| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10040070 |
| E.1.2 | Term | Septic shock |
|
| 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 |
| To demonstrate that treatment with drotrecogin alfa (activated) 24 mcg/kg/h administered as an intravenous infusion for 96 hours reduces 28 day all-cause mortality in adult patients with septic shock compared with placebo. |
|
| E.2.2 | Secondary objectives of the trial |
To demonstrate that treatment with drotrecogin alfa (activated) reduces 28-day all-cause mortality in adult patients with septic shock and severe protein C deficiency (baseline protein C level less than or equal to half the lower limit of normal) compared with placebo.
To demonstrate that treatment with drotrecogin alfa (activated) improves cardiovascular, respiratory, and renal organ function compared with placebo.
To demonstrate that treatment with drotrecogin alfa (activated) reduces 90-day and 180-day all-cause mortality in adult patients with septic shock compared with placebo.
To demonstrate that patients treated with drotrecogin alfa (activated) have a similar quality of life compared with patients treated with placebo.
To demonstrate that drotrecogin alfa (activated) has an acceptable safety profile in this patient population.
|
|
| 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-EVDP (1) Efficacy and Safety of Drotrecogin Alfa (Activated) in Adult Patients with Septic Shock
Dated 16-Aug-07
The primary objective is to collect and store blood samples from which DNA will be extracted and protein will be isolated for research into biomarkers associated with severe sepsis and treatment with drotrecogin alfa (activated). |
|
| E.3 | Principal inclusion criteria |
[1] Must be an adult (>=18 years old)
[2] Must have evidence of an infection for which the patient is receiving intravenous antimicrobial therapy (refer to Protocol Attachment EVDP.4 for guidelines).
[3] Must have systemic inflammatory response syndrome (SIRS). Patients must meet at least 2 of the criteria defined below during the 36 hours prior to study entry.
(a) Core temperature >=38° C (100.4° F) or <=36° C (96.8° F). Core temperature is defined as rectal, central catheter, or tympanic. If oral or axillary temperature is used, add 0.5° C or 1° F to the measured value. Hypothermia (<=36° C or 96.8° F) must be determined by a rectal or central catheter temperature.
(b) Heart rate >=90 beats/minute.
(c) Respiratory rate >=20 breaths per minute or a PaCO2 <=32 mm Hg or mechanical ventilation for an acute process.
(d) White blood cell count of >=12,000/mm3 or <=4000/mm3 or >10% immature neutrophils.
[4] Must have septic shock, which is defined as the following:
(a) The patient must have received >=30 mL/kg of intravenous fluid during the resuscitation period. The resuscitation period begins 4 hours prior to the initiation of vasopressor therapy and ends 4 hours after start of vasopressor therapy).
(b) The patient must have a continuous requirement for vasopressor support for at least 4 hours at a minimum dose of at least 1 of the vasopressors shown below:
norepinephrine >=5 mcg/min
dopamine >=10 mcg/kg/min
phenylephrine >=25 mcg/min
epinephrine >=5 mcg/min
vasopressin >=0.03 units/min
(c) Must have clinical signs consistent with hypoperfusion. The patient must meet at least 1 of the following criteria during the 36 hours prior to study entry:
Metabolic acidosis: base deficit >=5.0 mEq/L or venous bicarbonate <18 mEq/L or lactate >=2.5 mMol/L.
Acute oliguria/renal injury: urine output <0.5 mL/kg/h for 1 hour or a 50% increase in creatinine from a known or calculated baseline level (estimated using the MDRD equation or a similar estimation of baseline creatinine, refer to Protocol Attachment EVDP.6). Patients with a history of chronic renal disease must meet the metabolic acidosis or acute hepatic dysfunction criterion.
Acute hepatic dysfunction: AST or ALT >500 IU/dL or bilirubin >2 g/dL. Patients with a history of acute hepatitis or chronic liver disease must meet the metabolic acidosis or oliguria/renal injury criterion for evidence of hypoperfusion.
[5] Patients must remain vasopressor dependent throughout the pretreatment period and through the time of randomization at any vasopressor dose with the goal of maintaining a systolic blood pressure of approximately 90 mm Hg or higher or a mean arterial pressure of approximately 65 mm Hg or higher with reasonable attempts made to wean the patient from vasopressor support, if applicable. (Note: dopamine at doses <5 mcg/kg/min does not fulfill the criteria for vasopressor dependency.)
|
|
| E.4 | Principal exclusion criteria |
[6] Have receivedvasopressor therapy (at any dose) for greater than 24 hours prior to the start of study drug.
