STAT-STatin and Aspirin in Trauma

This protocol describes a Phase II, pragmatic, prospective, randomized, double-blind,
adaptive clinical trial comparing combination rosuvastatin and aspirin therapy to placebo.
Currently, there is no treatment for fibrinolysis shutdown or effective measures to prevent
macro- and micro-thrombosis post-injury, thus, placebos are acceptable as the control group.
Treatment for both groups would otherwise be by standard of care, which includes
pharmacologic thromboembolism prophylaxis. The safety of concomitant use of VTE
pharmacological prophylaxis with statins and aspirin is well documented in cardiac surgery
patients.

Eligible adult patients with anticipated ICU admission will be screened for eligibility in
the STAT trial (see inclusion/exclusion criteria) based on history, physical exam and
clinical data obtained during their initial treatment. If deemed eligible for enrollment in
the STAT trial, the patient, their legally authorized representative (LAR), or their proxy
decision-maker will be contacted by our on-site professional research assistants (PRAs) for
consent to enroll in the study. Only patients for whom consent is obtained within 24 hours
post-injury will be eligible for randomization into the treatment phase of the study.

Upon consent, blood samples will be obtained immediately after consent at 6, 12, 24, 48, 72,
120 and 168 hours after injury. Traditional and tPA-Challenge TEG will be performed on these
samples to evaluate the development of the three fibrinolysis phenotypes. Upon receiving an
order for prophylactic anticoagulation, the DHMC pharmacy will randomize the patient to the
control or intervention arms of the study. Randomization will occur using a
computer-generated block (groups of 20 patients) random number sequence in sealed, opaque
envelopes maintained at the DHMC pharmacy. Patients assigned to the intervention arm will
receive the standard of care anticoagulation plus the combination experimental drugs (20mg of
rosuvastatin daily and 325mg of aspirin) daily either orally or crushed via feeding tube.
These doses are consistent with those currently recommended in the postoperative period
following cardiac surgery. Patients assigned to the control group will receive
identical-looking placebos at the same time points as the experimental group either orally or
crushed via feeding tube.

Healthcare providers, PRAs and patients will be blinded to study allocation standard of care
anticoagulation plus the combination placebos (produced to look and group assignment
(double-blind design).

The DHMC pharmacist will be aware of the patient's treatment arm so that rapid un-blinding
will be possible in the event of an adverse event possibly related to a study medication. The
blood samples will be used to monitor for the type of fibrinolysis, the function of the
biochemical mediators of coagulation and potential side effects of these medications, as
explained in more detail below.

Study medications or placebo will be administered during ICU admission while patients are
receiving the standard of care dosing of prophylactic anticoagulation (i.e. heparin or
heparin-derivatives) and will be interrupted concomitantly with interruption of
pharmacological VTE prophylaxis. Patients diagnosed with VTE will be withdrawn from the study
drugs and will receive the appropriate VTE treatment per current ICU protocols.

The investigators will monitor function/damage of liver, renal and muscle before initiation
of therapy (if the patient already has a recent test of these functions up to 12 hours prior
to the initiation of therapy, the result of this test will be used to avoid unnecessary
sampling), and upon the end of the therapy or as clinically necessary (i.e., any clinical
indications of organ dysfunction). Stopping rules are:

1. Bleeding: Any ongoing bleeding requiring blood transfusion or operative procedure to
stop bleeding. Bleeding will be monitored via monitoring of the daily measurements of
hemoglobin levels, which are an integral part of the ICU protocols for trauma patients.
Study medications will be unblinded and stopped if there is an unexplained drop in
hemoglobin level greater than 2g/dl within 24 hours after enrollment leading to
discontinuation of VTE Prophylaxis OR a drop in hemoglobin level greater than 1g/dl
daily for three consecutive days leading to discontinuation of VTE Prophylaxis.

