Milwaukee County EMS Amiodarone, Lidocaine Or Placebo Study

Milwaukee County EMS ALPS Protocol Information

ALPS Study Executive Summary

The primary objective of the ALPS trial (Amiodarone, Lidocaine or Neither for Out-Of- Hospital Cardiac Arrest Due to Ventricular Fibrillation or Tachycardia [ALPS: Amiodarone, Lidocaine or Placebo Study]) is to determine if survival to hospital discharge is improved with early therapeutic administration of a new Captisol-Enabled formulation of IV amiodarone compared to placebo. The secondary objectives of the trial are to determine if survival to hospital discharge is improved with early therapeutic administration of: 1) Lidocaine compared to placebo, and 2) amiodarone compared to lidocaine. Adult patients with nontraumatic out-of-hospital cardiac arrest and VF/ VT, treated by Emergency Medical Services (EMS) with Advanced Life Support (ALS) capability are eligible for randomization. The study will be randomized, double-blind, and placebo-controlled. Although antiarrhythmics are commonly used in attempted resuscitation of ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT) arrest, the survival effects of these pharmacological treatments have never been established. The trial will integrate advances in scientific understanding of VF resuscitation and incorporate important improvements in study drug formulation and delivery, while preserving clinical compatibility with current “protocolized” approaches of out-of-hospital resuscitation. Thus the trial will test a scientific approach in a clinically-relevant manner, so that the results will have direct and widespread generalizability and in turn address a substantial public health challenge. The trial will be performed under an IND which has been approved by the Food and Drug Administration, monitored closely by an independent, NIH-appointed Data and Safety Monitoring Board, and approved by all Milwaukee Institutions Research Committees prior to study onset. The study is being performed in 11 study sites throughout North America by the NIH- funded Resuscitation Outcomes Consortium (ROC). Milwaukee is one of the ROC study sites.

ALPS Protocol Questions

1. How is placebo justified?

Collectively, the relevant questions regarding antiarrhythmic drug treatment are not just which therapy is best, but also whether drug treatment itself is beneficial. To adequately address these questions requires not only a comparison of the most promising available drug therapies, but the inclusion of a placebo control. Inclusion of placebo is both scientifically necessary and ethically justifiable. In its absence, proof of one agent's apparent superiority over another might only mean that one drug is less harmful than the other, not necessarily that either is truly beneficial. The fact that no pharmacologic agent has ever been demonstrated to improve survival to hospital discharge after cardiac arrest means that study patients assigned to placebo would not necessarily be deprived of a known lifesaving treatment. To the contrary, the recognized adverse effects of antiarrhythmic drugs (including hypotension, proarrhythmia and bradycardia) may

1 worsen rather than improve outcome from cardiac arrest. Furthermore, if ineffective, the deployment of antiarrhythmic drug treatments in an illness of such short temporal duration and limited treatment opportunity as cardiac arrest potentially deprives patients of timely administration of alternate and perhaps more beneficial therapies.

Given the uncertainty as to whether antiarrhythmic drugs improve outcome after cardiac arrest, current AHA Resuscitation Guidelines classify lidocaine as "class indeterminate" (indicating there is insufficient information to recommend for or against) and amiodarone as class IIb (indicating benefit may or may not exceed its risk), consistent with a state of equipoise (an equal distribution of weight; even balance; or equilibrium). Notably, a recent randomized clinical trial found no significant differences in survival when pharmacologic treatments (including antiarrhythmic drugs) were provided or withheld entirely during the resuscitation phase of out-of-hospital cardiac arrest. This finding further supports the presence of clinical equipoise with respect to the question being evaluated in this study. The recognized shortcomings of surrogate outcomes such as return of spontaneous circulation and admission alive to hospital in predicting ultimate survival from cardiac arrest is what spurred the creation and specific charge to the Resuscitation Outcomes Consortium: to identify treatment strategies that will improve survival. This trial has been carefully reviewed by the Food and Drug Administration, who agree that clinical equipoise exists for this trial and approved the protocol as written. The study will be carefully monitored by an independent Data and Safety Monitoring Board (appointed by NIH) and the study stopped if one group has significantly better survival.

2. How will EDs know how to treat patients on arrival in a blinded study (avoiding toxicity)?

All receiving hospital emergency departments will be informed in advance about the prehospital trial and its treatment components. On arrival of a study patient to the emergency department, paramedics will immediately identify the patient as an ALPS patient and give the emergency physician an ALPS study information card (see below) containing: 1) what medications the patient may already have received, 2) suggested emergency department treatment, and 3) contact information for immediate unblinding or immediate questions. Through these methods, hospital care providers will be informed of the possibility that subjects may have already received up to 180 mg of lidocaine or up to 450 mg of amiodarone. This permits administration of supplemental doses of these medications, if clinically required after hospitalization. For example, within the parameters of accepted clinical dosing guidelines, supplemental doses of lidocaine (an additional 100-120 mg or up to a total of 3 mg/kg over the first hour) or of amiodarone (up to 2 gms over the first 24 hours) may be administered within the initial hours of hospitalization. If needed, higher doses of lidocaine may be guided by measurement of plasma concentrations in accordance with current clinical practice. Because of the waning plasma concentrations of prehospital-administered study medications, it is not anticipated that the prior use of medications will be a clinical consideration after the first 1-2 hours of hospitalization. It is also the current impression of the investigators that amiodarone (which has a higher therapeutic index for dosing than lidocaine) is more likely to be used

2 preferentially over lidocaine for initial treatment of ventricular arrhythmias in hospitals, making it less likely that higher doses of lidocaine will be deployed after hospitalization. If unblinding is required for safety or treatment purposes during the course of the study, a 24/7 hotline is in place through which the study medication given by EMS will be promptly disclosed.

ALPS Study Information Card left with ED Physician by Paramedics:

ALPS Study Patient

This patient had ventricular fibrillation and may have already received:  Up to 180 mg of lidocaine IV …OR  Up to 450 mg of amiodarone IV

***SUGGESTED EMERGENCY DEPARTMENT TREATMENT***

 All standard hospital treatments may be given, including…  Up to 100-120mg of lidocaine now and over the next 2 hours (standard doses thereafter)  Amiodarone (or other drugs) in standard doses now

For Immediate Unblinding ONLY: Call 1-800- 238-5549 For Immediate Questions or Concerns: Call 414-805-6493 Additional questions: Contact Tom P. Aufderheide, MD at [email protected]