- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03988842
Standard-dose Apixaban AFtEr Very Low-dose ThromboLYSis for Acute Intermediate-high Risk Acute Pulmonary Embolism (SAFE-LYSE)
May 18, 2021 updated by: Victor Tapson, MD
The purpose of this study is to examine the degree to which pulmonary embolism (clot) can be dissolved when treated with a very low dose of a systemic thrombolytic drug (clot buster) along with standard anticoagulant therapy as compared to the standard of care anticoagulant therapy alone.
Study Overview
Status
Terminated
Conditions
Intervention / Treatment
Detailed Description
The OVERALL OBJECTIVE of this investigation is to determine whether very low-dose intravenous tissue-type plasminogen activator [tPA] (24 mg) + standard anticoagulation therapy (intravenous heparin) for treatment of acute PE (pulmonary embolism) in intermediate-high risk patients will have superior clot lysis (breakdown of clot) by chest CTA (computed tomography angiography) at 24 ± 6 hours post infusion compared to standard of care treatment alone.
Acute intermediate-high risk PE patients are those with acute symptoms <14 days), simplified Pulmonary Embolism Severity Index (sPESI)>0, normal systemic arterial blood pressure (>90mmHg) without vasopressor support, elevated biomarkers (troponin or BNP), and evidence of RV dysfunction (right ventricular to left ventricular ratio>0.9).The study is planned to evaluate the reduction in clot burden based on the obstruction index using the Refined Modified Miller Score (RMMS), improvement in right ventricular (RV) function, and overall safety in the two treatment groups.
40 Subjects with intermediate-high risk PE (hemodynamically stable PE with a RV/LV ratio ≥ 0.9, elevated biomarkers, and sPESI>0) will be recruited and randomized to one of two treatment groups: 24mg of systemic (IV) tPA + IV unfractionated heparin versus saline placebo + IV unfractionated heparin.
After delivery of the systemic (IV) tPA/placebo, patients will continue IV unfractionated heparin therapy for at least 24 hours.
If there is no evidence of active bleeding nor significant hemoglobin drop (i.e., ≥ 2 mg/dL), patients will be transitioned to standard dose apixaban, 10 mg twice-daily x one week followed by 5 mg twice-daily for at least 6 months.
Some patients will require indefinite apixaban therapy based on patient-specific factors, including unprovoked nature of PE event, and/or persisting DVT/PE risk factors.
Finally, consideration will be given for decreasing the apixaban dose to 2.5 mg twice-daily after 6 months.
Apixaban was selected as the anticoagulant of choice due to its very favorable bleeding profile in large clinical trials, which is an important consideration when prescribing an anticoagulant following systemic thrombolysis.
Within 24 ± 6 hours post study drug infusion, a repeat chest CTA and echocardiogram will be performed.
sPESI will also be calculated at this timepoint.At Day 30, 180 and 365, all subjects will have clinic visits which will include a physical exam, repeat echocardiogram if previous echo was abnormal, 6 minute walk test (6MWT), quality of life questionnaires, assessment of adverse and bleeding events and a review of concomitant medications including compliance with apixaban.
At Days 3, 7, 90 and 270, a remote health check will occur via telephone or email assessing adverse and bleeding events, alongside a review of concomitant medications (including an assessment of compliance with apixaban).The standard of care for patients with submassive PE is to either receive anticoagulant therapy, EKOS (Catheter Assisted Thrombolysis) or thromboectomy.
tPA is given at the FDA approved dose (100mg) occasionally at doses much higher than our study proposes.
PatientS with PE will have the initial CTA, echocardiogram and lab work as standard of care.
The follow up CTA is usually standard of care at Day 30 and the follow up echocardiograms are considered standard of care if the previous echocardiogram was abnormal.The study is being done as a proof of concept that low dose tPA is effective in clot lysis and will result in far less risk than the FDA dose.
