Clinical trial NCT02164981: A Proof of Concept Study of Intravenous Sodium Nitroprusside in Adults With Symptomatic Schizophrenia
Official title: A Randomized Double-Blind, Placebo-Controlled, Proof of Concept Study of Intravenous Sodium Nitroprusside in Adults With Symptomatic Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Schizophrenia
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Stanley Medical Research Institute
First posted: 2014-06-17
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in Positive and Negative Syndrome Scale (PANSS) - Total Score - Study Phases 1 and 2
timeFrame: For Phase 1, timeframe is Day 0 and Day 14; Phase 2 timeframe is Day 14 and Day 28
Secondary outcomes:
measure: PANSS - Positive Subscale - Phases 1 and 2
timeFrame: Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28
measure: PANSS - Negative Subscale - Phases 1 and 2
timeFrame: Phase 1 timeframe is Day 0 and Day 14; Phase 2 timeframe is Day 14 and Day 28
measure: PANSS - General Psychopathology Subscale - Phases 1 and 2
timeFrame: Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28
measure: Average Percent Change From Baseline in the PANSS Total Score After 2 Weeks of Treatment Using SPCD
timeFrame: For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28
measure: Percentage of Subjects With 20% or More Reduction From Baseline in PANSS Total Score After 2 Weeks of Treatment Using SPCD
timeFrame: For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28
measure: Average Percent Change From Baseline in the PANSS Positive Subscale Score After 2 Weeks of Treatment Using SPCD
timeFrame: For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28
measure: Average Percent Change From Baseline in the PANSS Negative Subscale Score After 2 Weeks of Treatment Using SPCD
timeFrame: For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28
measure: Average Percent Change From Baseline in the PANSS General Psychopathology Subscale Score After 2 Weeks of Treatment Using SPCD
timeFrame: For Phase 1, timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28
Other outcomes:
measure: Change in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) - Phases 1 and 2
timeFrame: Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28
measure: Average AIMS Total Scores (Items 1-7) by Group and Timepoint
timeFrame: 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
measure: Percent of Participants Rated as ≥ "Mild" or as "Yes" on AIMS Items 8-12
timeFrame: 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.
measure: Change in The University of California San Diego (UCSD) Performance-based Skills Assessment Brief (UPSA-B) - Phases 1 and 2
timeFrame: Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28
measure: Number of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS)
timeFrame: Screening Visit, Days 3 (Baseline 1), Days 7, 13 (Baseline 2), 21 and 28
measure: Systolic Blood Pressure Per Infusion Phase by Group
timeFrame: 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
measure: Diastolic Blood Pressure Per Infusion Phase by Group
timeFrame: 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
measure: Systolic Blood Pressure Per Infusion Phase by Group
timeFrame: 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
measure: Phase 2 - Diastolic Blood Pressure Per Infusion Phase by Group
timeFrame: 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
measure: Heart Rate Per Infusion Phase by Group
timeFrame: 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
measure: Heart Rate Per Infusion Phase by Group
timeFrame: 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
measure: ECG Measures at All Time Points by Group
timeFrame: Day 0 - Baseline (pre-infusion), During Infusion (@30 min), Post-Infusion (@60min)
measure: ECG Measures at All Time Points by Group
timeFrame: Day 14 - Baseline (pre-infusion), During Infusion (@30 min), Post-Infusion (@60min)
measure: Incidence of Treatment-Emergent Adverse Events (TEAEs)
timeFrame: The period of observation for collection of treatment-emergent adverse events extends from Day 0 treatment through the final visit at Day 28.
measure: Number of Subject Withdrawals Due to Treatment-Emergent Adverse Events (TEAEs)
timeFrame: The period of observation extends from Day 0 treatment through the final visit at Day 28
measure: 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
timeFrame: 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.
Locations:
city: Boston
country: United States
facility: Schizophrenia Clinical Research Program, Massachusetts General Hospital
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
city: Glen Oaks
country: United States
facility: Zucker Hillside Hospital
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center/Bellevue Hospital
state: New York
Study officials:
affiliation: Massachusetts General Hospital
name: Maurizio Fava, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Roy Perlis, MD MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.