A Phase I Trial Evaluating the Safety, Tolerability and Pharmacokinetics of Intravenously Administered M6229 in Critically Ill Sepsis Patients - "HistoSeps"
A Phase I Trial Evaluating the Safety, Tolerability and Pharmacokinetics of Intravenously Administered M6229 in Critically Ill Sepsis Patients - "HistoSeps"
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Mortality is high and survivors frequently suffer from long-term sequelae. Extracellular histones have been identified as essential mediators in the pathogenesis of sepsis and septic shock. These toxic molecules are released by damaged cells in response to infection and high extracellular levels can induce tissue injury and multiple organ dysfunction syndrome. Extracellular histones can be neutralized by complexation with the new candidate drug called M6229, a non-anticoagulant heparin, allowing the use of elevated dose levels relative to regular unfractionated heparin. This project aims at the roll-out of a first-in-man clinical study in sepsis patients evaluating the safety, tolerability, pharmacokinetics and pharmacodynamic effects of intravenously administered M6229 in subjects suffering from sepsis.
Inclusion Criteria:
Male or female patients aged ≥ 18 years old.
Signed informed consent by patient or legal representative.
Diagnosed with sepsis, defined by the Sepsis-3 criteria as a life-threatening organ dysfunction caused by a dysregulated host response to an infection.
Organ dysfunction is defined by 1 of the following:
a. Increase in SOFA score of ≥2. i. The baseline SOFA score can be assumed to be zero in patients not known to have pre-existing organ dysfunction.
b. Acute kidney injury i. Defined as eGFR < 15 mL/min. c. Acute respiratory distress syndrome i. Defined by the Berlin criteria. d. The need of mechanical ventilation. e. Alteration in mental status.
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:
Subject has an advance directive to withhold life-sustaining treatments.
Subject is breastfeeding or intents to get pregnant within 30 days of enrolling into the study.
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.
Clinical suspicion or confirmation of a viral hemorrhagic shock syndrome including, but not limited to, dengue fever.
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 <50 x109/L; ii. INR >2.0; iii. Baseline aPTT ≥45 seconds prior to enrolment, 1.5x upper limit of normal (ULN).
Use of any of the following treatments:
Confirmed antiphospholipid syndrome.
Known allergy to fish.
Cardiopulmonary resuscitation in the previous 7 days.
Liver failure defined as Child-Pugh Score Class C.
Abnormal liver function (ASAT and/or ALAT > 5 times upper limit of normal (ULN)).
Extracorporeal membrane oxygenation (ECMO) support dependent.
Pulmonary embolism or clinical suspicion of deep venous thrombosis (DVT).
Life expectancy of less than 24 hours.
Treating physician refusal.
Known adverse reaction to UFH, including heparin induced thrombocytopenia (HIT).
Participation in any other investigational drug study or other interventional study with interfering endpoints.
Any other clinical condition which, in the opinion of the investigator, would not allow safe completion of the protocol.