| 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 | PT |
| E.1.2 | Classification code | 10040047 |
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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 |
| To demonstrate that eritoran tetrasodium treatment of patients with severe sepsis results in a reduction in 28-day all-cause mortality. |
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| E.2.2 | Secondary objectives of the trial |
To confirm eritoran’s safety profile, and to demonstrate long-term benefit of eritoran treatment (reduction in 12-month mortality). In addition, the population pharmacokinetic (PK) profile of eritoran will be evaluated.
Exploratory objectives are to determine the effects of eritoran treatment on duration of ICU and overall hospital stay, duration of organ dysfunction (ie, duration of dialysis, duration of mechanical ventilation, or use of vasopressors within 28 days), levels of inflammatory markers, SOFA scores, infectious episodes subsequent to randomization, and pharmacoeconomic and quality of life (QoL)measures. Appropriateness of antibiotic regimen will also be explored. In addition, efficacy and safety measures will be examined using an exploratory population pharmacokinetic/ pharmacodynamic (PK/PD) analysis. |
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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 |
Study Title: The BioACCESS substudy
Protocol Version and Date: Amendment 03 dated 28 August 2008
Study Objectives: To collect genomic DNA to probe for interactions between genetic polymorphisms and eritoran tetrasodium efficacy and toxicity, as well as predisposition to sepsis.
NOTE: The BioACCESS substudy shall not be implemented in Czech Republic.
Other Sub-study:
Study Title: A substudy of ACCESS: The Measurement of Baseline Endotoxin Levels and comparison of its levels in patients with severe sepsis dosed with Eritoran Tetrasodium or Placebo.
Protocol Version and Date: Amendment C dated 10-Jan- 2008 for France and Belgium
Study Objectives: Baseline Endotoxin levels will be measured in approximately 300 subjects at designated sites to explore the possible relationship between endotoxin level, quantified by the endotoxin activity assay (EAA), and response to eritoran therapy, as measured by the 28-day, all cause mortality.
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| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years; no upper age limit
2. Confirmed early onset severe sepsis defined as:
• Objective evidence of infection likely to be caused by a bacterial or fungal pathogen. Examples of objective evidence may include clinical findings (eg, cellulitis or abscesses), cultures, Gram stains, X-rays, and surgical pathology specimens. A positive culture is not a requirement for entry into the trial, unless primary bacteremia is claimed as the sepsis episode.
• Occurrence of at least three of the four SIRS criteria below
These criteria should have occurred between 12 hours before and 4 hours after the onset of the qualifying organ dysfunction.
o Core (central, urinary, esophageal, or rectal) body temperature ≤ 36º C or core (preferred), oral, or tympanic body temperature ≥ 38 C
may be enrolled.
Non-core temperatures are not to be adjusted. (revised per Amendment 01)
o Heart rate ≥ 90 beats/minute (patients who cannot be assessed for sepsis induced tachycardia due to another medical condition known to increase heart rate, or those receiving treatment that prevents tachycardia, must have 2 of the remaining 3 SIRS criteria)
o Respiratory rate >20 breaths per minute or a PaCO2 < 32 mm Hg, or mechanical ventilation
o WBC count ≥ 12,000 cells/μL, ≤ 4000 cells/μL, or > 10% band forms
3. At least one of the following organ dysfunctions:
• Acute Lung Injury (ALI) / Acute Respiratory Distress Syndrome (ARDS):
o Acute onset of all four criteria below must occur together within a 24-hour interval, and the time of organ dysfunction is defined as the time that the final (fourth) criterion occurred:
- PaO2/FiO2 ≤ 300 (<200 in patients with pneumonia). If altitude > 1000 m, then PaO2/FiO2 ≤300 x (PB/760).
- Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph. The infiltrates may be patchy, diffuse, homogeneous, or asymmetric.
- Requirement for positive pressure ventilation via endotracheal tube or tracheostomy tube
- No clinical evidence of left atrial hypertension
o No history of severe chronic respiratory disease:
- FEV1 less than 20 mL/kg PBW (eg, 1.4 L for 70 kg), or
- FEV1/VC less than 50% predicted, or
- Chronic hypercapnia (PaCO2 greater than 45 mmHg) and/or chronic hypoxemia (PaO2 < 55 mm Hg) on FiO2 = 0.21, or
- Radiographic evidence of chronic over-inflation or chronic interstitial infiltration, or
- Hospitalization within the past 6 months for respiratory failure (PaCO2 > 50 mm Hg or PaO2 < 55 mm Hg or O2-Sat < 88% on FiO2 = 0.21), or
- Chronic restrictive, obstructive, neuromuscular, chest wall or pulmonary vascular disease resulting in severe exercise restriction (eg, unable to climb stairs or perform household duties), secondary polycythemia, severe pulmonary hypertension (mean > 40 mm Hg), or ventilator dependency
• Thrombocytopenia:
o Acute onset of platelet count < 100,000 or a reduction of 50% or more from prior known levels, without past history of thrombocytopenia, and without attributable cause other than infection
• Lactic acidosis: (revised per Amendment 03)
o Unexplained metabolic acidosis (arterial pH < 7.30 or a base deficit > 5.0 mmol/L) in association with an arterial or venous plasma lactate level > 2.2 mmol/L (19.8 mg/dL) (revised per Amendment 02 for those patients enrolled after approval of the amendment).
