• To evaluate the effect of POLB 001 on inflammatory responses following an intradermal LPS challenge in healthy volunteers• To evaluate the effect of POLB 001 on inflammatory responses following an intravenous LPS challenge in healthy volunteers
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Skin response by imaging
o Perfusion by laser speckle contrast imaging
o Erythema by multispectral imaging
o Clinical score
• Blister exudate analysis
o Flow cytometry (neutrophils, monocyte subsets, T cells, B cells, NK cells and
dendritic cells)
o Cytokines (IL-6, IL-8, TNF, IL-1β)
• Skin punch biopsy (3 mm)
o Explorative analysis of MK2, HSP-27 and p38 MAPK expression by qPCR)
• Safety and tolerability
o Vital signs (HR, temperature)
o Treatment-Emergent Adverse Events
o Electrocardiography
o Haematology and chemistry blood panels
• Blood
o Cytokines (IL-6, IL-8, IL-10, TNF, IL-1β)
o Leucocyte differential
o Vascular markers (VCAM, ICAM, P-selectin, E-selectin, by 4-plex MSD)
o CRP
o P38 MAPK phosphorylation levels
• Safety and tolerability
o Vital signs (HR, temperature)
o Treatment-Emergent Adverse Events
o Electrocardiography
o Haematology and chemistry blood panels
PK serum concentration analysis of POLB 001
Ex vivo LPS response (baseline versus pre-IV LPS challenge; IL-6 and TNF)
Secondary outcome
N.a.
Background summary
Activation of the p38 mitogen activated protein kinase (MAPK) pathway drives
various pro-inflammatory responses. Inhibition of the p38 pathway has been
advocated as a therapeutic strategy for chronic and acute inflammatory
conditions such as rheumatoid arthritis and sepsis. The synthetic compound POLB
001 is a potent and highly selective oral p38alpha/beta MAP kinase inhibitor.
Poolbeg Pharma has licensed this compound, now known under code POLB 001, for
further clinical evaluation. POLB 001 has previously been evaluated in a phase
1 single and multiple ascending dose study. Single doses administered were
between 0.15 mg and 600 mg and multiple doses were between 30 mg and 150 mg
twice a day for 6 days. No safety issues were reported across all doses
evaluated. The ex-vivo LPS assay showed a dose-dependent inhibition of TNF
release after administration. In the current study, doses will not exceed the
dose levels given in the previous performed MAD study. The current study will
generate critically important data that adds to the existing information from
the previous Phase 1 trial. Unlike the previous trial, volunteers will undergo
a local (dermal LPS) and systemic (intravenous LPS) inflammatory challenge that
will allow the potential effects of POLB 001 to be evaluated in-vivo.
Study objective
• To evaluate the effect of POLB 001 on inflammatory responses following an
intradermal LPS challenge in healthy volunteers
• To evaluate the effect of POLB 001 on inflammatory responses following an
intravenous LPS challenge in healthy volunteers
Study design
A randomized, double-blind, placebo-controlled, multiple dose, inflammatory
challenge study in healthy volunteers.
Intervention
POLB 001 or matching placebo will be administered orally, twice daily, for 7
consecutive days.
Study burden and risks
Study participants will not have health benefit from study participation. This
clinical study will be important to support further clinical evaluation of POLB
001 as therapeutic modality for severe acute inflammatory conditions. The study
will not only generate data on the safety/tolerability of POLB 001
administration, but also provide insight into the proximal pharmacological
activities of the compound, and potential dose- and time-dependent effects.
This information is critical for rational dose selection for future clinical
trials with POLB 001.
New Road 42
London E1 2AX
GB
New Road 42
London E1 2AX
GB
Listed location countries
Age
Inclusion criteria
1. Healthy male 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, coagulation,
and urinalysis. In the case of uncertain or questionable results, tests
performed during screening may be repeated to confirm eligibility or judged by
the investigator to be clinically irrelevant for healthy subjects.
2. BMI in the range of 18 to 32 kg/m2, a minimum body weight of 50 kg.
3. Fitzpatrick skin type I-III.
4. Able to give written informed consent and willing to comply with all
study-related procedures.
5. Has the ability to communicate well with the Investigator in the Dutch
language and willing to comply with the study restrictions.
Exclusion criteria
1. (A history of) any clinically significant medical condition or
abnormalities, as judged by the investigator.
2. History of sepsis, cardiovascular disease or malignancy.
3. History of trauma with likely damage to the spleen or surgery to spleen.
4. History of alcohol or drug abuse.
5. Any clinically significant febrile illness 30 days preceding study Day 1.
6. History of serious bleeding.
7. Clinical evidence of significant or unstable medical illness including
neurological, hematological, cardiovascular (including clinically significant
arrhythmia), hepatic, pulmonary, metabolic, gastrointestinal, renal,
psychiatric, endocrine, or infectious diseases or malignancies. Subjects who
have had splenectomy.
8. Previous participation in a systemic (i.v./inhaled) LPS challenge trial
within a year before the first study day.
9. Have any current and / or recurrent pathologically, clinically significant
skin condition at the lower forearms (i.e., atopic dermatitis) including
tattoos.
10. Antibiotic use, operation or intervention by surgeon/dentist within one
month before the first study day.
11. Subjects who have used any prescribed or non-prescribed systemic or topical
medication (including herbal remedies) within 7 days of the first dose
administration, or less than 5 half-lives (whichever is longer), and during the
study (except for vitamin/mineral supplements) unless, in the opinion of the
Investigator, the medication will not interfere with the study procedures or
compromise safety.
12. Subjects who have received any medications, including St John*s Wort, known
to chronically alter drug absorption or elimination processes within 30 days of
the first dose administration unless, in the opinion of the Investigator, the
medication will not interfere with the study procedures or compromise safety.
13. Any active inflammatory or infectious disease (e.g., periodontitis).
14. Known immunodeficiency.
15. Positive test results for Hepatitis B, Hepatitis C, HIV antibody.
16. Subjects who consume on average more than 3 units of alcohol per day (one
alcohol unit =1 beer [12 oz] =1 wine [5 oz] =1 spirits [1.5 oz]) or are unable
to abstain from using alcohol during the study.
17. Subjects with a positive urine drug screen/alcohol test result at screening
or first admission or a history of substance abuse in the last 12 months prior
to the start of the study.
18. Subjects who smoke more than 6 cigarettes or the equivalent in tobacco per
day and are unwilling to abstain from smoking during the study period (from
screening until EOS).
19. Loss or donation of blood over 500 mL within 3 months prior to screening or
donation of plasma within 14 days prior to screening.
20. Participation in an investigational drug or device study within 3 months,
or 5 half-lives whichever is longer, between last dosing in previous study and
first dosing in present study or more than 4 times in the past year.
21. Any vaccination within the last 3 months; COVID19 vaccination (or time of
infection) is allowed up until 2 weeks prior to the first POLB 001 /placebo
dosing.
22. Intention to receive any vaccination(s) before the last day of follow-up
(with the exception of vaccinations recommended for COVID19 as defined by
government vaccination guidelines).
Design
Recruitment
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 | EUCTR2022-001458-48-NL |
| CCMO | NL81214.056.22 |