Primary Objectives:Our primary objectives are:1. To evaluate the safety, tolerability and pharmacokinetics of intravenously (IV) administered M6229 in critically ill patients with sepsis with specific attention to anti-coagulation effects (based on…
ID
Source
Brief title
Condition
- Other condition
- Hepatobiliary neoplasms malignant and unspecified
Synonym
Health condition
Sepsis
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety:
1. Anti-coagulation effects of M6229 determined by a change in aPTT at
different time points during and after infusion of M6229.
Pharmacokinetics:
1. Plasma pharmacokinetic parameters of M6229. The following pharmacokinetic
parameters will be determined by non-compartmental analysis: Cmax, Css,Tmax,
AUC, Clearance, terminal half-life and volume of distribution.
Efficacy:
1. Change in histone plasma levels before and at different time-points after
M6229 administration.
Secondary outcome
Safety:
1. Incidence of excessive anti-coagulation effects
a. 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;
b. aPTT > 90 seconds.
2. Adverse reactions that are considered definitely and probably related to
M6229 as specified in the protocol.
3. Changes in laboratory tests that are considered definitely and probably
related to M6229.
4. Changes in vital parameters that are considered definitely and probably
related to M6229.
5. Changes in ECGs QTc that are considered definitely and probably related to
M6229
Pharmacokinetics:
1. Urine pharmacokinetic parameters of M6229.
Efficacy:
1. Change in plasma levels of other biomarkers (of inflammation and
coagulation/fibrinolysis) before and at different time-points after M6229
administration.
2. Correlation of histone plasma levels and other biomarkers with M6229 plasma
levels (PK/PD).
3. Clinical outcome parameters: organ dysfunction (based on SOFA score, ARDS,
AKI, liver function), organ support (mechanical ventilation, renal replacement
therapy, vasopression therapy), ICU and hospital mortality.
Background 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.
Study objective
Primary Objectives:
Our primary objectives are:
1. To evaluate the safety, tolerability and pharmacokinetics of intravenously
(IV) administered M6229 in critically ill patients with sepsis with specific
attention to anti-coagulation effects (based on changes in activated partial
thromboplastin time (aPTT)).
2. To evaluate the pharmacodynamic effect of different doses of M6229 by
assessing plasma levels of extracellular histones in the study patients, before
and at different time-points after M6229 administration.
Secondary objectives:
1. To evaluate the pharmacodynamic effect of different doses of M6229 by
assessing plasma levels of other biomarkers of inflammation and endothelial
cell damage in the study patients, before and at different time-points after
M6229 administration
2. To correlate changes in histones and other biomarkers with plasma levels of
M6229 (PK/PD).
3. To correlate changes in aPTT with plasma levels of M6229 (PK/PD safety)
4. To assess a selection of clinical outcome parameters.
5. Urine pharmacokinetic parameters of M6229.
6. To compare the collected data of patients infused with M6229 with historic
controls, using data from the MARS cohort.
Study design
Study design: Phase I clinical study.
This is a first-in-human, phase I, open-label, multicenter, clinical study to
investigate the safety, tolerability and pharmacokinetics of M6229 in
critically ill patients with sepsis. A modified continual reassessment method
(mCRM) with escalation overdose control (EWOC) will be used to control
potential dose related off-target pharmacological effect on coagulation (aPTT)
to remain acceptable and estimate a recommended dose level of M6229 for further
development. The mCRM with EWOC dose recommendation will solely be based on the
modeling of the probability of aPTT being above 90 seconds. The trial will be
conducted in the intensive care units (ICUs) of Amsterdam UMC, location AMC and
Maastricht UMC+ and aims to enroll 26 patients maximally.
Intervention
Intervention: Continuous six-hour intravenous infusion of M6229, a
non-anticoagulant fraction of heparin. Dose-escalation is based on a modified
continual reassessment method (mCRM) including escalation with overdose control
(EWOC).
Study burden and risks
Nature and extent of the burden and risks associated with participation,
benefit and group relatedness: This is the first time that M6229 is
administered to human subjects, with inherent risks. However, pre-clinical
studies with M6229, and pre-clinical and clinical studies with heparins
indicate that the risk of side effects is very low. Importantly, the
anticoagulant activity of M6229 is 2 orders of magnitude lower than that of
unfractionated heparin (UFH), as determined by its activity to inhibit total
thrombin generation in human plasma. Therefore, the therapeutic window of M6229
regarding histone neutralising capacity is expected to be greater than the
therapeutic window of heparin. Patients will be closely monitored in the ICU by
the study investigators and an experienced medical team. Serial coagulation and
other biochemistry parameters will be collected frequently during and after
infusion and when deemed harmful the administration of M6229 will be ceased
immediately. Even though efficacy is not the primary endpoint in this phase I
trial, participants might still experience benefit from M6229 administration,
as preclinical studies in sepsis animal models demonstrated reduced mortality
and organ dysfunction rates when receiving heparins.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
1. Male or female patients aged >= 18 year.
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.
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:
a. UFH to treat a thrombotic event within 12 hours before infusion;
b. LMWH within 24 hours before the infusion;
c. Warfarin (if used within 7 days before study entry AND if the INR
exceeds 2.0 at enrolment);
d. Direct oral anticoagulant (DOAC) use 3 days prior to enrollment.
e. Thrombolytic therapy within 3 previous days;
f. 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 [19].
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-000328-37-NL |
| ClinicalTrials.gov | NCT05208112 |
| CCMO | NL77116.000.21 |
| OMON | NL-OMON23213 |