Intravenously Administered M6229 in Critically Ill Sepsis Patients

NCT ID: NCT05208112

Last Updated: 2025-02-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-04-05
• Study Completion Date: 2023-09-28

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

M6229

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).

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Matisse Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Maastricht University

OTHER

Sponsor Role: collaborator

Maastricht University Medical Center

OTHER

Sponsor Role: collaborator

A.P.J. Vlaar

OTHER

Sponsor Role: lead

Responsible Party

A.P.J. Vlaar

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Alexander P Vlaar, MD, PhD, MBA

Role: PRINCIPAL_INVESTIGATOR

Department of Intensive Care Medicine, Amsterdam UMC, location AMC

Locations

Maastricht UMC+

Maastricht, Limburg, Netherlands

Amsterdam UMC, location AMC

Amsterdam, North Holland, Netherlands

Countries

Netherlands

Other Identifiers

NL77116.000.21

Identifier Type: -

Identifier Source: org_study_id