HistoSeps: Intravenously Administered M6229 in Critically Ill Sepsis Patients

Sponsor

A.P.J. Vlaar (Other)

Overall Status

Recruiting

CT.gov ID

NCT05208112

Collaborator

Matisse Pharmaceuticals (Other), Maastricht University (Other)

Enrollment

Location

7.9

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Sepsis Septic Shock Critical Illness	Drug: M6229	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

16 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Trial Evaluating the Safety, Tolerability and Pharmacokinetics of Intravenously Administered M6229 in Critically Ill Sepsis Patients - "HistoSeps"

Actual Study Start Date :

Apr 5, 2022

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Outcome Measures

Primary Outcome Measures

aPTT changes before, during and after infusion of M6229 [Safety and tolerability] [Up to 72 hours after start infusion]
Anti-coagulation effects of M6229 determined by a change in aPTT at different time points during and after infusion of M6229.
Peak plasma concentration (Cmax) [Pharmacokinetics] [Up to 72 hours after start infusion]
Peak plasma concentration of M6229 in plasma
Steady state concentration (Css) [Pharmacokinetics] [Up to 72 hours after start infusion]
Steady state concentration of M6229 in plasma
Time to peak concentration (Tmax) [Pharmacokinetics] [Up to 72 hours after start infusion]
Time to peak concentration of M6229 in plasma
Area under the plasma concentration versus time curve (AUC) [Pharmacokinetics] [Up to 72 hours after start infusion]
Area under the plasma concentration versus time curve of M6229
Clearance [Pharmacokinetics] [Up to 72 hours after start infusion]
Clearance of M6229
Terminal half-life (t1/2) [Pharmacokinetics] [Up to 72 hours after start infusion]
Terminal half-life is the time required for the plasma concentration of M6229 to fall by 50% during the terminal phase
Volume of distribution (Vd) [Pharmacokinetics] [Up to 72 hours after start infusion]
Volume of distribution of M6229
Histone plasma level changes before, during and after infusion of M6229 [Efficacy] [Up to 72 hours after start infusion]
Change in histone plasma levels before and at different time-points after M6229 administration

Secondary Outcome Measures

Incidence of excessive anti-coagulation effects [Safety and tolerability] [Up to 72 hours after start infusion]
Excessive anti-coagulation effects are: 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; aPTT > 90 seconds.
Incidence of adverse reactions [Safety and tolerability] [Up to 72 hours after start infusion]
Adverse reactions that are considered definitely and probably related to M6229 as specified in the protocol.
Changes in ECG corrected QT interval (QTc) [Safety and tolerability] [Up to 24 hours after start infusion]
Changes in ECGs QTc that are considered definitely and probably related to M6229
Amount of M6229 excreted in urine [Pharmacokinetics] [Up to 24 hours after start infusion]
Urine pharmacokinetic parameters of M6229 (amount of M6229 excreted in urine)
Change in plasma levels of D-Dimer before, during and after M6229 administration [Efficacy] [Up to 72 hours after start infusion]
Change in plasma levels of biomarkers of inflammation, coagulation and fibrinolysis (e.g. D-dimer, IL-6, IL-8) before and at different time-points after M6229 administration.
Change in plasma levels of interleukins before, during and after M6229 administration [Efficacy] [Up to 72 hours after start infusion]
Change in plasma levels of biomarkers of inflammation, coagulation and fibrinolysis (e.g. D-dimer, IL-6, IL-8) before and at different time-points after M6229 administration.
Correlation of histone plasma levels and abovementioned biomarkers with M6229 plasma levels (PK/PD) [Efficacy] [Up to 72 hours after start infusion]
Besides histone plasma levels, the investigators will also measure other biomarkers of inflammation, coagulation and fibrinolysis (e.g. D-dimer, IL-6, IL-8).
Severity of organ dysfunction based on Sequential Organ Failure Assessment (SOFA) score [Efficacy] [30 days]
SOFA scores will be reported. Moreover, the investigators will compare these data with historic controls. For this, data will be used from a subset of patients included in a previously conducted study conducted in two tertiary teaching hospitals in the Netherlands named "Molecular Diagnosis and Risk Stratification of Sepsis" (MARS) study. The MARS study was a prospective observational study performed between January 2011 and January 2014 in the ICUs of the Amsterdam UMC, location AMC and UMC Utrecht.
Time on mechanical ventilation [Efficacy] [30 days]
Ventilator free-days and time on mechanical ventilation. Data will be compared with historic controls from the MARS cohort.
Time on renal replacement therapy [Efficacy] [30 days]
Renal replacement therapy free-days and time on renal replacement therapy. Data will be compared with historic controls from the MARS cohort.
Time on vasopression therapy [Efficacy] [30 days]
Vasopressor free-days and time on vasopressors. Data will be compared with historic controls from the MARS cohort.
Length of stay [Efficacy] [30 days]
ICU and hospital length of stays. Data will be compared with historic controls from the MARS cohort.
Mortality rate [Efficacy] [30 days]
ICU and hospital mortality. Data will be compared with historic controls from the MARS cohort.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female patients aged ≥ 18 years old.
Signed informed consent by patient or legal representative.
ICU admittance for 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:

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.
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. M6229 has to be administered within 84 hours after ICU admission due to sepsis.

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 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:

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;

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:
UFH to treat a thrombotic event within 12 hours before enrolment;
LMWH at a higher dose than recommended for prophylactic use within 12 hours before the infusion;
Warfarin (if used within 7 days before study entry AND if the INR exceeds 2.0 at enrolment);
Direct oral anticoagulant (DOAC) use 3 days prior to enrollment.
Thrombolytic therapy within 3 previous days;
Use of IIb/IIIa inhibitors within the previous 7 days.
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.