Clinical trial NCT05208112: Intravenously Administered M6229 in Critically Ill Sepsis Patients
Official title: A Phase I Trial Evaluating the Safety, Tolerability and Pharmacokinetics of Intravenously Administered M6229 in Critically Ill Sepsis Patients - "HistoSeps"
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Sepsis
Septic Shock
Critical Illness
Keywords: sepsis
septic shock
histones
heparin
UFH
M6229
inflammation
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: Matisse Pharmaceuticals
name: Maastricht University
name: Maastricht University Medical Center
First posted: 2022-01-26
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Male or female patients aged ≥ 18 years old.
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.

   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.
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:

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 \<50 x109/L; ii. INR \>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:

   1. UFH to treat a thrombotic event within 12 hours before infusion;
   2. LMWH within 24 hours before infusion;
   3. Warfarin (if used within 7 days before study entry AND if the INR exceeds 2.0 at enrolment);
   4. Direct oral anticoagulant (DOAC) use 3 days prior to enrollment.
   5. Thrombolytic therapy within 3 previous days;
   6. 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.
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.

Primary outcomes:
measure: aPTT changes before, during and after infusion of M6229 [Safety and tolerability]
timeFrame: Up to 72 hours after start infusion
measure: Peak plasma concentration (Cmax) [Pharmacokinetics]
timeFrame: Up to 72 hours after start infusion
measure: Steady state concentration (Css) [Pharmacokinetics]
timeFrame: Up to 72 hours after start infusion
measure: Time to peak concentration (Tmax) [Pharmacokinetics]
timeFrame: Up to 72 hours after start infusion
measure: Area under the plasma concentration versus time curve (AUC) [Pharmacokinetics]
timeFrame: Up to 72 hours after start infusion
measure: Clearance [Pharmacokinetics]
timeFrame: Up to 72 hours after start infusion
measure: Terminal half-life (t1/2) [Pharmacokinetics]
timeFrame: Up to 72 hours after start infusion
measure: Volume of distribution (Vd) [Pharmacokinetics]
timeFrame: Up to 72 hours after start infusion
measure: Histone plasma level changes before, during and after infusion of M6229 [Efficacy]
timeFrame: Up to 72 hours after start infusion
Secondary outcomes:
measure: Incidence of excessive anti-coagulation effects [Safety and tolerability]
timeFrame: Up to 72 hours after start infusion
measure: Incidence of adverse reactions [Safety and tolerability]
timeFrame: Up to 72 hours after start infusion
measure: Changes in ECG corrected QT interval (QTc) [Safety and tolerability]
timeFrame: Up to 24 hours after start infusion
measure: Amount of M6229 excreted in urine [Pharmacokinetics]
timeFrame: Up to 24 hours after start infusion
measure: Change in plasma levels of D-Dimer before, during and after M6229 administration [Efficacy]
timeFrame: Up to 72 hours after start infusion
measure: Change in plasma levels of interleukins before, during and after M6229 administration [Efficacy]
timeFrame: Up to 72 hours after start infusion
measure: Correlation of histone plasma levels and abovementioned biomarkers with M6229 plasma levels (PK/PD) [Efficacy]
timeFrame: Up to 72 hours after start infusion
measure: Severity of organ dysfunction based on Sequential Organ Failure Assessment (SOFA) score [Efficacy]
timeFrame: 30 days
measure: Time on mechanical ventilation [Efficacy]
timeFrame: 30 days
measure: Time on renal replacement therapy [Efficacy]
timeFrame: 30 days
measure: Time on vasopression therapy [Efficacy]
timeFrame: 30 days
measure: Length of stay [Efficacy]
timeFrame: 30 days
measure: Mortality rate [Efficacy]
timeFrame: 30 days
Other outcomes:
Locations:
city: Maastricht
country: Netherlands
facility: Maastricht UMC+
state: Limburg
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location AMC
state: Noord-Holland
Study officials:
affiliation: Department of Intensive Care Medicine, Amsterdam UMC, location AMC
name: Alexander P Vlaar, MD, PhD, MBA
role: PRINCIPAL_INVESTIGATOR
References: