NCT02164981

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

Completed Phase 2 Results posted Last updated 2 October 2018

What this trial tests

Phase 2 trial testing sodium nitroprusside in Schizophrenia in 60 participants. Completed in 5 April 2017.

Timeline

1 May 2015

Primary endpoint
31 March 2017

5 April 2017

Quick facts

Lead sponsor	Massachusetts General Hospital
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	crossover
Masking	triple
Primary purpose	treatment
Enrollment	60
Start date	1 May 2015
Primary completion	31 March 2017
Estimated completion	5 April 2017
Sites	4 locations across United States

Drugs / interventions tested

• sodium nitroprusside (NITROPRUSSIDE) — full drug profile →
• Placebo

Conditions studied

• Schizophrenia — all drugs for Schizophrenia →

Sponsor

Massachusetts General Hospital

Who can join

Adults 18 to 65, any sex, with Schizophrenia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change in Positive and Negative Syndrome Scale (PANSS) - Total Score - Study Phases 1 and 2 Primary · 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

Phase 1 - Total Score - Baseline

Group	Value	95% CI
Drug	83.6	± 10.0
Placebo	79.8	± 8.9

Phase 1 - Total Score - Day 14

Group	Value	95% CI
Drug	77.6	± 12.2
Placebo	76.7	± 11.0

Phase 1 - Total Score - Change

Group	Value	95% CI
Drug	-6.0	± 11.3
Placebo	-2.5	± 7.1

Phase 2 - Total Score - Day 14

Group	Value	95% CI
Drug	74.0	± 12.0
Placebo	78.8	± 10.1

Phase 2 - Total Score - Day 28

Group	Value	95% CI
Drug	71.8	± 10.6
Placebo	74.7	± 9.0

Phase 2 - Total Score - Change

Group	Value	95% CI
Drug	-1.8	± 8.2
Placebo	-4.2	± 6.4

PANSS - Positive Subscale - Phases 1 and 2 Secondary · 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

Phase 1 - Positive Score - Baseline

Group	Value	95% CI
Drug	24.5	± 3.5
Placebo	22.3	± 3.1

Phase 1 - Positive Score - Day 14

Group	Value	95% CI
Drug	23.1	± 4.6
Placebo	21.3	± 3.6

Phase 1 - Positive Score - Change

Group	Value	95% CI
Drug	-1.8	± 1.8
Placebo	-0.81	± 2.7

Phase 2 - Positive Score - Day 14

Group	Value	95% CI
Drug	20.7	± 3.6
Placebo	21.8	± 3.6

Phase 2 - Positive Score - Day 28

Group	Value	95% CI
Drug	21.3	± 4.6
Placebo	22.3	± 3.4

Phase 2 - Positive Score - Change

Group	Value	95% CI
Drug	0.5	± 3.8
Placebo	0.5	± 2.17

PANSS - Negative Subscale - Phases 1 and 2 Secondary · 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

Phase 1 - Negative Score - Baseline

Group	Value	95% CI
Drug	20.8	± 5.8
Placebo - Placebo	20.6	± 4.8

Phase 1 - Negative Score - Day 14

Group	Value	95% CI
Drug	19.0	± 4.6
Placebo - Placebo	19.7	± 5.1

Phase 1 - Negative Score - Change

Group	Value	95% CI
Drug	-1.8	± 4.1
Placebo - Placebo	-1.0	± 2.8

Phase 2 - Negative Score - Day 14

Group	Value	95% CI
Drug	18.5	± 5.8
Placebo - Placebo	20.7	± 4.4

Phase 2 - Negative Score - Day 28

Group	Value	95% CI
Drug	18.0	± 6.2
Placebo - Placebo	19.8	± 4.7

Phase 2 - Negative Score - Change

Group	Value	95% CI
Drug	-0.1	± 0.9
Placebo - Placebo	-0.9	± 2.9

PANSS - General Psychopathology Subscale - Phases 1 and 2 Secondary · 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