If our study achieves its aims, the research will advance clinical practices in treating pulmonary embolism by reporting the safety of lower dose tPA and opening opportunities to further explore the use of lower dose tPA to improve patient safety and outcomes.
Study Type
Interventional
Enrollment (Actual)
4
Phase
- Phase 4
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
California
-
Los Angeles, California, United States, 90048
- Cedars-Sinai Medical Center
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 75 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Chest CT angiogram (CTA) evidence of proximal Pulmonary Embolism (PE) with a filling defect in at least one main pulmonary artery or lobar artery
- PE symptom duration ≤14 days
- Intermediate-high risk PE: defined as RV dysfunction with an RV/LV diameter ≥ 0.9, sPESI > 0, and either troponin > 0.05ng/mL or BNP > 100 pg/mL, and hemodynamically stable (systolic blood pressure > 90mmHg without the use of vasopressor support)
- Randomization within 24 + 4 hours of anticoagulation
- Signed and dated informed consent obtained from subject or legally authorized representative before initiation of any study procedures
Exclusion Criteria:
- Weight > 130kg or < 40 kg on day of randomization
- Stroke or transient ischemic attack (TIA), head trauma, or other active intracranial or intraspinal disease within one year
- Recent (within one month) or active bleeding from a major organ
- Major surgery within 14 days
- Clinician deems the subject too high-risk for bleeding using HAS-BLED criteria
- History of any hematologic disease or coagulopathy
- Cirrhosis (as determined by Child-Pugh B or C)
- History of heparin-induced thrombocytopenia (HIT)
- Hemodynamic instability defined as systolic blood pressure (SBP) less than 90mmHg and/or use of vasopressors for greater than 15 minutes
- Severe hypertension as defined as SBP greater than 180mmHg
- Cardiac arrest or active cardiopulmonary resuscitation (CPR)
- Receiving neuraxial anesthesia or undergoing spinal puncture
- Patient with prosthetic heart valves
- Evidence of irreversible neurological compromise
- Evidence of poor functional status
- History of major gastrointestinal bleed within the last month
- Active gastric or duodenal ulcers
- Use of thrombolytics or glycoprotein IIb/IIIa antagonists within 3 days prior to diagnosis
- Lovenox administration within 12 hours of randomization
- Direct-acting oral anticoagulant use (dabigatran, rivaroxaban, apixaban, or edoxaban) with last known dose within 48 hours
- Hemoglobin < 10 g/dL
- Creatinine clearances < 60 mL/min
- Platelets < 100 thousand/µL
- INR > 1.4
- Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 2 times upper limit of normal (ULN)
- Total bilirubin (TBL) ≥ 1.5 times ULN (except due to confirmed Gilbert's syndrome)
- Patient is pregnant (positive pregnancy test; women of childbearing capacity must be tested prior to enrollment) or breast feeding
- Patient who is a prisoner, or if subject who becomes compulsory detained
- Active cancer defined as diagnosis of cancer within six months before the study inclusion, or receiving treatment for cancer at the time of inclusion or any treatment for cancer during 6 months prior to randomization, or recurrent locally advanced or metastatic cancer
- Known allergy, hypersensitivity or thrombocytopenia from heparin, tPA, or apixaban or iodinated contrast except for mild-moderate contrast allergies for which steroid pre-medication can be administered within 12 hours prior to the CTA
- HIV/AIDS
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Alteplase & Unfractionated Heparin & Apixaban
Alteplase 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months.
|
Lyophilized powder for reconstitution in 50mg vials
Other Names:
Heparin sodium in 0.45% sodium chloride injection for intravenous use
Other Names:
Apixaban tablet
Other Names:
|
Active Comparator: Placebo & Unfractionated Heparin & Apixaban
Alteplase placebo solution 24mg intravenous infusion for 20 minutes followed by unfractionated heparin intravenous infusion over 24 hours followed by apixaban 10mg tablet twice-daily for one week followed by apixaban 5mg tablet twice-daily for at least 6 months.
