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

NCT ID: NCT02164981

Last Updated: 2018-10-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-05-01
• Study Completion Date: 2017-04-05

Brief Summary

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

Detailed Description

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

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

Conditions

Schizophrenia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Drug - Drug

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

Group Type: ACTIVE_COMPARATOR

sodium nitroprusside

Intervention Type: DRUG

intravenous

Placebo - Drug

Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside

Group Type: OTHER

sodium nitroprusside

Intervention Type: DRUG

intravenous

Placebo - Placebo

Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo

Interventions

sodium nitroprusside

intravenous

Intervention Type: DRUG

Placebo

Placebo

Intervention Type: OTHER

Other Intervention Names

Nitropress; 5% dextrose

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stanley Medical Research Institute

OTHER

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Maurizio Fava, MD

Director, Clinical Research Program

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Maurizio Fava, MD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Roy Perlis, MD MSc

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Locations

Schizophrenia Clinical Research Program, Massachusetts General Hospital

Boston, Massachusetts, United States

University of Massachusetts Medical School

Worcester, Massachusetts, United States

Zucker Hillside Hospital

Glen Oaks, New York, United States

New York University Langone Medical Center/Bellevue Hospital

New York, New York, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 30916714 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2014P001204

Identifier Type: -

Identifier Source: org_study_id

NCT02695589

Identifier Type: -

Identifier Source: nct_alias