2. Liver dysfunction: Alteration in liver chemistry is a rare sequela of statin therapy. A
meta-analysis of 13 placebo-controlled trials incorporating nearly 50,000 patients
examined the incidence of liver toxicity (defined as elevation of hepatic transaminases
greater than 3 times the upper limit of normal) in patients receiving statin therapy. 77
This study reported the incidence of elevated AST or ALT in statin-treated patients vs
placebo controls as 1.14% and 1.05%, respectively (OR 1.25; 95% CI 0.99

- 1.62). Further, the only individual drug associated with a statistically significant
elevation in transaminases over a follow-up interval exceeding 3 years was fluvastatin.
These and more recent data have informed expert opinion, 78 which ultimately prompted
the FDA in 2012 to revoke the recommendation that liver function tests be monitored in
patients taking statins. That said, given our at-risk patient population, the
investigators will use the accepted definition of 3 times the baseline of the AST test
as the criterion for interruption of therapy;

3. Renal dysfunction: While transient proteinuria has been observed in patients undergoing
statin therapy, acute kidney injury (AKI) is a rare complication. The JUPITER randomized
controlled trial incorporating approximately 17,000 patients and comparing rosuvastatin
to placebo found no difference in AKI (6.0% v 5.4%; p = 0.08) between the groups. 79 In
a randomized trial comparing rosuvastatin to atorvastatin, simvastatin, and pravastatin,
acute renal failure was observed in 2 of 420 patients receiving high-dose rosuvastatin.
80 The AKI as serum creatinine increase greater than 2x of baseline (>Grade 1, based on
AKIN criteria) as the criterion to interrupt therapy.

4. Muscle injury: Myositis and rhabdomyolysis are rare sequelae of statin therapy. A
meta-analysis of 26 studies incorporating nearly 130,000 patients identified an
incidence of between 1 and 4 per 10,000 patients developing rhabdomyolysis following
statin therapy. 81 This meta-analysis includes a study of 12,000 patients comparing the
efficacy of simvastatin 80mg with 20mg doses. In this study, the overall incidence of
myolysis and rhabdomyolysis were 0.5 and 0.1 per 1000 person-years, respectively,
wherein all cases of rhabdomyolysis occurred in the high dose cohort. 82 The accepted
definition of myositis is muscle pain in the setting of a serum creatine kinase
concentration greater than 10 times the patient's baseline.46 The investigators will use
this threshold to clinically quantify myositis, preceding potential development of
rhabdomyolysis, as well as the criterion to interrupt therapy.

5. If the study patient receives aspirin, as prescribed by their SICU attending,
administration of the study drug will be stopped.

6. Thrombocytopenia: If the study patient's platelet count decreases below 50,000 uL
requiring transfusion of platelets while receiving the study drug, administration of the
study drug will be stopped. This will be monitored and recorded in our twice daily
safety monitoring log.

Any of the above-mentioned stopping rules will be reported as an SAE and will trigger an
immediate review by the DSMB.

Inclusion Criteria: all adult trauma patients requiring admission to the surgical intensive
care unit (SICU) and expected hospital stay for at least 3 days. Outside hospital transfer
patients that require SICU admission less than 24 hours after their injury are also
eligible for enrollment.

Exclusion criteria for prophylactic anticoagulation and for the study are:

- Known inherited bleeding disorder or coagulopathy

- Known contraindication to pharmacologic anticoagulation

- Spinal column fracture with epidural hematoma

- Head trauma/central nervous system injury

- Severe TBI; defined as AIS Head >3

- Intracranial hemorrhage; subdural or epidural hematoma

- Neurosurgery service objection; neurosurgical contra-indications will be
documented

- Ongoing hemorrhage requiring blood product transfusion

- Thrombocytopenia (platelet count < 50,000)

- Non-operatively managed liver or spleen injuries Grade III or above

- Known chronic kidney disease (GFR < 15ml/min)

- Rising creatinine (Cr > 1.5x baseline) at the time of enrollment

- Inclusion in any other clinical trial

- Documented previous ischemic strokes

In addition, the following exclusion criteria apply:

- Receiving statin or aspirin therapy pre-injury, as potentially being assigned for
Control would increase patient's risks

- Known allergy or other contraindication to statins or aspirin

- Pregnant patients

- Prisoners, as their ability to freely consent is impaired

- Inability to obtain consent from patient or proxy prior to 48 hours post-injury

- VTE event (DVT or PE) diagnosed during current hospitalization prior to obtaining
informed consent