| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10040047 |
| E.1.2 | Term | Sepsis |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to demonstrate that, in patients with protein C levels less than the lower limit of normal, alternative therapy will result in a greater increase in protein C level from Study Day 1 to Study Day 7 compared with patients receiving standard therapy with drotrecogin alfa (activated). |
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| E.2.2 | Secondary objectives of the trial |
To assess the safety of higher doses and longer infusion durations of drotrecogin alfa (activated).
To investigate if compared with patients on standard therapy:
Patients with severe protein C deficiency and patients with moderate protein C deficiency, a higher dose/variable duration of therapy gives greater increase in protein C level from Day 1 to 7
Patients on alternative therapy who complete infusion before Day 4, if protein C levels are not significantly different.
If alternative therapy is associated with a decrease in 28 day all-cause and in-hospital mortality
If alternative therapy is associated with improvements in organ dysfunction.
If protein C level greater than the lower limit of normal is associated with lower 28 day all-cause mortality compared with a protein C level less than the lower limit of normal irrespective of treatment.
PK/PD relationship between plasma APC, protein C levels, serious bleeding events, and mortality.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Addendum F1K-MC-EVDK(1): A Phase 2 Study to Evaluate Dose and Duration of Treatment of Drotrecogin Alfa (Activated) Using Serial Measurements of Protein C in Patients with Severe
Sepsis and Multiple Organ Dysfunction. Approved 30 May 2006. To be performed in addition to all procedures required by protocol F1K-MC-EVDK or any subsequent amendments to that protocol.
Objectives: Blood samples for DNA are collected and banked for research to identify the genes and gene products associated with diseases and/or response to clinical trial medication. Protein samples isolated from blood samples may be used to identify patterns of protein expression to help understand disease state mechanisms in diseases such as severe sepsis and responses to
drugs in diseases such as severe sepsis.
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| E.3 | Principal inclusion criteria |
Adult patients (>=18 years old) with severe sepsis and multiple organ dysfunction
Patients with severe sepsis are defined by the following criteria. Both criteria must be met for a diagnosis of severe sepsis with multiple organ dysfunction.
Presence of a suspected or proven infection. Patients with a suspected infection must have evidence of an infection, such as white blood cells in a normally sterile body fluid, perforated viscus, chest x-ray consistent with pneumonia and associated with purulent sputum production, or a clinical syndrome associated with a high probability of infection, for example, purpura fulminans or ascending cholangitis.
Presence of multiple organ dysfunction, which is defined as two or more sepsis-associated organ dysfunctions defined below.
Note: A patient must have organ dysfunctions attributable to the sepsis episode. The organ dysfunctions must be newly developed and not explained by underlying disease processes or by the effects of concomitant therapy. A non-sepsis-induced organ dysfunction may not be used to qualify the patient for the study even if the organ dysfunction worsens as a result of the sepsis episode.
Cardiovascular: An arterial systolic blood pressure (SBP) of <=90 mm Hg or a mean arterial pressure (MAP) <=70 mm Hg for at least 1 hour despite adequate fluid resuscitation, adequate intravascular volume status, or the need for vasopressors to maintain SBP >=90 mm Hg or MAP >=70 mm Hg.
Adequate fluid resuscitation or adequate intravascular volume is defined as one or more of the following: (a) the administration of an intravenous fluid bolus (>=500 mL of crystalloid solution, >=20 g of albumin, or >=200 mL of other colloid administered over 30 minutes or less); (b) pulmonary arterial wedge pressure >=12 mm Hg; or (c) central venous pressure >=8 mm Hg.
Vasopressors are defined as the following: (a) dopamine >=5 g/kg/min or (b) norepinephrine, epinephrine, phenylephrine, or vasopressin at any dose. Dobutamine or dopexamine are not considered vasopressors.
Renal: Average output <0.5 mL/kg/h for 1 hour despite adequate fluid resuscitation (defined above).
In the presence of preexisting impairment of renal function (defined as a serum creatine concentration >2 times the upper limit of the normal reference range for the institution prior to the onset of sepsis), the patient must meet two of the other four organ dysfunction criteria.
Respiratory: Evidence of acute pulmonary dysfunction: PaO2/FiO2 <=250 (adjusted for altitude) and, if measured, a pulmonary capillary wedge pressure not suggestive of central volume overload. If the lung is also the suspected site of infection, the patient must have a PaO2/FiO2 <200.
Hematology: Platelet count <80,000/mm3 or a 50% decrease in platelet count from the highest value recorded over the 3 days prior to study entry.
Unexplained metabolic acidosis: Defined by (1) pH <=7.30 or base deficit >=5.0 mEq/L AND (2) a plasma lactate level >1.5 times the upper limit of normal for the reporting laboratory.
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| E.4 | Principal exclusion criteria |
Have documented multiple organ dysfunction for greater than 24 hours prior to the start of study drug or the first documented sepsis-induced organ dysfunction occurred greater than 36 hours prior to the start of study drug.
Weigh less than 30 kg or greater than 135 kg.
