Trial Synopsis

 
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Background and significance:

Sepsis and septic shock account for 10% of admissions to the intensive care unit and constitute the second most frequent cause of death among admitted patients. The mortality rate associated with septic shock ranges from 30% to 50% and death is often due to multiple organ dysfunction coupled with systemic inflammation. Given the pathobiological relationship between coagulation and inflammation in sepsis, treatment with anticoagulants has been investigated in this population. Multiple lines of evidence suggest that heparin, a widely available, inexpensive anticoagulant, may improve clinical outcomes in sepsis, but high quality evidence to guide practice is lacking. A recent survey of Canadian critical care physicians demonstrated extensive support for clinical trials of heparin in patients with severe sepsis and septic shock.

Hypothesis:

Intravenous (IV) unfractionated heparin (UFH) reduces mortality and morbidity when administered to patients with suspected septic shock.

Objective:

Our primary outcome of efficacy is vasopressor-free days.

Study Design:

A pragmatic open-label international randomized trial comparing therapeutic dose intravenous unfractionated heparin (UFH) to standard care venous thromboprophylaxis in patients diagnosed with septic shock.

Setting:

To increase the external validity/generalizability of the trial results, 20 sites in 4 countries will participate.

Study Population:

Patients with systemic inflammation, vasopressor dependent shock, and signs of organ dysfunction.

Interventions:

IV infusion of UFH at 18 IU/kg/hr, dosed according to total body weight and pragmatically adjusted according to usual care to achieve an activated partial thromboplastin time (aPTT) of 60-95 seconds for a maximum of 5 days (120 hours) or until death or ICU discharge. The dose of UFH has been informed by our observational study and meta-analysis that showed a benefit of UFH in patients receiving therapeutic doses. This dose is further supported by our translational analyses that showed restoration of Protein C levels and decreased cytokines with 18 IU/kg of UFH and reflects pragmatic dosing used in every clinical setting.

Control group:

Standard care for venous thromboprophylaxis (i.e. not therapeutic) which may include SC dalteparin 5000 IU, SC UFH 5000 IU twice daily, sequential compression devices or graduated compression stockings. 

Outcomes

At the end of the HALO international phase II trial, an international Data Safety Monitoring Board (DSMB) will be presented with by-group efficacy (vasopressor-free days) data in the context of 60-day mortality, and safety (bleeding and transfusion). With these data the DSMB will suggest: a) terminating enrollment for futility (lack of efficacy) or harm, or b) continuing to the phase III trial along with a recommended sample size to detect a clinically relevant difference in 60-day mortality. Patients will be analyzed according to the treatment group to which they are allocated. Analysis will consider potential differential treatment effects by country, baseline mortality rate, time-to-antibiotics, and characteristics of the infection. By-group data will remain blinded to study investigators so that these patients may be included in the HALO international phase III RCT. Our analytic approach provides a rationale to either stop, or to justify further investment in a large international phase III trial.

Duration of study intervention:

Maximum of 5 days (120 hours) or until death or discontinuation of vasopressor agents. All patients will then receive venous thromboprophylaxis according to local practice.

Sample Size:

We will randomize 500 patients. The primary purpose of a phase II trial is to decide whether progressing to a phase III trial is justified.

Interpretation of potential results:

All aspects of the HALO research program, including the international phase II RCT, have integrated core components of the knowledge-to-action cycle to facilitate incorporation of new evidence and ensure widespread uptake of new knowledge.

Timeline:

In the context of staggered site start up, we anticipate completing the trial within 3 years, allowing for 3 months to complete the final outcome assessment, data verification, and data analysis.