Phase 1 - General Score - Baseline

Group	Value	95% CI
Drug	37.6	± 6.0
Placebo - Placebo	36.4	± 5.1

Phase 1 - General Score - Day 14

Group	Value	95% CI
Drug	35.3	± 7.1
Placebo - Placebo	35.5	± 6.4

Phase 1 - General Score - Change

Group	Value	95% CI
Drug	-2.2	± 7.0
Placebo - Placebo	-0.6	± 3.9

Phase 2 - General Score - Day 14

Group	Value	95% CI
Drug	34.7	± 6.4
Placebo - Placebo	36.2	± 6.6

Phase 2 - General Score - Day 28

Group	Value	95% CI
Drug	32.4	± 5.6
Placebo - Placebo	32.4	± 5.3

Phase 2 - General Score - Change

Group	Value	95% CI
Drug	-2.1	± 5.2
Placebo - Placebo	-3.7	± 4.5

Average Percent Change From Baseline in the PANSS Total Score After 2 Weeks of Treatment Using SPCD Secondary · 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

Phase 1 Average Percent Change from Baseline

Group	Value	95% CI
Drug	-6.7	± 12.8
Placebo	-3.2	± 9.0

Phase 2 Average Percentage Change from Day 14

Group	Value	95% CI
Drug	-3.0	± 10.5
Placebo	-3.3	± 8.1

Percentage of Subjects With 20% or More Reduction From Baseline in PANSS Total Score After 2 Weeks of Treatment Using SPCD Secondary · 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

Phase 1 % of subjects with >=20% reduction

Group	Value	95% CI
Drug	16.67
Placebo	0

Phase 2 % of subjects with >=20% reduction

Group	Value	95% CI
Drug	0
Placebo	5.56

Average Percent Change From Baseline in the PANSS Positive Subscale Score After 2 Weeks of Treatment Using SPCD Secondary · 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

Phase 1 Average Percent Change from Baseline

Group	Value	95% CI
Drug	-7.9	± 8.1
Placebo	-3.2	± 13.6

Phase 2 Average Percentage Change from Day 14

Group	Value	95% CI
Drug	-3.5	± 15.4
Placebo	-2.9	± 12.5

Average Percent Change From Baseline in the PANSS Negative Subscale Score After 2 Weeks of Treatment Using SPCD Secondary · 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

Phase 1 Average Percent Change from Baseline

Group	Value	95% CI
Drug	-7.1	± 17.6
Placebo	-4.6	± 14.9

Phase 2 Average Percentage Change from Day 14

Group	Value	95% CI
Drug	-7.9	± 12.3
Placebo	-2.1	± 16.5

Average Percent Change From Baseline in the PANSS General Psychopathology Subscale Score After 2 Weeks of Treatment Using SPCD Secondary · 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

Phase 1 Average Percent Change from Baseline

Group	Value	95% CI
Drug	-4.8	± 18.3
Placebo	-1.8	± 10.9

Phase 2 Average Percentage Change from Day 14

Group	Value	95% CI
Drug	0.47	± 13.3
Placebo	-3.7	± 8.7

Change in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) - Phases 1 and 2 Secondary · 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 be

Phase 1 - Baseline

Group	Value	95% CI
Drug	26.2	± 14.3
Placebo - Placebo	26.5	± 14.5

Phase 1 - Day 14

Group	Value	95% CI
Drug	29.3	± 12.9
Placebo - Placebo	28.6	± 16.2

Phase 1 - Change

Group	Value	95% CI
Drug	3.1	± 3.9
Placebo - Placebo	1.4	± 5.1

Phase 2 - Day 14

Group	Value	95% CI
Drug	28.8	± 12.8
Placebo - Placebo	28.4	± 18.8

Phase 2 - Day 28

Group	Value	95% CI
Drug	30.3	± 13.6
Placebo - Placebo	31.0	± 18.0

Phase 2 - Change

Group	Value	95% CI
Drug	3.3	± 4.2
Placebo - Placebo	2.6	± 5.2

Average AIMS Total Scores (Items 1-7) by Group and Timepoint Secondary · 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.

Baseline 1

Group	Value	95% CI
Drug - Drug	0.72	± 1.41
Placebo - Drug	0.56	± 0.96
Placebo - Placebo	0.56	± 0.96

7 Hours Post-Infusion 1

Group	Value	95% CI
Drug - Drug	0.56	± 1.10
Placebo - Drug	0.31	± 0.48
Placebo - Placebo	0.31	± 0.48

Baseline 2

Group	Value	95% CI
Drug - Drug	0.44	± 0.92
Placebo - Drug	1.00	± 1.47
Placebo - Placebo	1.00	± 1.47

7 Hours Post-Infusion 2

Group	Value	95% CI
Drug - Drug	0.47	± 0.87
Placebo - Drug	0.54	± 0.88
Placebo - Placebo	0.54	± 0.88

Final follow-up

Group	Value	95% CI
Drug - Drug	1.00	± 2.09
Placebo - Drug	0.93	± 1.67
Placebo - Placebo	0.93	± 1.67

Percent of Participants Rated as ≥ "Mild" or as "Yes" on AIMS Items 8-12 Secondary · 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.

