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Prophylactic Topical Epinephrine to Reduce Bleeding in Transbronchial Lung Biopsies (PROPHET)

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ClinicalTrials.gov Identifier: NCT03126968
Recruitment Status : Recruiting
First Posted : April 25, 2017
Last Update Posted : February 1, 2019
Sponsor:
Information provided by (Responsible Party):
Robert Reed, University of Maryland, College Park

Brief Summary:
Bleeding poses potential for significant complication after transbronchial lung biopsies. The investigators hypothesize that prophylactic intrabronchial instillation of topical epinephrine will reduce the likelihood of bleeding. The investigators plan a double-blind, placebo controlled trial to evaluate this hypothesis.

Condition or disease Intervention/treatment Phase
Lung Transplant; Complications, Mechanical Lung Transplant; Complications Bleeding Hemoptysis Drug: Topical epinephrine Drug: Placebos Phase 2 Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Prophylactic Topical Epinephrine to Reduce Transbronchial Lung Biopsy-related Hemorrhage in Lung Transplant Recipients: a Prospective Double-blind Placebo-controlled Trial (PROPHylactic Epinephrine in Transbronchial Biopsy [PROPHET] Trial)
Actual Study Start Date : July 1, 2017
Estimated Primary Completion Date : July 30, 2020
Estimated Study Completion Date : July 30, 2020


Arm Intervention/treatment
Experimental: Prophylactic topical epinephrine
Study participants who meet inclusion and exclusion criteria and allocated to this arm will be randomized to receive prophylactic endobronchial topical epinephrine in a blinded manner prior to performance of transbronchial lung biopsy.
Drug: Topical epinephrine
Prophylactic topical epinephrine

Placebo Comparator: Placebo
Study participants who meet inclusion and exclusion criteria and allocated to this arm will be randomized to receive prophylactic endobronchial topical placebo in the form of normal saline in a blinded manner prior to performance of transbronchial lung biopsy.
Drug: Placebos
Topical placebo (normal saline)
Other Name: Placebo




Primary Outcome Measures :
  1. Major hemorrhage as defined by two independent reviewers. [ Time Frame: Primary outcome is defined as hemorrhage occurring up to 30 minutes after withdrawal of the bronchoscope and deemed related to transbronchial lung biopsy. ]

    The primary efficacy outcome of the PROPHET Study is the prevalence of major hemorrhage during bronchoscopy as defined by two independent reviewers who will review the procedure video while blinded to the individual patient information, study drug assignment, and any procedure related data not recorded on video. Hemorrhage will be graded according to the following grading system:

    1. No hemorrhage.
    2. Minor hemorrhage - Endobronchial hemorrhage resulting in segmental or more distal bronchus blood spillage.
    3. Intermediate hemorrhage - Endobronchial hemorrhage resulting in lobar bronchus blood spillage.
    4. Major hemorrhage - Endobronchial hemorrhage resulting in mainstem bronchus, more proximal blood spillage, or spillage into the uninvolved lung.


Secondary Outcome Measures :
  1. Occurrence of no, minor, or intermediate bleeding as defined by the independent reviewer. [ Time Frame: This outcome is defined as hemorrhage occurring during the bronchoscopic procedure and deemed related to transbronchial lung biopsy and up to 30 minutes following withdrawal of the bronchoscope. ]
    Prevalence of no-, minor, or intermediate hemorrhage during bronchoscopy as defined by two independent reviewers who will review the procedure video while blinded to the individual patient information, study drug assignment, and any procedure related data not recorded on video.

  2. Intra-procedural hemorrhage grading by the performing bronchoscopist [ Time Frame: This outcome will be analyzed at the time of procedure performance and up to 48 hours following the procedure. ]

    Intra-procedural hemorrhage will be graded by the performing bronchoscopist according to the following scale:

    1. No hemorrhage.
    2. Mild hemorrhage - Any bleeding originating from the biopsy target airway requiring wedging of the bronchoscope or "in and out" motion in order to achieve hemostasis.
    3. Moderate hemorrhage - Any bleeding originating from the biopsy target airway requiring in addition to maneuvering the bronchoscope application of iced saline or topical epinephrine or placing the patient with the bleeding lung in the dependent position.
    4. Severe hemorrhage - Any bleeding originating from the biopsy target airway requiring, in addition to the above-mentioned maneuvers, early termination of the procedure or necessitating application of balloon tamponade, endotracheal intubation, application of a bronchial blocker, or use of other invasive measures to achieve hemostasis, such as bronchial artery embolization or surgical intervention.

  3. Number of forceps passes performed [ Time Frame: This outcome will be analyzed at the time of procedure performance. ]
    Number of biopsy forceps passes performed during bronchoscopy.

  4. Number of adequate tissue samples obtained [ Time Frame: This outcome will be analyzed at the time of procedure performance. ]
    Number of adequate tissue samples obtained during bronchoscopy as assessed by the performing bronchoscopist.

