Breakthrough Platform Trial for PCAS

BPT-PCAS (Breakthrough Platform Trial for Post-Cardiac Arrest Syndrome) is a multicenter platform trial designed to evaluate whether early post-cardiac arrest care strategies can improve neurological recovery and survival in adult patients who remain comatose after return of spontaneous circulation (ROSC) following cardiac arrest and require intensive care management.

Despite advances in resuscitation and intensive care medicine, prognosis after post-cardiac arrest syndrome (PCAS) remains poor, particularly because of hypoxic-ischemic brain injury and systemic circulatory dysfunction. Many aspects of post-resuscitation intensive care management, including positioning strategies and targeted temperature management, are widely used in clinical practice but remain supported by limited high-quality randomized evidence, particularly during the ultra-early post-ROSC period.

BPT-PCAS is designed as a pragmatic multicenter cluster-randomized crossover platform trial conducted in Japan. Participating hospitals are randomized at the institutional level to predefined treatment strategies for fixed study periods. Hospitals subsequently cross over to alternative treatment strategies every 6 months according to a predefined allocation schedule. Randomization occurs at the hospital level rather than the individual patient level in order to facilitate immediate implementation of time-sensitive post-cardiac arrest interventions during emergency care.

The platform uses a master protocol structure with shared eligibility criteria, infrastructure, data management systems, and follow-up procedures across multiple intervention domains. Adult patients with persistent coma after ROSC who require intensive care are screened for eligibility under the master protocol. Individual domains may apply additional domain-specific inclusion and exclusion criteria.

The current platform includes multiple intervention domains evaluating different post-cardiac arrest care strategies.

One domain evaluates early head positioning strategies during intensive care management. This domain compares head elevation positioning (30°-45°) with near-supine positioning (0°-10°) initiated early after ICU admission in order to determine whether head positioning influences neurological recovery, mortality, and complications associated with cerebral perfusion, intracranial pressure, or respiratory management.

Another domain evaluates early targeted temperature management strategies in patients with non-shockable cardiac arrest rhythms. This domain compares early hypothermia (33-34°C) with normothermia (36-37.5°C) initiated as early as possible after ROSC in order to evaluate whether early temperature control improves neurological outcomes and survival.

Participants may simultaneously participate in more than one intervention domain when eligibility criteria are met. Aside from the assigned study interventions, all other intensive care management is performed according to local institutional practice and study protocols.

The primary and secondary outcomes differ according to each intervention domain and include neurological outcomes assessed using the modified Rankin Scale (mRS), mortality, and predefined safety outcomes. Follow-up assessments are performed during hospitalization and at 30 and 90 days after hospital admission.

Because eligible patients are critically ill and frequently incapable of providing prospective informed consent at the time of enrollment, this study permits deferred consent procedures in accordance with Japanese ethical guidelines for emergency research. Consent from legally acceptable representatives or patients themselves is obtained as soon as feasible after hospital admission whenever possible.

The study also includes predefined interim analyses and centralized data management using REDCap-based electronic data capture systems. Statistical analyses are performed using intention-to-treat principles with methods appropriate for cluster-randomized crossover trial designs.

Inclusion criteria

Master Platform Eligibility:

• Adult patients aged 18 years or older
• Return of spontaneous circulation after cardiac arrest
• Persistent coma after return of spontaneous circulation (GCS motor score <6)
• Requirement for intensive care management

Head Positioning Domain Eligibility:

• Non-traumatic out-of-hospital or in-hospital cardiac arrest
• Systolic blood pressure ≥80 mmHg or mean arterial pressure ≥65 mmHg (fluid resuscitation and vasopressor use permitted; transient hypotension recoverable within 20-30 minutes is acceptable)

Temperature Control Domain Eligibility:

• Initial non-shockable cardiac arrest rhythm
• Systolic blood pressure ≥80 mmHg or mean arterial pressure ≥65 mmHg (fluid resuscitation and vasopressor use permitted; transient hypotension recoverable within 20-30 minutes is acceptable)
• Ability to initiate temperature control therapy within 240 minutes after return of spontaneous circulation

Exclusion criteria

Master Platform Exclusion:

• Refusal of intensive care management
• Extracorporeal cardiopulmonary resuscitation (ECPR)
• Pregnancy or possible pregnancy
• Cardiac arrest due to intracranial hemorrhage, subarachnoid hemorrhage, cerebral infarction, acute aortic dissection, or terminal cancer (including suspected cases)
• Severe chronic obstructive pulmonary disease requiring home oxygen therapy
• Poor pre-arrest neurological function (CPC 3-4) or poor overall functional status (OPC 3-4)
• Pre-existing do-not-attempt-resuscitation (DNAR) order
• Expected early death
• Inability to obtain consent from a legally acceptable representative or the participant
• Enrollment judged inappropriate by the investigator

Head Positioning Domain Exclusion:

• Body temperature <30°C on hospital arrival
• Refusal of consent for participation in the head positioning domain
• Enrollment judged inappropriate by the investigator
• Patients using Impella® (a percutaneous mechanical circulatory support catheter) at the time of ICU admission
• Patients using an intra-aortic balloon pump (IABP) at the time of ICU admission
• Patients for whom feedback-controlled device-based temperature management or fever prevention is not being performed and is not planned at the time of ICU admission

Temperature Control Domain Exclusion:

• rCAST <4.5
• rCAST ≥17.0
• Traumatic cardiac arrest
• Body temperature <30°C on hospital arrival
• Refusal of consent for participation in the temperature control domain
• Enrollment judged inappropriate by the investigator