Have a platelet count <30,000/mm3.
Patients with active internal bleeding or at increased risk for bleeding, for example:
Any major surgery, defined as surgery that requires general or spinal anesthesia, performed within the 12-hour period immediately preceding the drotrecogin alfa (activated) infusion, or any postoperative patient who demonstrates evidence of active bleeding, or any patient with planned or anticipated surgery during the infusion period (for example, patients with staged surgeries or burn patients with planned excisions and grafting during the infusion period). (Note: Peritoneal lavage alone is not considered planned surgery.)
Biopsy or surgical procedure of a closed-space within the 12 hours immediately preceding the drotrecogin alfa (activated) infusion where there is a high risk of significant bleeding and where it would not be possible to control bleeding by external pressure.
History (within the previous 3 months) of stroke or severe head trauma that required hospitalization or intracranial surgery.
History of intracranial arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion.
Patients with an epidural catheter or who are anticipated to receive an epidural catheter during drotrecogin alfa (activated) infusion.
History of congenital bleeding diatheses (for example, hemophilia).
Gastrointestinal bleeding within the 6 weeks prior to study entry that required medical intervention unless definitive endoscopic procedure or surgery has been performed.
Trauma patients at increased risk of bleeding (for example, flail chest; significant contusion to lung, liver, or spleen; retroperitoneal bleed; pelvic fracture; compartment syndrome).
Patients with known esophageal varices, chronic jaundice, cirrhosis, or chronic ascites.
Have a concurrent need for any of the following medications during the drotrecogin alfa (activated) infusion:
Therapeutic heparin, defined as unfractionated heparin >15,000 units/day within 8 hours of study entry or low molecular weight heparin used at any dose higher or more frequent than the recommended dose in the product label for prophylaxis within 12 hours of study entry.
Warfarin, if used within 7 days of study entry or warfarin-type medications within <5 half-lives at the time of study entry and where the prothrombin time (PT) is prolonged beyond the upper limit of normal for the institution.
Antiplatelets such as ticlopidine, clopidogrel, or acetylsalicylic acid (ASA) >650 mg/day or compounds that contain ASA >650 mg/day within 3 days prior to study entry.
Thrombolytic therapy (unless used to treat an intra-catheter thrombosis; however, care should be taken to avoid systemic administration) if used within 3 days of study enrollment (for example, streptokinase, tPA, rPA, and urokinase).
Glycoprotein IIb/IIIa receptor antagonists within 7 days of study entry.
Antithrombin infusion of >10,000 units within 12 hours of study entry.
Protein C concentrate infusion within 24 hours of study entry.
(Other anticoagulants, such as direct thrombin inhibitors (for example, hirudin, argatroban, bivalirudin, desirudin, lepirudin, ximelegatran, or melegatran) and factor Xa inhibitors (for example, fondaparinux) and other synthetic heparinoids within <5 half-lives of study entry.
Recombinant factor VIIa within the past 30 days
Are not expected to survive 28 days given their preexisting uncorrectable medical condition.
HIV/AIDS patients with known end-stage processes (for example, progressive multi-focal leukoencephalopathy [PML], mycobacterium avium complex [MAC], Epstein-Barr virus [EBV], or lymphoma, or a known CD4 count <50 cells/mm3).
Are moribund and death is perceived to be imminent (within 24 hours).
Are not committed to aggressive management of the patient. For example, the patient’s family or primary physician is unwilling to allow red blood cell transfusions, or an advanced directive to withhold life-sustaining treatment, with the exception of cardiopulmonary resuscitation, is present.
Have received treatment within the last 30 days with drotrecogin alfa (activated).
Have received treatment within the last 30 days with a drug or device that has not received regulatory approval for any indication at the time of study entry.
Are pregnant or lactating and the milk is to be ingested by the newborn.
Fail to give written informed consent or the patient’s legal representative fails to give written informed consent.
Are investigative site personnel directly affiliated with this study or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
Are Lilly employees.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy measure is mean change in protein C level from Study Day 1 to Study Day 7.
Twenty-eight-day all-cause mortality. The 28-day time point is defined as 672 hours from the start of the drotrecogin alfa (activated) infusion. For non-drug-interventional patients, the 28-day time point is defined as 672 hours from the end of the pretreatment period.
In-hospital mortality. Patients who remain hospitalized in the study hospital at Study Day 90 will be classified as “discharged alive.”
Sequential Organ Failure Assessment (SOFA) scoring system will be used to assess organ function. SOFA scores are based on local laboratory data, vasopressor dosages, and the need for mechanical ventilation. Organ systems to be assessed using SOFA methodology include cardiovascular, respiratory, renal, liver, and hematology.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.3.1 | Comparator description |
| Xigris standard approved therapy |
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| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Enrollment in the study will continue until 422 patients have received randomized therapy.
Patients will be assessed until Study Day 28. Patients remaining in the study hospital on Study Day 28 will be followed until they are discharged from the study hospital, have died or Study Day 90. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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