Prehospital Non-invasive Cooling of Comatose Patients After Cardiac Arrest

1 CLINICAL TRIAL PLAN 1.1 Trial Objective The objective of this outcome clinical trial is to evaluate the effectiveness and safety of ultra-early therapeutic hypothermia in cardiac arrest patients using the CAERvest® device.

1.2 Trial Design This clinical trial is a single centre randomized controlled two arm clinical trial. Randomization will be in a 1:1 ratio. The patients will be randomized to a Test Arm (OOH-Cooling; prehospital and in-hospital cooling) or to a Control Arm (Control-Cooling; in-hospital cooling only). The study will include up to 80 patients (40 subjects in each arm).

1.3 Patient Population Subjects will include out of hospital cardiac arrest patients with return of spontaneous circulation, who meet the trial eligibility requirements.

1.4 Clinical Trial Procedures 1.4.1 Patient Screening Patient screening will be conducted by emergency physicians of the emergency medical system (EMS) system of Vienna by help of the Field Supervisor System of the EMS. All out of hospital cardiac arrest, patients with return of spontaneous circulation will be evaluated for inclusion into the trial. The subject's eligibility for the study will be evaluated based on the criteria outlined above in the inclusion/exclusion criteria section.

Enrollment becomes official once eligible subjects meet inclusion/exclusion criteria and the patient is randomized to either Test or Control Arm of the trial.

Subjects may withdraw from the trial at any time at their own discretion with or without reason. Withdrawn subjects will not undergo any additional follow-up, except as desired by mutual agreement of subject and physician. In all cases of withdrawal, the reason(s) for withdrawal (if given) will be recorded upon study termination.

1.4.2 Pre-Cooling Assessment Procedures

Prior to inclusion to the trial, each subject will be assessed for the following:

- Assessment of patient clinical features, signs and symptoms

- Review of Inclusion/Exclusion Criteria

- Patient Randomization

- Availability of an ICU bed at the study centre 1.4.3 Informed Consent The reviewing Medical Ethics Committee (MEC) must review and approve an Informed Consent Form (ICF) specific to this study.

Since this trial is conducted in patients suffering from cardiac arrest, patients will be unconscious and unable to give consent. As it is a prerequisite for cooling and therefore one of the exclusion criteria that the patient has to be comatose on inclusion a formal informed consent will not be possible. According to the law on medicinal devices in Austria, the need for informed consent will be waived. As soon as patients recover and are able to understand the purpose and nature of the trial, they will be informed about their inclusion and informed consent will be sought. If information becomes available that may be relevant to the subject's willingness to continue participating in the trial, the investigator must inform the subject in a timely manner, and a revised written informed consent must be obtained.

The informed consent process (including time and date of discussion), will be documented in the subject's medical record and signed/dated by the individual (investigator or designee) who recorded it. The original signed consent form must be filed in the subject's medical record and a copy of the signed informed consent documentation given to the subject.

In obtaining and documenting informed consent, the investigator must comply with the applicable regulatory requirement(s) and adhere to ICH ( International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guideline for good clinical practice (GCP) and the requirements in the Declaration of Helsinki.

1.4.4 Randomization Patients who meet all eligibility criteria for participation will be randomly assigned to either the Test Arm (prehospital + in-hospital cooling) or Control Arm (in-hospital cooling only) in a 1:1 ratio.

Randomization will be done by using a previously prepared sealed envelope. The treating emergency physician at the patient side will open the envelope and act according to the enclosed direction. Subjects will be considered to be enrolled in the Test Arm or Control Arms of the trial when all inclusion and exclusion criteria have been met and randomization assignment has been completed.

1.4.5 Standardized Care Prior to the Cooling Procedure Subjects will receive standard postresuscitation care as part of current clinical practice in the treatment of cardiac arrest (European Resuscitation Council Guidelines 2015). Clinicians will be encouraged to manage the subject in a standardized manner.

For measuring the core temperature an oesophageal temperature probe will be inserted and connected to the defibrillator prehospital immediately after randomization and before start of prehospital cooling (in the Test Arm).

1.4.6 Prehospital Cooling Arm: Temperature Management Protocol and Data Collection Time Points Treatment with therapeutic hypothermia will begin immediately after randomization and placement of the oesophageal temperature probe with the CAERvest® device. The device will be filled with the provided fluid and then be placed on the patient's chest. After admission to the emergency department cooling will then be continued as soon as possible with an endovascular cooling device (Thermogard XP®, Zoll, San Jose, USA) set at a temperature of 33.0 °C. The subject's core temperature will then be further measured by an oesophageal temperature probe connected to ICU-Monitor and the Thermogard XP®. The cooling device will be removed, when a temperature below 34°C is reached. Cooling will be maintained for 24 hours (starting after reaching the target temperature range of under 34°C) and will be followed with active rewarming (at 0.25 °C/h) to attain normothermia (36.0 °C). After rewarming, the temperature will be controlled to be below 37.5°C for 48 hours after cardiac arrest. After this time point pyrexia will be treated with common pharmaceutical measures. Sedation, analgesia and relaxation will be discontinued earliest at a core temperature of 36.5°C.