|
Heparin sodium in 0.45% sodium chloride injection for intravenous use
Other Names:
Apixaban tablet
Other Names:
Saline solution reconstituted to mimic Alteplase 50mg vial
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Extent of Clot Lysis in the Experimental Arm
Time Frame: Baseline, 24 hours
|
Change in percentage of clot lysis in the experimental arm only as measured using the Refined Modified Miller Score (RMMS) from the baseline CTA to the 24 hour CTA after 24mg of systemic (IV) tPA + standard anticoagulation therapy (experimental arm).
|
Baseline, 24 hours
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Extent of Clot Lysis Between the Experimental Arm and the Active Comparator Arm
Time Frame: Baseline, 24 hours
|
Change in percentage of clot lysis between the experimental arm and the active comparator arm as measured using the Refined Modified Miller Score (RMMS) from the baseline CTA to the 24 hour CTA after 24mg of systemic (IV) tPA + standard anticoagulation therapy (experimental arm) compared to 24mg of systemic (IV) placebo + standard anticoagulation therapy (active comparator arm).
|
Baseline, 24 hours
|
Change in Right Ventricular to Left Ventricular Diameter (RV/LV) Ratio
Time Frame: Baseline, 24 hours
|
RV/LV ratio as measured by chest CTA from baseline to 24 ± 6 hours after the infusion of very low dose systemic (IV) tPA in patients with acute intermediate-high risk PE compared with placebo.
|
Baseline, 24 hours
|
Change in RV/LV Ratio From Baseline Echocardiogram
Time Frame: Baseline, 24 hours and 30 days
|
Change from baseline in echocardiographic parameters as measured by the RV/LV ratio within 24 hours ± 6 hours and at 30 ± 5 days after the end of the systemic (IV) tPA infusion compared with placebo.
|
Baseline, 24 hours and 30 days
|
Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) From Baseline Echocardiogram
Time Frame: Baseline, 24 hours and 30 days
|
Change from baseline in echocardiographic parameters as measured by the tricuspid annular plane systolic excursion (TAPSE) within 24 hours ± 6 hours and at 30 ± 5 days after the end of the systemic (IV) tPA infusion compared with placebo.
|
Baseline, 24 hours and 30 days
|
Change in Right Ventricular Systolic Pressure (RVSP) From Baseline Echocardiogram
Time Frame: Baseline, 24 hours and 30 days
|
Change from baseline in echocardiographic parameters as measured by the estimated right ventricular systolic pressure (RVSP) within 24 hours ± 6 hours and at 30 ± 5 days after the end of the systemic (IV) tPA infusion compared with placebo.
|
Baseline, 24 hours and 30 days
|
Change in the Collapse of the Inferior Vena Cava (IVC) From Baseline Echocardiogram
Time Frame: Baseline, 24 hours and 30 days
|
Change from baseline in echocardiographic parameters as measured by the collapse of the inferior vena cava (IVC) with respiration within 24 hours ± 6 hours and at 30 ± 5 days after the end of the systemic (IV) tPA infusion compared with placebo.
|
Baseline, 24 hours and 30 days
|
Change in the Requirement for Oxygen Therapy After 6 Minute Walk Test (6MWT)
Time Frame: 30 days, 60 days, and 1 year
|
6MWT distance as measured by the requirement for oxygen therapy at 30 day, 60 day and one year ± 14 days clinic follow-up compared with placebo.
|
30 days, 60 days, and 1 year
|
Change in Borg Dyspnea Scale Score After 6 Minute Walk Test (6MWT)
Time Frame: 30 days, 60 days, and 1 year
|
6MWT distance as measured by the Borg Dyspnea Scale score (Borg score) at 30 day, 60 day and one year ± 14 days clinic follow-up compared with placebo.
The Borg Scale measures self-reported intensity and severity of breathlessness (dyspnea) and fatigue before, during, and after a 6MWT.
