Evidence map›Paper›PMID 40824474›Full record

ArticleIntensive care medicine experimental2025

A phase I trial evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenously administered low-anticoagulant heparin (M6229) in critically ill sepsis patients.

Niels van Mourik, Rombout B E van Amstel, Marleen A Slim, Lonneke A van Vught, Tom van der Poll, Joram Huckriede, Femke de Vries, Sjef J de Kimpe, Raf Crabbé, Simone J M van Leeuwen and 5 more

Registry-linked trialAbstract read
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In one paragraph

Article in Intensive care medicine experimental, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07285603 (A Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, and Pharmacokinetics of M6229 Administered as a 120-hour Continuous Infusion at Three Sequential Dose Levels Versus Placebo in Healthy Subjects), which is not on this map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT07285603 phase1completednot on this map

A Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, and Pharmacokinetics of M6229 Administered as a 120-hour Continuous Infusion at Three Sequential Dose Levels Versus Placebo in Healthy Subjects

TypeinterventionalSponsorMatisse PharmaceuticalsRan2024 to 2025Enrolled15ConditionsHealthy SubjectsArmsM6229, Placebo
3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors.

Niels van MourikDepartment of Intensive Care Medicine, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands. n.vanmourik@amsterdamumc.nl.ORCID http://orcid.org/0000-0003-3826-4135
Rombout B E van AmstelDepartment of Intensive Care Medicine, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.
Marleen A SlimDepartment of Intensive Care Medicine, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.
Lonneke A van VughtDepartment of Intensive Care Medicine, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.
Tom van der PollCenter for Experimental and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Joram HuckriedeDepartment of Biochemistry, Cardiovascular Research Institute (CARIM), Maastricht University, Maastricht, The Netherlands.
Femke de VriesDepartment of Biochemistry, Cardiovascular Research Institute (CARIM), Maastricht University, Maastricht, The Netherlands.
Sjef J de KimpeMatisse Pharmaceuticals B.V, Geleen, The Netherlands.
Raf CrabbéMatisse Pharmaceuticals B.V, Geleen, The Netherlands.
Simone J M van LeeuwenMatisse Pharmaceuticals B.V, Geleen, The Netherlands.
Peter F EkhartMatisse Pharmaceuticals B.V, Geleen, The Netherlands.
Chris P M ReutelingspergerDepartment of Biochemistry, Cardiovascular Research Institute (CARIM), Maastricht University, Maastricht, The Netherlands.
Gerry A F NicolaesDepartment of Biochemistry, Cardiovascular Research Institute (CARIM), Maastricht University, Maastricht, The Netherlands.
Alexander P J VlaarDepartment of Intensive Care Medicine, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.
Marcella C A MüllerDepartment of Intensive Care Medicine, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.

Funding

Ministry of Economic Affairs/Health Holland TKI PPP
6 · The paper itself

Abstract

backgroundHistones released in response to cellular injury are important mediators of organ failure and death in sepsis. Preclinical studies demonstrate that neutralization of histones in sepsis is associated with improved outcome. M6229 is a low-anticoagulant heparin able to neutralize histones. We aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of M6229 in critically ill patients with sepsis.

methodsThis was a first-in-human, phase I, monocenter trial in patients with sepsis admitted to the intensive care unit (ICU). Patients received a single 6 h intravenous infusion of M6229. A modified continual reassessment method (mCRM) with escalation overdose control was used for dose-escalation. The model was based on the probability of activated partial thromboplastin time (aPTT) being above 90 s (i.e., dose limiting pharmacologic event, DLPE). Three cohorts were studied (1: 0.15 mg/kg/h; 2: 0.45 mg/kg/h; 3: 0.90 mg/kg/h).

resultsTen patients were included. The aPTT increased proportionally with increasing dosages of M6229 and decreased rapidly after infusion cessation. One DLPE occurred (aPTT of 100 s). Based on the mCRM model and data safety monitoring board recommendations, the maximum tolerated dose was defined as 0.9 mg/kg/h for a 6 h infusion of M6229. No serious adverse events were related to study drug infusion. An increase in QTc was probably related to infusion in one patient. M6229 showed close to dose-proportional pharmacokinetics. Total histone H3 and H2b plasma levels increased during and/or in the hours after M6229 infusion in all patients. In four out of five patients with plasma samples positive for histone H3, proteolytic cleavage was observed after infusion start. A decrease in sequential organ failure assessment score was observed in the days after infusion in 70% of patients.

conclusionsM6229 was deemed safe to use in critically ill sepsis patients. Our results suggest intravascular neutralization of histones by M6229. Future clinical studies need to confirm our findings and the efficacy of M6229.

Indexed as

HeparinHistonesM6229NeutralizationPharmacokineticsPhase ISafetySepsisSeptic shock

Identifiers

PMID40824474
PMCPMC12360993

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.