Baseline - Overall Severity Index (Item 8)

Group	Value	95% CI
Drug - Drug	5.6
Placebo - Drug	6.3
Placebo - Placebo	11.1

Follow-Up - Overall Severity Index (Item 8)

Group	Value	95% CI
Drug - Drug	16.7
Placebo - Drug	18.8
Placebo - Placebo	16.7

Baseline - Incapacitation (Item 9)

Group	Value	95% CI
Drug - Drug	0.0
Placebo - Drug	0.0
Placebo - Placebo	5.6

Follow-Up - Incapacitation (Item 9)

Group	Value	95% CI
Drug - Drug	0.0
Placebo - Drug	6.3
Placebo - Placebo	0.0

Baseline - Awareness (Item 10)

Group	Value	95% CI
Drug - Drug	11.1
Placebo - Drug	6.3
Placebo - Placebo	5.6

Follow-Up - Awareness (Item 10)

Group	Value	95% CI
Drug - Drug	5.6
Placebo - Drug	18.8
Placebo - Placebo	5.6

Baseline - Dental Problem (Item 11; % yes)

Group	Value	95% CI
Drug - Drug	22.2
Placebo - Drug	31.3
Placebo - Placebo	16.7

Follow-Up - Dental Problem (Item 11; % yes)

Group	Value	95% CI
Drug - Drug	27.8
Placebo - Drug	37.5
Placebo - Placebo	22.2

Adverse events — posted to ClinicalTrials.gov

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.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Drug - Drug

Serious: 0/23 (0%)

Deaths: 0/23

Placebo - Drug

Serious: 0/19 (0%)

Deaths: 0/19

Placebo - Placebo

Serious: 0/18 (0%)

Deaths: 0/18

Other adverse events (33 terms — click to expand)

Reaction	System	Drug - Drug	Placebo - Drug	Placebo - Placebo
Hypotension	Cardiac disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Chest Pain	Cardiac disorders	—	—	—
Low O2 Saturation Rate	Respiratory, thoracic and mediastinal disorders	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—
Palpitations	Cardiac disorders	—	—	—
Flushing	Vascular disorders	—	—	—
Nausea/Vomiting	Gastrointestinal disorders	—	—	—
Abnormal ECG	Cardiac disorders	—	—	—
Decreased Libido	Reproductive system and breast disorders	—	—	—
Dizziness	Vascular disorders	—	—	—
Lightheadedness	General disorders	—	—	—
Abdominal Pain	Gastrointestinal disorders	—	—	—
Anxiety	Psychiatric disorders	—	—	—
Increased Appetite	Gastrointestinal disorders	—	—	—
Congestion	Respiratory, thoracic and mediastinal disorders	—	—	—
Drowsiness	General disorders	—	—	—
Dry Mouth	General disorders	—	—	—
Feeling Nervous or Hyperactive	Psychiatric disorders	—	—	—
Hot Flashes	Vascular disorders	—	—	—
Irregular Heart Activity	Cardiac disorders	—	—	—
Pelvic Pain	General disorders	—	—	—
Tingling	Nervous system disorders	—	—	—
White Blood Cell Decrease	Immune system disorders	—	—	—
Blurred Vision	Eye disorders	—	—	—
Elevated ALT Levels	Hepatobiliary disorders	—	—	—
Folliculitis	Skin and subcutaneous tissue disorders	—	—	—
Heat Exhaustion	General disorders	—	—	—
Hypersomnia	Psychiatric disorders	—	—	—
Increased Heart Rate	Cardiac disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Hypertension	Cardiac disorders	—	—	—

Data from ClinicalTrials.gov NCT02164981 adverse events section.

Sponsor's own description

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

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Efficacy and Tolerability of Adjunctive Intravenous Sodium Nitroprusside Treatment for Outpatients With Schizophrenia: A Randomized Clinical Trial.
   Brown HE, Freudenreich O, Fan X, Heard SO, et al · · 2019 · cited 19× · PMID 30916714 · DOI 10.1001/jamapsychiatry.2019.0151