2014P001204
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 4

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

Conditions

Schizophrenia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• PANSS - Positive Subscale - Phases 1 and 2

  Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28

• 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

• 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

• 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

• 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

Other Outcomes (16)

• 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

• 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

• 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.

Study Arms (3)

Drug - Drug

ACTIVE COMPARATOR

Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside

Drug: sodium nitroprusside

Placebo - Drug

OTHER

Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside

Drug: sodium nitroprusside

Placebo - Placebo

PLACEBO COMPARATOR

Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose

Other: Placebo

Interventions

sodium nitroprusside DRUG

intravenous

Also known as: Nitropress

Drug - Drug; Placebo - Drug

Placebo OTHER

Placebo

Also known as: 5% dextrose

Placebo - Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Stanley Medical Research Institute: collaborator

Study Sites (4)

Schizophrenia Clinical Research Program, Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

University of Massachusetts Medical School

Worcester, Massachusetts, 01605, United States

Location

Zucker Hillside Hospital

Glen Oaks, New York, 11004, United States

Location

New York University Langone Medical Center/Bellevue Hospital

New York, New York, 10016, United States

Location

Related Publications (1)

• Brown HE, Freudenreich O, Fan X, Heard SO, Goff D, Petrides G, Harrington AL, Kane JM, Judge H, Hoeppner B, Fava M, Perlis RH. Efficacy and Tolerability of Adjunctive Intravenous Sodium Nitroprusside Treatment for Outpatients With Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry. 2019 Jul 1;76(7):691-699. doi: 10.1001/jamapsychiatry.2019.0151.

  PMID: 30916714 DERIVED

MeSH Terms

Conditions

Schizophrenia

Interventions

Nitroprusside; Glucose

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Ferricyanides; Cyanides; Anions; Ions; Electrolytes; Inorganic Chemicals; Ferric Compounds; Iron Compounds; Hydrogen Cyanide; Nitrogen Compounds; Hexoses; Monosaccharides; Sugars; Carbohydrates

Results Point of Contact

• Title: Maurizio Fava, MD
• Organization: Massachusetts General Hospital

MFAVA@mgh.harvard.edu

617-724-2513

Study Officials

• Maurizio Fava, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

• Roy Perlis, MD MSc

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Clinical Research Program

Study Record Dates

• First Submitted: June 13, 2014
• First Posted: June 17, 2014
• Study Start: May 1, 2015
• Primary Completion: March 31, 2017
• Study Completion: April 5, 2017
• Last Updated: October 2, 2018
• Results First Posted: October 2, 2018

Record last verified: 2018-09

Locations

US (4)