  5. Early termination of the procedure [ Time Frame: This outcome will be analyzed at the time of procedure performance. ]
    Early termination of the procedure due to bleeding complication, defined as non-achievement of the target number of tissue samples as designated by the performing bronchoscopist prior to the procedure related to hemorrhage.

  6. Duration of the procedure [ Time Frame: Duration of the procedure from first bronchoscope insertion to last bronchoscope withdrawal. ]
    Duration of the procedure from first bronchoscope insertion to last bronchoscope withdrawal.

  7. Total volume of iced saline used [ Time Frame: This outcome will be analyzed at the time of procedure performance. ]
    Total volume (mL) of iced saline used during the procedure.

  8. Total dose of unblended topical epinephrine used [ Time Frame: This outcome will be analyzed at the time of procedure performance. ]
    Total dose (mg) of unblended topical epinephrine used during the procedure.

  9. Any use of hemostatic measures [ Time Frame: This outcome will be analyzed at the time of procedure performance. ]
    Any use of hemostatic procedures including balloon tamponade, endobronchial blocker, bronchial artery embolization, emergency surgery.

  10. Any use of devices or procedures with intention of securing the airway [ Time Frame: This outcome will be analyzed at the time of procedure performance. ]
    Any use of devices or procedures with intention of securing the airway including oral airway, nasal airway, laryngeal mask, endotracheal intubation, emergency cricothyroidotomy, and emergency tracheostomy.

  11. Unplanned admission to the hospital. [ Time Frame: This outcome will be analyzed at the time of procedure performance and up to 48 hours following the procedure. ]
    Unplanned admission to the hospital.

  12. Pathologic diagnosis achieved. [ Time Frame: Up to 30 days post-procedure. ]
    Biopsy resulting in acquisition of a specimen which allows a viable pathologic diagnosis.

  13. All-cause mortality [ Time Frame: Within 3 hours on instillation of study drug. ]
    All-cause mortality

  14. Acute cardiovascular event [ Time Frame: Within 30 minutes of instillation of the study drug. ]
    Acute cardiovascular event, including cardiac arrest, new onset chest pain, acute myocardial ischemia, pulmonary edema, acute ischemic stroke, critical limb ischemia, acute mesenteric ischemia.

  15. Acute closed angle glaucoma [ Time Frame: Within 30 minutes of instillation of the study drug. ]
    Acute closed angle glaucoma

  16. New onset ECG changes suggestive of myocardial ischemia [ Time Frame: Within 30 minutes of instillation of the study drug. ]
    New onset ECG changes suggestive of myocardial ischemia, including ST segment changes (defined: ≥1 mm ST segment elevation or ≥3 mm ST segment depression in ≥2 precordial or limb ECG leads that correspond together to one of the cardiac walls), new onset ventricular tachycardia, significant increase (≥10 per minute) in occurrence of ventricular ectopic beats, new onset supraventricular arrhythmia, new onset bundle branch block, and new onset 2nd or 3rd degree atrioventricular block.

  17. Significant change in heart rate [ Time Frame: Within 30 minutes of instillation of the study drug. ]
    Significant change in heart rate, defined as heart rate of >120 bpm and/or increase by ≥30 bpm above the baseline or heart rate <60 bpm and/or ≥30 bpm below the baseline.

  18. Significant change in systolic blood pressure [ Time Frame: Within 30 minutes of instillation of the study drug. ]
    Significant change in systolic blood pressure, defined as increase in systolic blood pressure >180 mm Hg and/or ≥40 mm Hg above the baseline; increase in diastolic blood pressure >110 mm Hg and/or ≥20 mm Hg above the baseline; or fall in systolic blood pressure <90 mm Hg and/or ≥20 mm Hg below the baseline.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male and female subjects, ≥18 years of age.
  • Single- or double-lung transplant recipients scheduled for bronchoscopy with TBLB.
  • Willingness to sign an informed consent for study participation.

Exclusion Criteria:

  • Age <18 years.
  • Pregnancy.
  • Inability to understand and provide a written informed consent.

Exclusion criteria for TBLB:

  • Platelet count <50 K/microL.
  • International normalized ratio (INR) >1.5.
  • Known bleeding diathesis.
  • Use of prophylactic or therapeutic dose of unfractionated heparin within 6 hours of the procedure.
  • Use of prophylactic dose of low molecular weight heparin within 12 hours of the procedure.
  • Use of therapeutic dose of low molecular weight heparin within 24 hours of the procedure.
  • Use of oral direct thrombin inhibitors or oral factor 10a inhibitors within 48 hours of the procedure.
  • Use of clopidogrel, ticlopidine, ticagrelor, or prasugrel within 5 days of the procedure.
  • Uremia, defined as estimated glomerular filtration rate (eGFR) ≤30 mL/min.
  • Moderate to severe pulmonary hypertension as defined by a mean pulmonary artery pressure of >40 mm Hg on right heart catheterization or an estimated pulmonary artery systolic pressure of >62 mm Hg on transthoracic echocardiography, both performed within 1 year of the procedure.
  • An additional synchronous procedure with possible bleeding (bronchoalveolar lavage and endobronchial biopsy allowed).
  • Decompensated liver cirrhosis, defined as the presence of clinically significant ascites, clinical evidence of esophageal or gastric varices, or history of bleeding from gastric or esophageal varices.
  • Prior history of TBLB-related airway bleeding requiring admission to the hospital or advanced measures to achieve hemostasis, including endotracheal intubation, bronchial blocker application, bronchial artery embolization, or surgical intervention.

