E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe pneumonia with Sepsis and Septic Shock |
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E.1.1.1 | Medical condition in easily understood language |
Severe pneumonia and Blood poisoning |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040070 |
E.1.2 | Term | Septic shock |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
Evaluating the safety and efficacy of co-administration of Eptifibatide and Iloprost as compared to placebo in addition standard care in severe pneumonia patients with severe sepsis or septic chock.
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. At least 18 years of age AND
2. Suspected or proven bacterial pneumonia requiring administration of antibiotics:
• Clinical diagnosis of pneumonia, (i.e. new or increased cough, production of purulent sputum or a change in the character of sputum in subjects who normally have purulent sputum, typical auscultatory findings of pneumonia on chest examination) and:
• chest radiograph or CT within the last 24 hr showing a pulmonary infiltrate
3. Dyspnea and/or tachypnea (>20 breaths/minute) or mechanical ventilation
4. Two or more systemic inflammatory response syndrome (SIRS) criteria within the last 24 hours:
-Temperature </= 36˚ C or >/= 38˚C
-Heart rate >/= 90 beats per minute
-Mechanical ventilation for acute respiratory process or respiratory rate >/= 20 breaths per minute or PaC02 < 4.2 kPa
-WBC >/= 12,000/mm³ OR </= 4,000/mm³ OR > 10% bands
5. At least one organ failure beyond respiratory failure (cerebral, cardiovascular, hepatic, renal or coagulation within the last 24 hours (> 2 in SOFA score for the specific organ system) AND
6. Can be randomized into trial and dosed < 48 h after severe sepsis diagnosis AND
7. Consent is obtainable
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E.4 | Principal exclusion criteria |
1. Patient is pregnant or breast-feeding
2. Patient weigh more than 125 kg
3. Patients with known allergy towards any of the investigational products or contraindications which should be excluded according to the investigational product specifications
4. Investigators clinical decision deeming study participation not favourable for the patient
5. Patients in whom the clinician finds antithrombotic therapy contraindicated – prophylaxis included
6. Patients at increased risk of bleeding: Surgery in the previous 6 h, expected surgery within 72 h, epidural or spinal puncture in the previous 12 h, platelet count less than 20,000/mm3 or TEG MA<40 mm in the previous 24 h, INR > 2; if available TEG should be measured and the patient will only be excluded if the R-time is >10 min, need of blood products for bleeding in the previous 6 h, treatment with any antithrombotics within 12 h (profylaxis excepted), current or previous intracranial bleeding or traumatic brain or spinal injury within the last month.
7. Patients requiring any form of antithrombotics (beyond profylaxis) in therapeutic doses or prothrombotics in any dose, including,
a. unfractionated heparin within 8 hours before the infusion (prophylactic heparin up to 15,000 U/day permitted).
b. Low-molecular-weight heparin at inclusion(prophylactic doses permitted). If TEG analysis is available the patient will only be excluded if the R-time > 10 min.
c. Having received Warfarin and TEG R>10 min at inclusion
d. Acetylsalicylic acid more than 650 mg/day within 3 days before the study.
e. Thrombolytic therapy within 3 days before the study (catheter clearance doses permitted).
f. Glycoprotein IIb-IIIa antagonists within 3 days before the study.
g. Antithrombin III with dose greater than 10,000 U within 12 hours before the study.
h. Protein C within 24 hours of the study.
8. Previous diagnosed condition that might mimic or complicate the course and
evaluation of the infectious disease process (severe bronchiectasis, lung abcess or empyema, aspiration pneumonia, active tuberculosis, pulmonary malignancy, cystic fibrosis, severe chronic interstitial pneumonia, severe COPD or other forms of chronic lung disease requiring home oxygen treatment)
9. Patient not expected to survive more than 30 days because of uncorrectable medical
or surgical condition other than sepsis
10.Patient with acute or chronic renal failure requiring dialysis (renal failure without need
for dialysis permitted).
11. Patient with hematological malignancies of any kind
12. Patients who have undergone transplantation of bone marrow, liver, pancreas, heart,
lung, or bowel (kidney transplant permitted)
13. Patient has known hypercoagulable condition:
APC resistance
Hereditary protein C, protein S, or antithrombin III deficiency
Anticardiolipin or antiphospholipid antibody
Lupus anticoagulant
Homocysteinemia
Recent or highly suspected pulmonary embolism or deep venous thrombosis (within 3
mo)
14. Patients with known congenital hypocoagulable diseases
15. Patient with known AIDS
16. Patient with known primary pulmonary hypertension
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in platelet count from baseline to 72 hours post treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary end point is evaluated throughout the 72 hour treatment period and after 28 and 90 days |
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E.5.2 | Secondary end point(s) |
•Severe bleeding (intracranial or clinical bleeding with the use of 3 RBC units or more) (KyperSept trial)
•Any bleeding
•Endothelial activation (changes in markers): sE-selectin, ICAM-1, HMGB-1, vWF, sTM, sCD40L Syndecan-1, IL-6, Protein C, sFlt-1, sVCAM-1
•Difference in day 7, 28 and 90 day mortality between patients receiving Eptifibatide and Iloprost and placebo
•Changes in SOFA score from baseline to 72 h and day 5 and 7 post randomisation
•Days of vasopressor, ventilator and renal replacement therapy and use of blood product (in ICU) after randomisation
•Occurrence of deep venous thrombosis at compression ultrasound at day 3 and 7 after randomisation
•DIC score changes from baseline to Day 1, 3 and 7
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoint are evaluated througout the 72 hour treatment period and after 7, 28 and 90 days |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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 | No |
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.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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All patients who withdraw from the trial for any reason and at any time should have an end of trial examination. Patients will be examined for any status changes that require further follow-up. All withdrawn patients will be followed-up as the remaining patients in the trial. If consent is withdrawn, the person making the withdrawal will be asked for permission to follow up for 90 days after randomisation. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |