Protocol Review July 8, 2016 Katie Oldmixon, RN MGH DCC Protective Effects of Propranolol in Adults Following Severe Burn Injury Protocol Review July 8, 2016 Katie Oldmixon, RN MGH DCC

Collect baseline specimens Study Summary Timeline First dose of drug Burn Center Admission Burn Center Discharge Randomization Burn Injury < 96 hrs Dosing: dose every 8 hours (holding per protocol for MAP < 50 or HR < 55) < 72 hrs Alert pharmacy Collect baseline specimens Calculate dosing target heart rate and max dose First dose of study drug with 96 hrs of injury Must be admitted to burn center within 72 hrs of injury (and meet all inclusion criteria and NO exclusions) Screening Obtain Consent Treatment day 14: Obtain on-study specimens (+/- 2 days) Treatment day 4: Obtain peak and trough specimens around first dose of the day (1st 10 subjects at site)

Screening All patients who are admitted to the burn center with > 20% TBSA burn should be entered into the screening log

Screening A screening case report form (CRF) should be completed in StudyTRAX on all patients who are admitted to the burn center with > 20% TBSA burn

Example 1 16 year old patient admitted to your burn center on 11/1/13 at 1300 with burn of 30 % TBSA Date/time of burn injury: 10/31/13 at 2300 Should you enter this patient into screening log? YES Should you complete the screening CRF in StudyTRAX? Can you randomize and enroll this patient into the trial based on the info above? NO (patient meets age exclusion)

Example 2 54 year old patient admitted to your burn center on 12/1/13 at 1900 with burn of 20 % TBSA Date/time of burn injury: 11/29/13 at 2300 Meets all inclusion criteria and no exclusions After obtaining consent and randomizing, first dose of study drug must be administered by 12/3 at 2300 Obtain consent Alert pharmacy Collect baseline specimens Calculate dosing target heart rate and max dose injury admit drug deadline 11/29@ 2300 12/1@ 1900 12/3@ 2300 48 hours 72 hours 96 hours

Before First Dose: Calculate Target Heart Rate The target of propranolol dosing is a 20% reduction in mean heart rate. Mean heart rate (MHR)should be calculated over at least a four hour period. This period should occur at least 8 hours post burn injury and after patient stabilization has occurred, and no longer than 96 hours post burn. Calculation: MHR x 0.80=THR (target heart rate) MHR=158 158 x 0.80=126 (THR)

Before First Dose: Calculate maximum dose for your patient: MAX DOSE: 1 mg/kg of treatment weight (i.e. ideal body weight) every eight hours If after escalating the dose to 1 mg/kg of treatment weight (i.e. ideal body weight) every eight hours does not achieve the goal heart rate then the dose will remain at that level unless needed to be titrated lower due to safety issues.

Ideal Body Weight and Max Dose Formula: Males: IBW (kg) = 50 + 2.3 (height (in) – 60) Females: IBW (kg) = 45.5 + 2.3 (height (in) – 60) Male patient: 68 in tall has IBW of 68.4 kg MAX dose for this patient would is 70 mg study drug every 8 hours

Bedside Source Document Info needed for CRF completion

Study Drug Dosing and Titration Begin dose at 0.02 mg/kg IBW Increase by 0.1 mg/kg IBW every 6 hours until reaching THR or maximum dose (unless patient meets HR or BP threshold for holding dose) Once target heart rate achieved, maintain the current dose unless need to hold due to safety issues (see holding parameters below). Hold the dose of study drug for bradycardia (if pre-dose heart rate is < 55) Hold the dose for hypotension (pre-dose MAP < 50) Other condition as determined by treating physician After reaching THR, if HR increases above the target, dose can be increased until reaching THR or maximum dose (unless patient meets HR or BP threshold for holding dose) NOTE: heart rate and MAP should be checked and recorded prior to each dose

Resumption of Treatment Resumption of treatment after holding for low HR or MAP: Following withheld dose, restart at ½ the dose previously administered Titrate again to achieve targeted heart rate (20% of mean heart rate)

Dosing example You have enrolled a 35 year old female patient with IBW of 57 kg. You have determined her target heart rate to be 112 bpm. Based on the information below, what dose should be administered at 2400 on 7/15? 57x0.2=11.4 (round to 11mg) 57x0.1=5.7 (round to 6mg) 41 mg

Dosing (cont) Your patient continues to receive 41 mg q 6 hours for the next several days. On 7/20 at 0600 her HR is 52. What dose (if any) should be administered? None. Dose should be held due to HR <55 bpm. At 1200 her HR is 70 and MAP 62. What dose (if any) should be administered? 20 mg. Once HR >55 and MAP >50, drug can be restarted at half of the last dose given. If HR is greater than target HR, titrate as before

Study Withdrawal Subjects may be withdrawn from the study if, in the judgment of the patient’s burn surgeon, the patient has any of the following: acute myocardial event (myocardial infarction with elevated troponin level, new onset angina) septic shock with one of the following: mixed venous saturation of <70%, elevated lactate, oxygen debt extensive operations by another service (i.e. trauma, gastrointestinal bleed) or severe hypoxemia (defined as a P:F ratio <150) Subjects may choose to withdraw from the study at any time for any reason

Sample Collection Plasma samples for inflammatory markers, hormones, corticosteroids, and constitutive acute phase proteins: Baseline Sample: The baseline samples must be collected prior to administration of study drug. Treatment Day 14: The treatment day 14 sample is acceptable +/- two days from day 14 (acceptable on treatment days 12-16).

Sample Collection (cont) Propranolol kinetics: Baseline (trough) sample: On treatment day FOUR collect immediately PRIOR to administering the first dose of study drug that day. Kinetics Sample Procedure: Kinetic samples should be collected at the following time intervals AFTER the first dose on treatment day four: 30 minutes after dose 1 hour after dose 2 hours after dose 4 hours after dose 6 hours after dose (and prior to the next dose) May collect peak and tough samples on the following day if not able on day 4

Sample Collection (cont) Samples need to be centrifuged, separated, and stored within 30 minutes of collection Labels for cryotubes for all samples (kinetics and plasma) are provided by the DCC There are two labels available for each blood draw and time point Samples should be stored in a -80 degree freezer until shipping Propranolol 200013 008 Peak: 30 min 6 digit accession number Sample time point

Adverse Event Reporting Investigators will determine daily if any clinical adverse experiences occur during the study period. The investigator will evaluate any changes in laboratory values and physical signs and will determine if the change is clinically important and different from what is expected in the course of treatment of patients with severe burn injury.   If clinically important and unexpected adverse experiences occur, they will be recorded on the adverse event case report form.

Serious Adverse Events Events that meet the following criteria are considered immediately reportable SAEs and should be reported to the DCC within 24 hours of discovery: Serious in nature Unexpected (“An adverse event is considered expected if it is known to be associated with severe burn injury or treatments related to a burn injury, related to the underlying medical condition of the subject, is directly related to study outcome or is otherwise mentioned in the protocol, informed consent or other study documents”) Possibly study related

Unanticipated Problem Unanticipated Problem (UP): any incident, experience, or outcome that meets all of the following criteria: Unexpected, in terms of nature, severity, or frequency, given the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and the characteristics of the subject population being studied; Related or possibly related to participation in the research, in this guidance document, possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research; Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized. UPs should be promptly reported to HRPO and to the DCC.

SAE Reporting Timeline

Questions? Randomization website (RS2): http://rs2.partners.org/rs2/ Data entry website (StudyTRAX): https://studytrax.partners.org/