Each item is scored 0 - 10 (0 = no breathlessness at all; 10 = most severe breathlessness that you have ever experienced), yielding a total between 0 and 20.
|
30 days, 60 days, and 1 year
|
Change in Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Questionnaire
Time Frame: 30 days, 6 months, and 1 year
|
Quality of life (QOL) as measured by the PROMIS PF-6at 30 days, 6 months and one year ± 14 days clinic follow-up compared with placebo.
The PROMIS PF-6 measures self-reported physical function for everyday tasks (i.e., yard work, shopping, walking up/down stairs).
Each item is score 1 - 5 (1 = unable to do/cannot do; 5 = without any difficulty/not at all), yielding a total between 6 and 30.
|
30 days, 6 months, and 1 year
|
Change in Pulmonary Embolism Quality of Life (PEmb-QOL) Questionnaire
Time Frame: 30 days, 6 months, and 1 year
|
Quality of life (QOL) as measured by the PEmb-QOL at 30 days, 6 months and one year ± 14 days clinic follow-up compared with placebo.
The PEmb-QOL measures self-reported QOL after a Pulmonary Embolism.
The PEmb-QOL has nine sub-scales with higher scores indicating worse outcomes.
Each item is score 1 - 5 (1 = unable to do/cannot do; 5 = without any difficulty/not at all), yielding a total between 6 and 30.
|
30 days, 6 months, and 1 year
|
Number of Recurrent Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) Events
Time Frame: 30 days, 60 days, 6 months, and 1 year
|
Measured as the number of recurrent DVT and/or PE events in patients at 30 days, 60 days, 6 months, and 1 year compared to placebo.
|
30 days, 60 days, 6 months, and 1 year
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: Victor F Tapson, MD, Cedars-Sinai Medical Center
- Principal Investigator: Aaron S Weinberg, MD, Cedars-Sinai Medical Center
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
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- Kucher N, Boekstegers P, Muller OJ, Kupatt C, Beyer-Westendorf J, Heitzer T, Tebbe U, Horstkotte J, Muller R, Blessing E, Greif M, Lange P, Hoffmann RT, Werth S, Barmeyer A, Hartel D, Grunwald H, Empen K, Baumgartner I. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014 Jan 28;129(4):479-86. doi: 10.1161/CIRCULATIONAHA.113.005544. Epub 2013 Nov 13.
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- Piazza G, Hohlfelder B, Jaff MR, Ouriel K, Engelhardt TC, Sterling KM, Jones NJ, Gurley JC, Bhatheja R, Kennedy RJ, Goswami N, Natarajan K, Rundback J, Sadiq IR, Liu SK, Bhalla N, Raja ML, Weinstock BS, Cynamon J, Elmasri FF, Garcia MJ, Kumar M, Ayerdi J, Soukas P, Kuo W, Liu PY, Goldhaber SZ; SEATTLE II Investigators. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv. 2015 Aug 24;8(10):1382-1392. doi: 10.1016/j.jcin.2015.04.020.
- Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. doi: 10.1056/NEJMoa1207541. Epub 2012 Dec 8.
- Tapson VF, Sterling K, Jones N, Elder M, Tripathy U, Brower J, Maholic RL, Ross CB, Natarajan K, Fong P, Greenspon L, Tamaddon H, Piracha AR, Engelhardt T, Katopodis J, Marques V, Sharp ASP, Piazza G, Goldhaber SZ. A Randomized Trial of the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Intermediate-Risk Pulmonary Embolism: The OPTALYSE PE Trial. JACC Cardiovasc Interv. 2018 Jul 23;11(14):1401-1410. doi: 10.1016/j.jcin.2018.04.008.
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- Kohn CG, Mearns ES, Parker MW, Hernandez AV, Coleman CI. Prognostic accuracy of clinical prediction rules for early post-pulmonary embolism all-cause mortality: a bivariate meta-analysis. Chest. 2015 Apr;147(4):1043-1062. doi: 10.1378/chest.14-1888. Review.
