Prophylactic Topical Epinephrine to Reduce Bleeding in Transbronchial Lung Biopsies

The role of prophylactic topical epinephrine in improving hemostasis and prevention of
clinically-significant pulmonary hemorrhage has never been studied formally in the past,
despite its common use by pulmonologists performing bronchoscopic TBLB. Lung transplant
recipients undergo multiple bronchoscopies and TBLBs for surveillance and evaluation of ACR
as well as lung infection, especially during the first year post-transplantation. This
population may have a predilection to TBLB-related bleeding and may benefit from measures to
reduce the frequency and magnitude of this relatively common complication.

In the PROPHET trial, the investigators intend to assess the degree of biopsy-related
bleeding, measures taken to control bleeding, and potential effects of bleeding on completion
of the intended procedure in 50 bronchoscopy procedures performed on single and double lung
transplant recipients, randomized to prophylactic topical epinephrine versus placebo (normal
saline). The study participant, physician performing the TBLB, and independent observer
reviewing the procedure recording will all be blinded to the randomization. Further use of
measures to control bleeding that occurs during the procedure as well as the decision to
complete the procedure as planned or to abort it prematurely will be left to the discretion
of the performer. In this way, the investigators aim to elucidate a potential role of topical
epinephrine in the prevention of TBLB-related airway bleeding in lung transplant recipients
and assess whether the dose and volume of instillation used in the investigators' institution
comprises an effective means to prevent hemorrhagic complications of TBLB.

HYPOTHESIS

The investigators hypothesize that prophylactic instillation of topical epinephrine prior to
performance of TBLB will decrease the frequency and extent of biopsy-related hemorrhage as
well as result in fewer procedures being aborted earlier than intended due to bleeding
complications as well as shorter overall procedure time due to the preventive effect on
bleeding. Concomitantly, the investigators hypothesize that the instillation of topical
epinephrine will not be associated with a serious adverse event profile in comparison to
placebo.

SPECIFIC AIMS

In this randomized-controlled double blind placebo controlled clinical trial post-lung
transplant patients scheduled to receive bronchoscopy with TBLB as part of their routine
standard of care will be randomized to receive a fixed dose and volume of topical
endobronchial epinephrine versus matching volume of placebo which will be instilled into the
target biopsy airway prior to performance of TBLB. This study will specifically aim at
providing the following information:

Aim 1: Demonstrate the feasibility of assessments of bleeding related to TBLB, including:

1. The degree of TBLB-related bleeding using a standardized grading scale used by the
physician performing the procedure to quantify the degree of procedure-related bleeding.

2. The degree of TBLB-related bleeding using a standardized grading scale used by two
independent observers blinded to patient data and study drug assignment who will review
a video recording of the procedure to quantify the degree of procedure-related bleeding.

3. The magnitude of inter-observer variability in grading TBLB-related hemorrhage based on
review of video recording of the procedure.

Aim 2: Evaluate the hypothesis that prophylactic administration of topical epinephrine
results in reductions in TBLB-related hemorrhage in lung transplant recipients, including:

1. The frequency of active measures taken to control pulmonary hemorrhage once it occurred.

2. The proportion of procedures completed as planned in terms of obtaining a predefined
target number of biopsy specimens.

3. Comparison between single- and double-lung transplant recipients in terms of prevalence
and degree of TBLB-related hemorrhage.

4. Identification of clinical factors associated with an increased or decreased risk of
procedure-related hemorrhage.

Aim 3: Evaluate the hypothesis that prophylactic administration of topical epinephrine
affects the overall efficiency of bronchoscopy with TBLB performance, including:

1. Overall duration of the bronchoscopic procedure.

2. The proportion of procedures completed as planned in terms of number of adequate
biopsies obtained as assessed by the physician performing the bronchoscopy.

3. The proportion of procedures resulting in acquisition of adequate biopsy samples that
allows proper pathologic evaluation of assignment of a pathologic diagnosis.

Aim 4: Explore the hypothesis that instillation of our prespecified dose and volume of
topical epinephrine into the target biopsy airway is not associated with an adverse event
profile that is significantly different from placebo, including:

1. The prevalence of clinically significant hemodynamic changes.

2. The prevalence of cardiac adverse events, including conduction abnormalities,
arrhythmia, and myocardial ischemia.

3. The prevalence of other vascular adverse events, including stroke, mesenteric ischemia,
and critical limb ischemia.

4. Identification of clinical factors associated with an increased or decreased risk of
drug-related adverse events.

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.