Part 1:• To evaluate the effect of IV sevuparin on inflammatory responses following an intradermal (ID) LPS challenge.Part 2:• To evaluate the effect of IV sevuparin on safety and tolerability and inflammatory responses following an intravenous (IV…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part 1
• Microvascular function
- Laser speckle contrast imaging, basal flow and with heating protocol
- Multispectral imaging
• Blister exudate
- Flow cytometry (Neutrophils, monocyte subsets, T cells, B cells, NK cells,
dendritic cells)
- Cytokines (including IL-1b, IL-6, IL-8 and TNF-a)
• Safety and tolerability
- Vital signs
- Treatment-Emergent Adverse Events
- Electrocardiography
- Haematology and chemistry blood panels, including HIT antibodies
Part 2
• Microvascular function
- Laser speckle contrast imaging, with heating protocol
- Sidestream Darkfield Imaging
- Passive limb movement
• Blood
- Leucocyte differential
- Cytokines (including IL-6, IL-8, IL-10 and TNF-a)
- Flow cytometry (Neutrophils, monocyte subsets, T cells, B cells, NK cells,
dendritic cells, including neutrophil extracellular traps)
- Explorative biomarkers: acute phase reactants and components measurable in
blood, serum and plasma of relevance for septic inflammation may be measured
and reported separately.
• Pharmacokinetics
• Safety and tolerability
- Vital signs
- Treatment-Emergent Adverse Events
- Electrocardiography
- Haematology and chemistry blood panels, including HIT antibodies
- NRS (self-rated sickness feeling)
Part 3
• Coagulation parameters (including APTT, PT, INR, anti-fXa, anti-fIIa and
D-dimer)
• Safety and tolerability
- Vital signs
- Treatment-Emergent Adverse Events
- Electrocardiography
- Haematology and chemistry blood panels, including HIT antibodies
Secondary outcome
Not applicable
Background summary
In search for novel treatments for sepsis, heparin and its derivatives have
been suggested as potential candidates. Heparin, aside from its anticoagulant
properties, is also known to possess anti-inflammatory properties and has been
shown to impede neutrophil adhesion and degranulation, as well as inhibiting
neutrophil effector functions, although the anticoagulant properties of both
unfractionated heparin and low-molecular weight heparins (LMWHs) have reduced
their application in this setting. To decrease the risk of bleeding associated
with heparins, modifications to the structure have led to a reduction in the
anticoagulant properties while retaining anti-inflammatory effects, including
inactivation of neutrophil-derived proteins.
Sevuparin (DF02) is a low-anticoagulant heparin derivative from which the
high-affinity anti-thrombin III-binding pentasaccharide motif has been removed,
resulting in a lack of direct effect on factor Xa and thrombin. Sevuparin has
been explored clinically as a treatment for malaria and sickle cell disease and
is thought to possess properties suitable for treatment of vascular
hyperpermeability in sepsis
Study objective
Part 1:
• To evaluate the effect of IV sevuparin on inflammatory responses following an
intradermal (ID) LPS challenge.
Part 2:
• To evaluate the effect of IV sevuparin on safety and tolerability and
inflammatory responses following an intravenous (IV) LPS challenge.
Part 3:
• To evaluate the interaction between subcutaneous (SC) enoxaparin and SC
sevuparin on coagulation parameters
• To evaluate the safety/tolerability of sevuparin in interaction with
enoxaparin
Study design
Parts 1 and 2:
A randomized, placebo-controlled, inflammatory challenge study in healthy
volunteers during IV infusion of sevuparin:
Part 1: ID LPS challenge,
Part 2: IV LPS challenge,
Study Parts will be executed in the order 1-2.
Part 3:
A randomized, placebo-controlled, 2-way cross over study to investigate the
interaction effect of SC injection of sevuparin with enoxaparin.
Intervention
Part 1 and Part 2 volunteers will either receive sevuparin (low dose,
intermediate dose or high dose) or placebo. This will be administered by IV
infusion (bolus loading dose followed by continuous infusion over 6 hours).
Subjects of part 1 will also receive 4 intradermal injections of LPS and
subjects in part 2 will receive and intravenous LPS.