1.4.7 Control Arm: Temperature Management Protocol and Data Collection Time Points Treatment with therapeutic hypothermia will begin as soon as possible after admission to the emergency department with an endovascular cooling device (Thermogard XP®) set at a temperature of 33.0 °C. The subject's core temperature will be measured via an oesophageal temperature probe connected to ICU-Monitor and the Thermogard XP®. Cooling will be maintained for 24 hours (starting after reaching the target temperature range of under 34°C) and will be followed with active rewarming (at 0.25 °C/h) to attain normothermia (36.0 °C). After rewarming, the temperature will be controlled to be below 37.5°C for 48 hours after cardiac arrest. After this time point pyrexia will be treated with common pharmaceutical measures. Sedation, analgesia and relaxation will be discontinued earliest at a core temperature of 36.5°C.

1.4.8 Follow-up Subjects enrolled in the study will undergo defined follow up time points after return of spontaneous circulation (ROSC). At 6h, 12h, 24h, 44-52h, 68-76h, 6-8days, 1 month and 6 months data will be collected according to the Utstein-style guidelines (data on details of the cardiac arrest, baseline demographic data, Pittsburgh Brain Stem Score, Cerebral Performance Category score, and Overall Performance Category score). At specific time points, blood samples for laboratory examinations and blood gases will be obtained as a standard procedure after cardiac arrest. At 6 months, quality of life will be assessed with the Short Form (36) Health Survey (SF-36) and the Health Utilities Index Mark 3 system (HUI3) by researchers blinded to study allocation.

1.4.9 Patient Withdrawal and Discontinuation The term "patient withdrawal" refers to the patient deciding to terminate their participation in the trial. The term "discontinuation" refers to the physician deciding that the patient will not continue trial participation as defined below.

A subject has the right to withdraw from the trial at any time and for any reason without prejudice to his or her future medical care by the physician or the institution. Trial withdrawal by a subject specifically means withdrawal of consent from further participation in the trial. Subjects who withdraw consent after enrollment will be evaluated to the time of withdrawal, and withdrawal of consent precludes any further trial related treatment or data collection. If possible, a complete, final physical examination should be performed on all subjects who withdraw from the trial. At a minimum, every effort should be made to document subject outcome at the time of trial withdrawal.

A subject may be discontinued from the clinical investigation for the following reasons:

- Any unanticipated adverse reaction which is, in the opinion of the Investigator, related to the treatment and will endanger the well-being of the patient if treatment is continued;

- Development of any illness(es), infection or condition(s) that might interfere with the Clinical Investigational Plan;

- Non-compliance with the clinical investigation procedures deemed by the Investigator to be sufficient to cause discontinuation;

- Any problem deemed by the Investigator to be sufficient to cause discontinuation.

Investigator will treat all subjects discontinued from the investigation due to an unanticipated adverse reaction, directly related to the investigation, until the reaction resolves.

Investigator will not replace subjects who have withdrawn from the clinical investigation if they have received the investigational device. If possible, Investigator will perform any procedures or assessments planned for the subject at the time of withdrawal.

All subjects are expected to continue in the trial through the final follow-up assessment or until BodyChillz Ltd notifies the Investigator in writing, that further follow-up is no longer required, except in the event of death or upon the subject's request for early withdrawal from the clinical trial.

1.4.10 Patient Lost to Follow-up The investigator will attempt to contact a subject at least three times prior to designating them as lost-to-follow-up subjects. The investigator will document the date and type of attempted communication. The investigator will complete and sign the Study Exit Form when a subject is lost to follow-up.

1.4.11 Early Termination of the Clinical Investigation Both the Sponsor and Investigator reserve the right to terminate the clinical investigation at any time. If necessary, and after review and consultation with Principal Investigator, Sponsor will make a final determination on whether to terminate the study.

A clinical investigation or Investigator may be terminated for any of the following reasons, or for reasons not listed that affect patient safety or integrity of the trial:

- Unsatisfactory rate of patient enrollment or compliance to eligibility criteria.

- Repeated noncompliance with the investigational plan.

- Inaccurate, incomplete, and/or untimely submission of data.

- Inadequate accountability of the investigational device. The sponsor may terminate this trial if there are new, previously unknown adverse events related to the device or cooling procedure, deaths, serious adverse events / adverse events exceeding those reported as related to device/cooling procedures in previous trials. The sponsor will make the final determination on whether to terminate the study.

1.4.12 Trial Exit The Trial Exit Form (CRF) should be completed at the time a subject is exited from the trial. A subject will be considered to have exited from the trial for any of the following reasons.

- Subject completes follow-ups required by the investigational plan.

- Subject dies.

- Subject requests to be withdrawn.

- Physician requests that patient be withdrawn to protect the welfare of the patient.

- Patient is lost to follow-up.