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SepsisPhase 1HistoSepsNCT05208112

Intravenously Administered M6229 in Critically Ill Sepsis Patients

A Phase 1 study testing M6229 in people with Sepsis and Septic Shock, run by A.P.J. Vlaar at 2 sites in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Sepsis, Septic Shock, Critical Illness
What is being tested?
M6229
Type of treatment
Injection or infusion
How many people
10 participants
Where
2 sitesNetherlands
Study dates
5 Apr 2022to 28 Sep 2023
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
  • 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 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.

Who cannot join

  • 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:
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  • 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.
  • 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.

Trial locations and contacts

2 sites in 1 country.

Netherlands2 sites

  • Amsterdam UMC, location AMC

    Amsterdam, North Holland, 1105AZ

  • Maastricht UMC+

    Maastricht, Limburg, 6229HX

Other trials in Netherlands

About this study

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

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.

Being tested
M6229
Keywords
sepsis, septic shock, histones, heparin, UFH, M6229, inflammation
Medical subject headings
Sepsis, Shock, Septic, Critical Illness, Inflammation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • M6229Drug

    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).

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 72 hours after start infusion

  2. Peak plasma concentration (Cmax) [Pharmacokinetics]

    Peak plasma concentration of M6229 in plasma

    Measured: Up to 72 hours after start infusion

  3. Steady state concentration (Css) [Pharmacokinetics]

    Steady state concentration of M6229 in plasma

    Measured: Up to 72 hours after start infusion

  4. Time to peak concentration (Tmax) [Pharmacokinetics]

    Time to peak concentration of M6229 in plasma

    Measured: Up to 72 hours after start infusion

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

    Area under the plasma concentration versus time curve of M6229

    Measured: Up to 72 hours after start infusion

  6. Clearance [Pharmacokinetics]

    Clearance of M6229

    Measured: Up to 72 hours after start infusion

  7. 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

    Measured: Up to 72 hours after start infusion

  8. Volume of distribution (Vd) [Pharmacokinetics]

    Volume of distribution of M6229

    Measured: Up to 72 hours after start infusion

  9. 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

    Measured: Up to 72 hours after start infusion

Secondary outcomes (13)

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

    Excessive anti-coagulation effects are:

    1. 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;
    2. aPTT > 90 seconds.

    Measured: Up to 72 hours after start infusion

  2. Incidence of adverse reactions [Safety and tolerability]

    Adverse reactions that are considered definitely and probably related to M6229 as specified in the protocol.

    Measured: Up to 72 hours after start infusion

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

    Changes in ECGs QTc that are considered definitely and probably related to M6229

    Measured: Up to 24 hours after start infusion

  4. Amount of M6229 excreted in urine [Pharmacokinetics]

    Urine pharmacokinetic parameters of M6229 (amount of M6229 excreted in urine)

    Measured: Up to 24 hours after start infusion

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

    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.

    Measured: Up to 72 hours after start infusion

  6. Change in plasma levels of interleukins before, during and after M6229 administration [Efficacy]

    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.

    Measured: Up to 72 hours after start infusion

  7. Correlation of histone plasma levels and abovementioned biomarkers with M6229 plasma levels (PK/PD) [Efficacy]

    Besides histone plasma levels, the investigators will also measure other biomarkers of inflammation, coagulation and fibrinolysis (e.g. D-dimer, IL-6, IL-8).

    Measured: Up to 72 hours after start infusion

  8. Severity of organ dysfunction based on Sequential Organ Failure Assessment (SOFA) score [Efficacy]

    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.

    Measured: 30 days

  9. Time on mechanical ventilation [Efficacy]

    Ventilator free-days and time on mechanical ventilation. Data will be compared with historic controls from the MARS cohort.

    Measured: 30 days

  10. Time on renal replacement therapy [Efficacy]

    Renal replacement therapy free-days and time on renal replacement therapy. Data will be compared with historic controls from the MARS cohort.

    Measured: 30 days

  11. Time on vasopression therapy [Efficacy]

    Vasopressor free-days and time on vasopressors. Data will be compared with historic controls from the MARS cohort.

    Measured: 30 days

  12. Length of stay [Efficacy]

    ICU and hospital length of stays. Data will be compared with historic controls from the MARS cohort.

    Measured: 30 days

  13. Mortality rate [Efficacy]

    ICU and hospital mortality. Data will be compared with historic controls from the MARS cohort.

    Measured: 30 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Jan 2022
  2. Study start5 Apr 2022
  3. Primary completion28 Sep 2023
  4. Study completion28 Sep 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05208112
Sponsor's protocol ID
NL77116.000.21
Acronym
HistoSeps
Status last verified
Feb 2025
First submitted
30 Sep 2021
Last updated
11 Feb 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing M6229 in people with Sepsis and Septic Shock, run by A.P.J. Vlaar at 2 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

aPTT changes before, during and after infusion of M6229 [Safety and tolerability] (time frame: Up to 72 hours after start infusion). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05208112.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Feb 2025.

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