How do I screen patients for severe sepsis?

Clinical Trials

Click here for a listing of current Xigris clinical trials.

In addition to its Phase I and Phase 2 studies, Xigris has been evaluated in a Phase 3 randomized, placebo-controlled, multicenter, international study of 1690 patients with severe sepsis.

Please click on the links below to view trial data.

PROWESS study results
Xigris (drotrecogin alfa [activated]) and prophylactic heparin in severe sepsis

PROWESS study results

In this breakthrough study known as PROWESS, treatment with Xigris resulted in a statistically significant increase in the survival rate of high-risk patients.

Efficacy
The Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study was initiated in July 1998. Enrollment was suspended at the second interim analysis in June 2000 because Xigris demonstrated a significant survival benefit that exceeded the prospectively set stopping rules.

Analysis indicated a statistically significant 29% relative reduction in risk of death among high-risk (APACHE II score ≥25) patients (P=0.0002). In these patients, survival rates were 69% for Xigris patients, compared to 56% for standard therapy patients at 28 days. The difference in survival was sustained through 2.5 years of follow-up.

Organ function
In PROWESS, Xigris improved respiratory function. Xigris patients had a significantly higher MAP by day 5 (P=0.01).

By Day 7, the difference had widened, so that 65% of Xigris patients, compared to 56% of standard therapy patients, had no need for vasopressor support (P=0.01 over Days 1-7).

Compared with patients on standard therapy alone, 37% fewer Xigris patients died of septic shock.

Xigris improved cardiovascular function. Xigris patients had significantly faster resolution of respiratory dysfunction over days 1 through 7 (P=0.009), and 55% fewer Xigris patients died of respiratory failure.

Xigris also improved renal function. Patients with kidney dysfunction (defined as baseline renal SOFA=2 [creatinine 2.0-3.4 mg/dL]) receiving Xigris had a 45% decrease in serum creatinine by Day 7 (P=0.03).

Safety in high-risk patients
The rate of serious bleeding events^* attributable to Xigris during infusion was limited to 1.5% (2.2% for Xigris patients compared to 0.7% for standard therapy patients; P=NS). The rate of serious bleeds in high-risk Xigris patients receiving heparin was 2.6% vs 0.7% in standard therapy patients receiving heparin. One (0.2%) intracranial hemorrhage was observed in a Xigris patient and was associated with severe thrombocytopenia (platelet count <30,000/mm³).^†

The use of Xigris was not associated with any other adverse events.

Xigris (drotrecogin alfa [activated]) and prophylactic heparin in severe sepsis

A study in adult high-risk severe sepsis patients
Study Design: Randomized, double-blind, placebo-controlled, equivalency trial of 1935 adult severe sepsis patients with high disease severity (eg, APACHE II ≥25 and/or 2 acute organ dysfunctions) all receiving Xigris.

*Unfractionated sodium heparin given every 12 hours.

^†Enoxaparin 40 mg given every 24 hours.

^‡24 mcg/kg/hr for 96 hour infusion.

Data on file, Eli Lilly and Company.

Objective: An equivalency study to investigate the outcome and safety profile of prophylactic heparin when concomitantly administered with Xigris (96-hour infusion at 24 mcg/kg/hr).

Primary endpoint: 28-day all-cause mortality

Secondary endpoint:

Relative incidence of venous thrombotic events
Safety profile of Xigris and concomitant heparin

Baseline Characteristics in XPRESS^* and PROWESS^†

Primary endpoint: 28-Day mortality

The mortality rates for both the Xigris and placebo and the Xigris and heparin arms of the XPRESS study were consistent with the mortality rate in adult high-risk severe sepsis patients in PROWESS who were treated with Xigris
The Xigris survival benefit was not diminished by concomitant use of prophylactic heparin

Survival curve (Kaplan Meier)

Safety endpoints

Data on file, Eli Lilly and Company.

Combining low-dose heparin with Xigris did not increase the risk of serious bleeding events in high-risk severe sepsis patients. Only the incidence of non-serious bleeding was increased

Subgroup analyses of serious adverse events and mortality stratified by baseline heparin exposure

Clinicians should consider continuing prophylactic heparin when initiating Xigris therapy unless discontinuation is considered medically necessary.

Mortality and the rate of serious adverse events were increased in the subgroup of 434 patients whose low-dose heparin was stopped on study entry by randomization to placebo. This finding was based on prospectively defined exploratory subgroup analyses; however, the explanation for the finding is unclear.

*Serious bleeding events were defined as any intracranial hemorrhage, any life-threatening bleed, any bleeding event requiring the administration of ≥3 units of packed red blood cells per day for 2 consecutive days, or any bleeding event assessed as a serious adverse event.