Exclusion criteria for application of topical epinephrine:

  • Systolic heart failure with an ejection fraction (EF) of <35% as assess by echocardiography performed within one year prior to the procedure.
  • Myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, or coronary artery bypass surgery within 6 months prior to the procedure.
  • Symptoms and/or ECG findings suggestive of ongoing cardiac ischemia on the day of the procedure.
  • Moderate- to severe-grade cardiac valvulopathy as assessed by echocardiography performed within one year prior to the procedure.
  • Inadequately controlled supraventricular arrhythmia, including atrial fibrillation, atrial flutter, and atrio-ventricular node re-entrant tachycardia (AVNRT) as revealed by ECG or cardiac monitoring at the time of the procedure.
  • Presence of an internal cardioverter/defibrillator.
  • History of second or third degree (complete) heart block or sick sinus syndrome.
  • Baseline ECG or cardiac monitoring revealing frequent occurrence (≥10 events per minute) of atrial or ventricular ectopy documented prior to or at the time of the procedure.
  • History of ventricular arrhythmias requiring pharmacologic or electrical cardioversion within the 2 years preceding the procedure.
  • Serum potassium of <3.0 mmol/L within the week prior to the procedure.
  • Serum glucose level of ≥300 mg/dL within the week prior to the procedure.
  • Any history of critical ischemia related to peripheral arterial disease.
  • Persistent resting heart rate (HR) measurement of ≥120 beats per minute prior to or at the time of the procedure.
  • Persistent resting systolic blood pressure (SBP) measurement of ≥180 mm Hg prior to or at the time of the procedure.
  • Persistent resting diastolic blood pressure (DBP) measurement of ≥110 mm Hg prior to or at the time of the procedure.
  • History of acute closed-angle glaucoma within one year of the procedure.
  • Diagnosis of pheochromocytoma requiring pharmacologic therapy with an alpha adrenoreceptor blocker at the time of the procedure.
  • Diagnosis of thyrotoxicosis requiring pharmacologic therapy with an anti-thyroid agent at the time of the procedure.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03126968


Contacts
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Contact: Robert M Reed, MD +1-410-328-8141 rreed@som.umaryland.edu
Contact: Or Kalchiem-Dekel, MD +1-410-328-8141 orkalchiemdekel@umm.edu

Locations
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United States, Maryland
University of Maryland Medical Center - Midtown Campus Recruiting
Baltimore, Maryland, United States, 21201
Contact: Robert M Reed, MD    410-328-8141    rreed@som.umaryland.edu   
Contact: Or Kalchiem-Dekel, MD    +1-410-328-8141    orkalchiemdekel@umm.edu   
Sub-Investigator: Bich-Chiu Tran, MD         
Sub-Investigator: Nirav G Shah, MD         
Sub-Investigator: Edward M Pickering, MD         
Sub-Investigator: Aldo Iacono, MD         
University of Maryland Medical Center Recruiting
Baltimore, Maryland, United States, 21201
Contact: Robert M Reed, MD    410-328-8141    rreed@som.umaryland.edu   
Contact: Or Kalchiem-Dekel, MD    +1-410-328-8141    orkalchiemdekel@umm.edu   
Sub-Investigator: Nirav G Shah, MD         
Sub-Investigator: Edward M Pickering, MD         
Sub-Investigator: Bich-Chieu Tran, MD         
Sub-Investigator: Mark Sperry, MD         
Sub-Investigator: Aldo Iacono, MD         
Sponsors and Collaborators
University of Maryland, College Park
Investigators
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Principal Investigator: Robert M Reed, MD University of Maryland, College Park

Publications of Results:
Other Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Robert Reed, Associate Professor, University of Maryland, College Park
ClinicalTrials.gov Identifier: NCT03126968     History of Changes
Other Study ID Numbers: HP-00070208
First Posted: April 25, 2017    Key Record Dates
Last Update Posted: February 1, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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.: Yes
Additional relevant MeSH terms:
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Hemoptysis
Hemorrhage
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Epinephrine
Racepinephrine
Epinephryl borate
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Adrenergic beta-Agonists
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Mydriatics
Sympathomimetics
Vasoconstrictor Agents