- Dalla-Volta S, Palla A, Santolicandro A, Giuntini C, Pengo V, Visioli O, Zonzin P, Zanuttini D, Barbaresi F, Agnelli G, et al. PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. J Am Coll Cardiol. 1992 Sep;20(3):520-6.
- Marti C, John G, Konstantinides S, Combescure C, Sanchez O, Lankeit M, Meyer G, Perrier A. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. 2015 Mar 7;36(10):605-14. doi: 10.1093/eurheartj/ehu218. Epub 2014 Jun 10.
- Daley MJ, Murthy MS, Peterson EJ. Bleeding risk with systemic thrombolytic therapy for pulmonary embolism: scope of the problem. Ther Adv Drug Saf. 2015 Apr;6(2):57-66. doi: 10.1177/2042098615572333. Review.
- Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-352. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7. Erratum In: Chest. 2016 Oct;150(4):988.
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Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
July 25, 2019
Primary Completion (Actual)
April 5, 2020
Study Completion (Actual)
April 5, 2020
Study Registration Dates
First Submitted
May 24, 2019
First Submitted That Met QC Criteria
June 13, 2019
First Posted (Actual)
June 18, 2019
Study Record Updates
Last Update Posted (Actual)
June 11, 2021
Last Update Submitted That Met QC Criteria
May 18, 2021
Last Verified
April 1, 2021
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Ischemia
- Pathologic Processes
- Necrosis
- Heart Diseases
- Cardiovascular Diseases
- Vascular Diseases
- Respiratory Tract Diseases
- Lung Diseases
- Embolism and Thrombosis
- Infarction
- Embolism
- Pulmonary Embolism
- Pulmonary Heart Disease
- Ventricular Dysfunction
- Ventricular Dysfunction, Right
- Pulmonary Infarction
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Fibrinolytic Agents
- Fibrin Modulating Agents
- Protease Inhibitors
- Factor Xa Inhibitors
- Antithrombins
- Serine Proteinase Inhibitors
- Anticoagulants
- Heparin
- Apixaban
- Calcium heparin
- Tissue Plasminogen Activator
- Plasminogen
Other Study ID Numbers
- Pro00054951
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
No
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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GlaxoSmithKlineCompleted
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Sociedad Española de Neumología y Cirugía TorácicaCompletedPulmonary Hypertension | Pulmonary ThromboembolismsSpain
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Imperative Care, Inc.RecruitingCardiovascular Diseases | Vascular Diseases | Embolism | Thrombosis | Thromboembolism | Acute Pulmonary Embolism | Thrombus; Embolism | Emboli, PulmonaryUnited States
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Suzhou Zenith Vascular Scitech Co., Ltd.Not yet recruitingPE - Pulmonary Embolism | PE - Pulmonary ThromboembolismChina
Clinical Trials on Alteplase
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University of ManitobaHoffmann-La RocheTerminated
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Sun Yat-Sen Memorial Hospital of Sun Yat-Sen UniversityShenzhen Hospital of Southern Medical UniversityRecruitingStroke, Acute IschemicChina
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Niguarda HospitalCompletedStroke | Cerebrovascular AccidentItaly
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Boehringer IngelheimCompletedAcute Respiratory Distress SyndromeSpain, Germany, Italy, Belgium, Mexico, Netherlands, India, France, Malaysia, Austria, Brazil, Russian Federation, Turkey
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University of North Carolina, Chapel HillGenentech, Inc.CompletedIschemic StrokeUnited States
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University Hospital, CaenSuspendedSubarachnoid HemorrhageFrance
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Centre Hospitalier Sud FrancilienCompletedAcute Ischemic Stroke Due to Medium-vessel-occlusionFrance
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Xinqiao Hospital of ChongqingZhejiang UniversityRecruitingStroke, Acute IschemicChina
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Xuanwu Hospital, BeijingRecruitingAcute Ischemic Stroke | Arterial Thrombosis | Posterior Circulation Brain InfarctionChina
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The University of Texas Health Science Center,...Genentech, Inc.CompletedIschemic StrokeUnited States