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

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

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

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Other: Placebo; Drug: sodium nitroprusside

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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Schizophrenia Clinical Research Program, Massachusetts General Hospital
    • Worcester, Massachusetts, United States, 01605
      • University of Massachusetts Medical School
  • New York
    • Glen Oaks, New York, United States, 11004
      • Zucker Hillside Hospital
    • New York, New York, United States, 10016
      • New York University Langone Medical Center/Bellevue Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Drug - Drug; Phase 1 - intravenous sodium nitroprusside Phase 2 - intravenous sodium nitroprusside	Drug: sodium nitroprusside; intravenous; Other Names: Nitropress
Other: Placebo - Drug; Phase 1 - intravenous dextrose Phase 2 - intravenous sodium nitroprusside	Drug: sodium nitroprusside; intravenous; Other Names: Nitropress
Placebo Comparator: Placebo - Placebo; Phase 1 - intravenous dextrose Phase 2 - intravenous dextrose	Other: Placebo; Placebo; Other Names: 5% dextrose

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) - Phases 1 and 2	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 between 40 and 60 (normal range) and < 40 (below normal range).	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	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 (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	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 (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.
Change in The University of California San Diego (UCSD) Performance-based Skills Assessment Brief (UPSA-B) - Phases 1 and 2	The University of California San Diego (UCSD) Performance-based Skills Assessment Brief (UPSA-B) consists of two of the five original UPSA domains, finances and communication. Each subscale contributes 50 points; total scores range from 0 to 100 points with higher scores reflecting better performance.	Phase 1 timeframe is Baseline and Day 14; Phase 2 timeframe is Day 14 and Day 28
Number of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS)	The Columbia Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events through any treatment. It is a clinical interview providing a summary of both ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present. The C-SSRS can also be used during treatment to monitor for clinical worsening or improvement. It contains 5 rating scale questions (yes/no) for suicidal ideation increasing severity and 5 rating scale questions (yes/no) for suicidal behavior of increasing severity. The time frame is for both lifetime and the past six months for the Baseline/Screening scale and since the last visit for the Since Last Visit scale.	Screening Visit, Days 3 (Baseline 1), Days 7, 13 (Baseline 2), 21 and 28
Systolic Blood Pressure Per Infusion Phase by Group	Infusion 1 (Day 0) - Systolic Blood Pressure at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.	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
Diastolic Blood Pressure Per Infusion Phase by Group	Infusion 1 (Day 0) - Diastolic Blood Pressure at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.	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
Systolic Blood Pressure Per Infusion Phase by Group	Infusion 2 (Day 14) - Systolic Blood Pressure at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.	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
Phase 2 - Diastolic Blood Pressure Per Infusion Phase by Group	Infusion 2 (Day 14) - Diastolic Blood Pressure at all time points by group	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
Heart Rate Per Infusion Phase by Group	Infusion 1 (Day 0) - Heart rate at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.	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
Heart Rate Per Infusion Phase by Group	Infusion 2 (Day 14) - Heart rate at all time points by group "Phase" in this analysis refers to the infusion stage as defined in the protocol.	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
ECG Measures at All Time Points by Group	Infusion 1 (Day 0) - ECG measures at all time points by group	Day 0 - Baseline (pre-infusion), During Infusion (@30 min), Post-Infusion (@60min)
ECG Measures at All Time Points by Group	Infusion 2 (Day 14) - ECG measures at all time points by group	Day 14 - Baseline (pre-infusion), During Infusion (@30 min), Post-Infusion (@60min)
Incidence of Treatment-Emergent Adverse Events (TEAEs)	Incidence of Treatment-Emergent Adverse Events (TEAE) by Treatment Group. A treatment emergent adverse event (TEAE) is an AE that either began following initiation of study treatment or was present prior to the initiation of the treatment, but increased in frequency or severity following initiation treatment, regardless of causality.	The period of observation for collection of treatment-emergent adverse events extends from Day 0 treatment through the final visit at Day 28.
Number of Subject Withdrawals Due to Treatment-Emergent Adverse Events (TEAEs)	Incidence of Treatment-Emergent Adverse Events (TEAE) by Treatment Group. A treatment emergent adverse event (TEAE) is an AE that either began following initiation of study treatment or was present prior to the initiation of the treatment, but increased in frequency or severity following initiation treatment, regardless of causality.	The period of observation extends from Day 0 treatment through the final visit at Day 28
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	The Systematic Assessment for Treatment Emergent Effects-Systematic Inquiry (SAFTEE-SI): This is a self-rated 77-item questionnaire organized into 13 body areas assessing possible adverse events during the course of the trial.	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.

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Stanley Medical Research Institute
• Investigators: Principal Investigator: Roy Perlis, MD MSc, Massachusetts General Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): March 31, 2017
• Study Completion (Actual): April 5, 2017

Study Registration Dates

• First Submitted: June 13, 2014
• First Submitted That Met QC Criteria: June 13, 2014
• First Posted (Estimate): June 17, 2014

Study Record Updates

• Last Update Posted (Actual): October 2, 2018
• Last Update Submitted That Met QC Criteria: September 4, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Nitric Oxide Donors; Nitroprusside
• Other Study ID Numbers: 2014P001204

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No