[7] Have sepsis-induced organ dysfunction (respiratory, renal, hematologic, or unexplained metabolic acidosis; refer to Protocol Attachment EVDP.3 for definitions) for greater than 36 hours prior to the start of the study drug infusion.
[8] Have single organ dysfunction and recent surgery (within 30 days of study entry).
Surgery is defined as a surgical procedure that requires general or spinal anesthesia or a biopsy or surgical procedure of a closed space in which there is a high risk of significant bleeding and it would not be possible to control bleeding by external pressure.
[9] Have had surgery performed within the 12-hour period immediately preceding the study drug infusion, or are postoperative with evidence of active bleeding, or have planned or anticipated surgery during the infusion period (for example, patients with staged surgeries or burn patients with planned excisions and grafting; peritoneal lavage alone is not considered planned surgery). (Refer to exclusion criterion [8] for
definition of surgery.)
[10] Have a platelet count <30,000/mm3.
[11] Have a prothrombin time-international normalized ratio (INR) >5.0.
[12] Have active internal bleeding or are at increased risk for bleeding, for
example:
(a) History (within the previous 3 months) of stroke or severe head trauma that required hospitalization or intracranial surgery.
(b) History of intracranial arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion.
(c) Patients with an epidural catheter in place or who are anticipated to receive an epidural catheter during the study drug infusion.
(d) History of congenital bleeding diatheses (for example, hemophilia).
(e) Gastrointestinal bleeding within the 6 weeks prior to study entry that required medical intervention unless definitive/curative endoscopic procedure or surgery has been performed.
(f) Patients with known esophageal varices, chronic jaundice, cirrhosis, or chronic ascites.
(g) Trauma patients at increased risk of life-threatening bleeding (for example, flail chest; significant contusion to lung, liver, or spleen; retroperitoneal bleed; pelvic fracture; compartment syndrome).
[13] Are receiving any of the following medications at study entry or will
have a concurrent need for any of the following medications during the
study drug infusion:
(a) Therapeutic heparin, defined as unfractionated heparin >15,000 U/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 DVT prophylaxis within 12 hours of study entry.
(b) Direct thrombin inhibitors, such as argatroban, ximelagatran, melagatran, bivalirudin, lepirudin, or recombinant hirudins within 3 days of study entry.
(c) Thrombolytic therapy, such as streptokinase, tPA, rPA, or urokinase (unless used to treat intra-catheter thrombosis) within 3 days of study entry.
(d) Warfarin, if used within 7 days of study entry or warfarin-type medications within 5 half-lives of study entry and where the prothrombin time is prolonged beyond the upper limit of normal for the institution.
(e) Antiplatelet medications, such as ticlopidine, clopidogrel, or ascetylsalicylic acid (ASA) >650 mg/day or compounds that contain ASA >650 mg/day, within 3 days of study entry.
(f) Glycoprotein IIb/IIIa receptor antagonists, such as abciximab or eptifibatide, within 7 days of study entry.
(g) Recombinant factor VIIa within 30 days of study entry.
(h) Antithrombin infusion of >10,000 units within 12 hours of study entry.
(i) Protein C concentrate infusion within 24 hours of study entry.
[14] Are not expected to survive 28 days given their preexisting uncorrectable medical condition, for example, patients with, or suspected to have the following conditions:
(a) Poorly controlled neoplasms
(b) End-stage cardiac disease
(c) Cardiac arrest requiring cardiopulmonary resuscitation or with pulseless electrical activity or asystole within the past 30 days
(d) End-stage lung disease
(e) End-stage liver disease
(f) HIV/AIDS with known end-stage processes.
Refer to Protocol Attachment EVDP.5 for further guidelines.
[15] Are moribund and death is perceived to be imminent (within 24 hours).
[16] Are not committed to aggressive management of the patient. For example, the patient’s family or primary physician is unwilling to place the patient on mechanical ventilation or an advanced directive to withhold life support, with the exception of cardiopulmonary resuscitation, is present. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy measure is 28-day all-cause mortality. The 28-day time point is defined at 672 hours from randomization. All patients will be classified as either “alive at Study Day 28” or, if dead, “dead at Study Day 28.” |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 |
|
| 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
|
| Enrollment in the study will continue until 1500 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 at Study Day 90 and Study Day 180. |
|
| 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 | 9 |
| 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 | 9 |
Print