^†At the time of enrollment in the PROWESS study, the patient had a platelet count above 30,000/mm³. The patient's platelet count fell to less than 30,000/mm³ after Xigris therapy was initiated.

Bleeding is the most common adverse reaction associated with Xigris therapy. Please see Important Safety Information and full Prescribing Information for Xigris.

Reference:

Steingrub J, Sanchez, P, Zeckel M, et al. Safety of Drotrecogin Alfa (activated). Results of MERCURY, a retrospective multicenter observational study [abstract]. Presented at the 33rd Critical Care Congress. 2004.

IMPORTANT SAFETY INFORMATION

Xigris is indicated for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death (eg, as determined by APACHE II*).

Xigris is not indicated in adult patients with severe sepsis and lower risk of death. Xigris is not indicated in pediatric patients with severe sepsis.

CONTRAINDICATIONS

Xigris increases the risk of bleeding. Xigris is contraindicated in patients with the following clinical situations in which bleeding could be associated with a high risk of death or significant morbidity:

Active internal bleeding
Recent (within 3 months) hemorrhagic stroke
Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma
Trauma with an increased risk of life-threatening bleeding
Presence of an epidural catheter
Intracranial neoplasm or mass lesion or evidence of cerebral herniation

Xigris is contraindicated in patients with known hypersensitivity to drotrecogin alfa (activated) or any component of this product.

WARNINGS

Bleeding

Bleeding is the most common serious adverse effect associated with Xigris therapy. Each patient being considered for therapy with Xigris should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy.

Certain conditions, many of which led to exclusion from the Phase 3 trial, are likely to increase the risk of bleeding with Xigris therapy. Therefore, for patients with severe sepsis who have one or more of the following conditions, the increased risk of bleeding should be carefully considered when deciding whether to use Xigris therapy:

Concurrent therapeutic heparin to treat an active thrombotic or embolic event
Platelet count <30,000 x 10⁶/L, even if the platelet count is increased after transfusions
Prothrombin time-INR >3.0
Recent (within 6 weeks) gastrointestinal bleeding
Recent administration (within 3 days) of thrombolytic therapy
Recent administration (within 7 days) of oral anticoagulants or glycoprotein IIb/IIIa inhibitors
Recent administration (within 7 days) of aspirin >650 mg per day or other platelet inhibitors
Recent (within 3 months) ischemic stroke
Intracranial arteriovenous malformation or aneurysm
Known bleeding diathesis
Chronic severe hepatic disease
Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location

Invasive procedures increase the risk of bleeding among patients receiving Xigris. Xigris should be discontinued prior to the performance of invasive surgical procedures or other procedures associated with special risks for bleeding.

Mortality in patients with single organ dysfunction and recent surgery

Among the small number of patients enrolled in PROWESS with single organ dysfunction and recent surgery (surgery within 30 days prior to study treatment) all-cause mortality was numerically higher in the Xigris group (28-day: 10/49; in-hospital: 14/48) compared to the placebo group (28-day: 8/49; in-hospital: 8/47).

In an analysis of the subset of patients with single organ dysfunction and recent surgery from a separate, randomized, placebo-controlled study (ADDRESS) of septic patients not at high risk of death all-cause mortality was also higher in the Xigris group (28-day: 67/323; in-hospital: 76/325) compared to the placebo group (28-day: 44/313; in-hospital: 62/314). Patients with single organ dysfunction and recent surgery may not be at high risk of death irrespective of APACHE II score and therefore not among the indicated population.

Clinicians should consider continuing prophylactic heparin when initiating Xigris therapy, unless discontinuation is considered medically necessary

In a randomized study of prophylactic heparin versus placebo in 1935 adult severe sepsis patients treated with Xigris, mortality and the rate of serious adverse events were increased in the subgroup of 434 patients whose low-dose heparin was stopped on study entry by randomization to placebo. This finding was based on prospectively defined exploratory subgroup analyses; however, the explanation for the finding is unclear.

ADVERSE REACTIONS

Bleeding is the most common adverse reaction associated with Xigris therapy. In the Phase 3 study, serious bleeding events were observed during the 28-day study period in 3.5% of Xigris-treated and 2.0% of placebo-treated patients. The difference in serious bleeding occurred primarily during infusion. The incidence of intracranial hemorrhage (ICH) was 0.2% for Xigris-treated and 0.1% for placebo-treated patients. ICH has been reported in Xigris-treated patients in non-placebo controlled trials with an incidence of approximately 1% during infusion. The risk of ICH may be increased in patients with risk factors for bleeding such as severe coagulopathy and severe thrombocytopenia. Should clinically important bleeding occur, immediately stop the Xigris infusion.

*APACHE (Acute Physiology And Chronic Health Evaluation).

Please refer to the full Prescribing Information for Xigris.