Q: There is a pause for enrollment of "Severe" state patients who are receiving organ support in an ICU at time of randomization. What does this mean for currently enrolled patients and for patients our centre is screening for the trial?

The ATTACC trial considers patients as Severe if they are in an ICU AND receiving organ support (defined as non-invasive mechanical ventilation [BIPAP or CPAP] used for acute respiratory support, invasive mechanical ventilation, high-flow nasal cannula oxygen ≥30LPM, and vasopressor or inotrope support).

Relevant scenarios are detailed below:

Participant enrolled from the ICU on organ support (as above) and randomized to therapeutic anticoagulation: This patient is classified as Severe, and should discontinue study-assigned anticoagulation, but continue to be followed for study duration. Clinicians should treat such patients as per usual practice, which may include standard, low-dose thromboprophylaxis. Please update the antithrombotic log in eSOCDAT accordingly. Further enrolment of patients meeting these criteria is paused.

Participant was enrolled from the ward and was not on organ support at the time of enrolment: This patient is classified as Moderate, and should continue on study assigned anticoagulation. Enrollment of patients meeting these criteria continues. To date, the majority of participants in ATTACC are enrolled in the Moderate state; after reviewing interim safety and efficacy data, the DSMB did not advise changes to the study protocol in thesis group.

Participant was enrolled in ICU but was not on organ support at the time (e.g., in ICU for isolation, renal replacement therapy alone; absent a mode of organ support described above): This patient is classified as Moderate, and should continue on study assigned anticoagulation. Further enrollment of patients meeting these criteria is permitted.

Participant was enrolled on ward and was on organ support while on the ward (e.g., high flow nasal cannula oxygen on the ward): This patient is classified as Moderate, and should continue on study assigned anticoagulation. Further enrolment of patients meeting these criteria is permitted. Patients deemed sufficiently stable for the ward are considered to represent a group of patients with severe degree of critical illness than those receiving organ support in an ICU. For this reason, the cut-off between Moderate and Severe is delineated here. The investigators note that definitions of an ICU may be fluid during the pandemic, and as such a repurposed ward acting as an ICU is appropriately considered an ICU.

Participant enrolled on ward but has been transferred to the ICU and is now receiving organ support: This patient is classified as Moderate, and, per the current protocol, should continue on study assigned anticoagulation. The interim analysis analyzed such patients as Moderate, and the DSMB recommended no changes to the protocol for Moderate patients. The question has been raised as to whether therapeutic anticoagulation should be discontinued in these patients. This is a matter of ongoing consideration. The DSMB is aware of the particular uncertainty pertaining to anticoagulation decisions for these patients, and is closely monitoring effectiveness and safety in this specific patient group. If clinical judgment leads to switching to intermediate or prophylactic dos anticoagulation, please nonetheless continue all follow up as all patients remain in this intent-to-treat trial.

Effort should be made to administer the study drug (therapeutic anticoagulation or usual care) as close to the time as randomization as possible. Should a patient be randomized in the moderate state, but progress to the severe state before study drug is administered, this patient should not receive therapeutic anticoagulation given an acquired exclusion criteria prior to drug administration.

Q: What does this mean if I am in the process of initiating my site?

Full speed ahead with this process. Enrollment continues for patients not in the ICU on organ support. The majority of patients enrolled in ATTACC are enrolled in the non-ICU level of care subset. Therefore, we anticipate the impact of this pause on the pace of enrollment in ATTACC to be modest.

Is enrollment in the Severe state permanently suspended?

The study team is actively analyzing the trial data and planning next steps. It is possible that the intervention arms in the severe state may be modified. We'll communicate with sites when a decision has been made.