Sepsis Sepsis severe infection leading to organ dysfunction
Conditions
Interventions
Intervention: Continuous six-hour intravenous infusion of M6229, a
non-anticoagulant fraction of heparin. Dose-escalation is based on a modified
continual reassessment method (mCRM) including escala
Sponsors
Academisch Medisch Centrum
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Male or female patients aged >= 18 year. 2. Signed informed consent by patient or legal representative. 3. Diagnosed with sepsis, defined by the Sepsis-3 criteria as a life-threatening organ dysfunction caused by a dysregulated host response to an infection. 4. The patients have to be included in the study within 72 hours of ICU admission due to sepsis or within 72 hours after sepsis diagnosis on the ICU. M6229 has to be administered within 84 hours after ICU admission due to sepsis or within 84 hours after sepsis diagnosis on the ICU
Exclusion criteria
Exclusion criteria: 1. Subject has an advance directive to withhold life-sustaining treatments. 2. Subject is breastfeeding or intents to get pregnant within 30 days of enrolling into the study. 3. Subject is of childbearing potential and has a positive pregnancy test. a. A woman is considered to be of childbearing potential under the age of 60 years, unless surgically sterile. 4. Clinical suspicion or confirmation of a viral hemorrhagic shock syndrome including, but not limited to, dengue fever. 5. Bleeding risk: a. Clinical: i. Active bleeding; ii. Head trauma; iii. Intracranial surgery or stroke in the past 3 months; iv. History of intracerebral arteriovenous malformation, cerebral aneurysm or mass lesions of the central nervous system; v. Cerebral haemorrhage; vi. History of a bleeding diatheses; vii. Gastrointestinal bleeding in the past 6 weeks; viii. Presence of an epidural or spinal catheter; ix. Contraindication for IV therapeutic UFH. b. Laboratory: i. Platelet count 2.0; iii. Baseline aPTT >=45 seconds prior to enrolment, 1.5x upper limit of normal (ULN). 6. Use of any of the following treatments: a. UFH to treat a thrombotic event within 12 hours before infusion; b. LMWH within 24 hours before the infusion; c. Warfarin (if used within 7 days before study entry AND if the INR exceeds 2.0 at enrolment); d. Direct oral anticoagulant (DOAC) use 3 days prior to enrollment. e. Thrombolytic therapy within 3 previous days; f. Use of IIb/IIIa inhibitors within the previous 7 days. 7. Confirmed antiphospholipid syndrome. 8. Known allergy to fish. 9. Cardiopulmonary resuscitation in the previous 7 days. 10. Liver failure defined as Child-Pugh Score Class C [19]. 11. Abnormal liver function (ASAT and/or ALAT > 5 times upper limit of normal (ULN)). 12. Extracorporeal membrane oxygenation (ECMO) support dependent. 13. Pulmonary embolism or clinical suspicion of deep venous thrombosis (DVT). 14. Life expectancy of less than 24 hours. 15. Treating physician refusal. 16. Known adverse reaction to UFH, including heparin induced thrombocytopenia (HIT). 17. Participation in any other investigational drug study or other interventional study with interfering endpoints. 18. Any other clinical condition which, in the opinion of the investigator, would not allow safe completion of the protocol.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety: 1. Anti-coagulation effects of M6229 determined by a change in aPTT at different time points during and after infusion of M6229. Pharmacokinetics: 1. Plasma pharmacokinetic parameters of M6229. The following pharmacokinetic parameters will be determined by non-compartmental analysis: Cmax, Css,Tmax, AUC, Clearance, terminal half-life and volume of distribution. Efficacy: 1. Change in histone plasma levels before and at different time-points after M6229 administration. | — |
Secondary
| Measure | Time frame |
|---|---|
| Safety: 1. Incidence of excessive anti-coagulation effects a. Clinical evidence or suspicion of severe non-surgical bleeding, defined as the administration of >= 2 units of blood products in 24 hours from start of infusion; b. aPTT > 90 seconds. 2. Adverse reactions that are considered definitely and probably related to M6229 as specified in the protocol. 3. Changes in laboratory tests that are considered definitely and probably related to M6229. 4. Changes in vital parameters that are considered definitely and probably related to M6229. 5. Changes in ECGs QTc that are considered definitely and probably related to M6229 Pharmacokinetics: 1. Urine pharmacokinetic parameters of M6229. Efficacy: 1. Change in plasma levels of other biomarkers (of inflammation and coagulation/fibrinolysis) before and at different time-points after M6229 administration. 2. Correlation of histone plasma levels and other biomarkers with M6229 plasma levels (PK/PD). 3. Clinical outcome parameters: organ dysfunction (based on SOFA score, ARDS, AKI, liver function), organ support (mechanical ventilation, renal replacement therapy, vasopression therapy), ICU and hospital mortality. | — |
Countries
Netherlands
Outcome results
None listed