Part 3 volunteers will receive subcutaneous injections of sevuparin (or
placebo) and enoxaparin
Study burden and risks
A study population of healthy male and female volunteers is deemed appropriate
for this study examining the effects of sevuparin of dermal and systemic LPS
responses and the interaction between subcutaneous enoxaparin and sevuparin on
coagulation responses. Although there are significant differences in the immune
response between males and females, the study will also allow enrolment of
female volunteers to provide generalization of study data across sexes, and is
also expected to aid volunteer recruitment. Furthermore, sevuparin effects on
LPS responses are expected not to differ between sexes. Importantly, females
have previously been safely exposed to LPS challenges exceeding a 1 ng/kg dose.
For coagulation responses, no significant differences between males and females
are anticipated.
The risk to the subjects can be assessed as acceptable and it is not expected
that the subjects participating in this study will benefit from it.
Olof Palmes gata 29 IV
Stockholm 11122
SE
Olof Palmes gata 29 IV
Stockholm 11122
SE
Listed location countries
Age
Inclusion criteria
1. Healthy male and female volunteers aged 18 to 55 years, inclusive. Health
status is defined by absence of evidence of any active or chronic disease
following a detailed medical and surgical history, a complete physical
examination including vital signs, 12-lead ECG, haematology, blood chemistry,
and urinalysis;
2. BMI in the range of 18 to 30 kg/m2, a minimum body weight of 50 kg and a
maximum body weight of 112 kg;
3. Be able to abstain from smoking from 24 hours prior to dosing until study
discharge visit;
4. No history of alcohol or drug abuse;
5. No history of trauma with likely damage to the spleen or surgery to spleen;
6. Free from any clinically significant febrile illness 30 days preceding study
Day 1;
7. Non-atopic constitution, including non-asthmatic;
8. Fitzpatrick skin type I-III (applicable to Part 1 and 2 only);
9. No use of any prescription drugs, including aspirin or other non-steroid
anti-inflammatory drugs;
10. Able to give written informed consent and willing to comply with all
study-related procedures;
11. Female subjects of childbearing potential and male subjects who have sexual
intercourse with a woman of childbearing potential must be willing to practice
effective contraception during the study and be willing and able to continue
contraception for at least 90 days after their last dose of study treatment.
Women of childbearing potential are defined as all women physiologically
capable of becoming pregnant, unless they meet one of the following conditions:
• Postmenopausal: 12 months of natural (spontaneous) amenorrhea or 6 weeks
after surgical bilateral oophorectomy with or without hysterectomy;
• Posthysterectomy.
For the purposes of the study, effective contraception is defined as follows:
• Females: Using 1 or more of the following acceptable methods of
contraception: surgical sterilization (e.g., bilateral tubal ligation),
intrauterine contraception/device, hormonal contraception, or any 2 barrier
methods (a combination of male or female condom with diaphragm, sponge or
cervical cap).
• Males: Effective male contraception includes a vasectomy with negative semen
analysis at follow up, or the use of condoms.
Abstinence can be considered an acceptable method of contraception at the
discretion of the investigator. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post ovulation methods) and withdrawal are not considered
acceptable methods of contraception.
Exclusion criteria
1. History of sepsis or history of clinically significant cardiovascular
disease, syncope or malignancy;
2.Haemorrhagic diathesis (easy bruising, epistaxis, gastro-intestinal bleeding);
3.First degree family history of premature cardiovascular disease event (if
diagnosed before 50 years of age);
4.Previous participation in a systemic (i.v./inhaled) LPS challenge trial or
prior exposure to systemic endotoxin within a year before the first study day
(applicable to Part 1 and 2 only) or previous exposure to sevuparin in study
Part 1 or 2 (applicable to Part 3 only);
5.Subjects who have received any of the following excluded medications within
prescribed 14 days of the first dose administration: aspirin, anti-platelet
therapy, anticoagulant therapy and prophylactic and therapeutic LMWH or
un-fractioned heparin
6. Subjects who have received prophylactic/therapeutic LMWH or un-fractioned
heparin within the last year;
7. Subjects who have any current and / or recurrent pathologically, clinically
significant skin condition at the lower forearms (i.e. atopic dermatitis);
including tattoos (applicable to Part 1 and 2 only).
8. Subject is female and is pregnant (based upon serum pregnancy test at
screening and urine pregnancy test pre-dose to the first sevuparin/placebo
administration), breast-feeding, or planning to become pregnant during the
study or within 90 days after last dose of study treatment.
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-004977-29-NL |
| CCMO | NL79064.056.21 |