Intravenously Administered M6229 in Critically Ill Sepsis Patients

NCT05208112 | Completed Phase 1 DMC

• 1 other identifier: NL77116.000.21
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 2

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.

Conditions

Sepsis; Septic Shock; Critical Illness

Keywords

sepsis; septic shock; histones; heparin; UFH; M6229; inflammation

Outcome Measures

Primary Outcomes (9)

• aPTT changes before, during and after infusion of M6229 [Safety and tolerability]

  Anti-coagulation effects of M6229 determined by a change in aPTT at different time points during and after infusion of M6229.

  Up to 72 hours after start infusion

• Peak plasma concentration (Cmax) [Pharmacokinetics]

  Peak plasma concentration of M6229 in plasma

  Up to 72 hours after start infusion

• Steady state concentration (Css) [Pharmacokinetics]

  Steady state concentration of M6229 in plasma

  Up to 72 hours after start infusion

• Time to peak concentration (Tmax) [Pharmacokinetics]

  Time to peak concentration of M6229 in plasma

  Up to 72 hours after start infusion

• Area under the plasma concentration versus time curve (AUC) [Pharmacokinetics]

  Area under the plasma concentration versus time curve of M6229

  Up to 72 hours after start infusion

• Clearance [Pharmacokinetics]

  Clearance of M6229

  Up to 72 hours after start infusion

• Terminal half-life (t1/2) [Pharmacokinetics]

  Terminal half-life is the time required for the plasma concentration of M6229 to fall by 50% during the terminal phase

  Up to 72 hours after start infusion

• Volume of distribution (Vd) [Pharmacokinetics]

  Volume of distribution of M6229

  Up to 72 hours after start infusion

• Histone plasma level changes before, during and after infusion of M6229 [Efficacy]

  Change in histone plasma levels before and at different time-points after M6229 administration

  Up to 72 hours after start infusion

Secondary Outcomes (13)

• Incidence of excessive anti-coagulation effects [Safety and tolerability]

  Up to 72 hours after start infusion

• Incidence of adverse reactions [Safety and tolerability]

  Up to 72 hours after start infusion

• Changes in ECG corrected QT interval (QTc) [Safety and tolerability]

  Up to 24 hours after start infusion

• Amount of M6229 excreted in urine [Pharmacokinetics]

  Up to 24 hours after start infusion

• Change in plasma levels of D-Dimer before, during and after M6229 administration [Efficacy]

  Up to 72 hours after start infusion

Interventions

M6229 DRUG

Continuous intravenous infusion of M6229, a low-anticoagulant fraction of heparin. Dose-escalation is based on a modified continual reassessment method (mCRM) including escalation with overdose control (EWOC).

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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:
• UFH to treat a thrombotic event within 12 hours before infusion;
• LMWH within 24 hours before 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.

Sponsors & Collaborators

• A.P.J. Vlaar: lead
• Matisse Pharmaceuticals: collaborator
• Maastricht University: collaborator
• Maastricht University Medical Center: collaborator

Study Sites (2)

Maastricht UMC+

Maastricht, Limburg, 6229HX, Netherlands

Location

Amsterdam UMC, location AMC

Amsterdam, North Holland, 1105AZ, Netherlands

Location

MeSH Terms

Conditions

Sepsis; Shock, Septic; Critical Illness; Inflammation

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Disease Attributes

Study Officials

• Alexander P Vlaar, MD, PhD, MBA

  Department of Intensive Care Medicine, Amsterdam UMC, location AMC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 30, 2021
• First Posted: January 26, 2022
• Study Start: April 5, 2022
• Primary Completion: September 28, 2023
• Study Completion: September 28, 2023
• Last Updated: February 11, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

NL (2)