• Shock:
o Acute onset of systolic blood pressure < 90 mm Hg or mean arterial pressure < 65 mm Hg. Blood pressure is poorly responsive to at least one hour of aggressive fluid resuscitation with a crystalloid or colloid, and vasopressors are required to maintain mean arterial pressure > 65 mm Hg.
o Mechanically ventilated patients must exhibit hypotension due to sepsis before the institution of mechanical ventilation or be hypotensive for at least 60 minutes following intubation to qualify for the study on the basis of shock
• Acute Renal Failure:
o Urine output < 0.5 mL/kg ideal body weight/hr for at least two hours, despite administration of at least 500 mL crystalloid or 200 mL colloid over a 30 minute period. Subjects with chronic renal disease cannot qualify for the study based on renal failure alone, but can be enrolled if they meet criteria for another organ failure(revised per amendment 03)
Note: The formula for calculating the ideal body weight is provided in reference 17 and under Appendix 10.
4. A reasonable likelihood that administration of study drug can be started within 12 hours of documented organ dysfunction
5. APACHE II Score (at screening) of 21 to 37, inclusive (revised per Amendment 02)
6. There must be a commitment to full patient support. If a patient’s family has not committed to aggressive management of the patient’s condition or has requested that the patient be classified as “Do not resuscitate” or “Do not treat,” the patient is excluded. If a family directive allows all resuscitative efforts other than chest compression, the patient may be enrolled. |
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| E.4 | Principal exclusion criteria |
1. Pregnancy or breast feeding
2. Extensive (> 20% body surface area) third degree burns within prior 7 days
3. Patients whose death from sepsis or an underlying condition is considered imminent
4. Patients with an expected survival of less than 2 months due to a pre-existing and uncorrectable medical condition, or those in a chronic vegetative state
5. Patients currently receiving immunosuppressive therapy
Consult Appendix 9 for a list of representative excluded therapies. Any subsequent modification to this list will be in the form of memos to the study sites. For agents not listed, patients should be off such therapies for a time sufficient to restore immune function. (revised per Amendment 01).
6. Patients with granulocyte counts < 1000/mm3 unless the decreased count is believed to be due to sepsis
7. Patients who required cardiopulmonary resuscitation in the 4 weeks prior to evaluation for enrollment
8. HIV-positive patients with a last known CD4 count ≤ 50/mm3, or end-stage processes (eg, systemic M. avium infection, progressive multifocal leukoencephalopathy)
9. Patients with significant hepatic impairment (Child-Pugh class C), portal hypertension, or esophageal varices
10. Patients with severe congestive heart failure (eg, NYHA Class IV, ejection fraction < 35%)
11. Weight >150 kg at time of evaluation for enrollment.
12. Any one of the following (revised per Amendment 01):
• Ongoing or planned high-flux continuous hemofiltration or hemodiafiltration for the indication of sepsis in the absence of renal impairment
NOTE: Continuous hemofiltration or hemodiafiltration using ultracentrifugation volumes ≤ 35 mL/kg/hr for renal replacement therapy, and hemodialysis, are permissible.
• Ongoing or planned use of endotoxin removal devices, such as polymyxin B columns or cartridges
• Ongoing or planned use of IV polymyxins (e.g, polymyxin B or colistin [polymyxin E])
• Ongoing or planned plasma exchange performed for the indication of sepsis
13. IL-2 or interferon therapy within 30 days prior to enrollment
14. Patients must not have taken any investigational medications or been treated with an investigational device (ie, not approved by the relevant regulatory agency for any indication) within the 30-day period prior to enrollment into the study
15. Cancer patients with active disease* or who have not completed their chemotherapy regimen (added per Amendment 01)
• Patients believed to be free of active disease may be eligible, provided they have received no cancer chemotherapy or other cancer treatment for a minimum of 3 months (unless a longer exclusionary period is specified for an agent used in treatment) (see Appendix 9).
• Prophylactic use of tamoxifen for prevention of breast cancer is permitted.
• Adjuvant hormonal therapy is permitted.
*Subjects with basal cell carcinoma, cervical carcinoma in situ, or low-grade prostate cancer are eligible.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is all-cause mortality at Day 28. The difference in mortality rates between treatment groups will compared using a chi-square test.
Key secondary endpoint:
Mortality at 1 year
Other endpoints of interest:
• Length of ICU stay within 28 days
• Length of hospital stay within 28 days
• Duration of dialysis within 28 days
• Duration of mechanical ventilation within 28 days
• Duration of use of vasopressors within 28 days
• Measurement of inflammatory markers (cytokines) and procalcitonin
• SOFA score
• Mortality at 3 and 6 months
• Incidence of infection episodes subsequent to randomization
• Pharmacoeconomics
• Quality of Life
• Adequacy of initial antibiotic treatment
• Pharmacogenetics
Safety assessments include adverse events, ECG parameters, vital signs, physical examinations, and clinical laboratory values. |
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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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | 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 | 2 |
| 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 |
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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
|
| Last visit of the last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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