Effects of p38 MAPK Inhibitor POLB 001 on in Vivo LPS Challenge Responses

Study Overview
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Brief Summary
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A single center trial to evaluate the effect of POLB 001 on inflammatory responses following an intradermal LPS challenge in healthy volunteers.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose Study to Evaluate Safety, PK and the Immunosuppressive Effects of p38 MAPK Inhibitor POLB 001 on the Intradermal and Intravenous LPS Challenge Response in Healthy Volunteers

Conditions
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Influenza, Human

Intervention / Treatment
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* Drug: POLB 001
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male volunteers aged 18 to 55 years, inclusive. BMI in the range of 18 to 32 kg/m2 a minimum body weight of 50 kg. Fitzpatrick skin type I-III. Able to give written informed consent and willing to comply with all study-related procedures. Has the ability to communicate well with the Investigator in the Dutch language and willing to comply with the study restrictions. Exclusion Criteria: (A history of) any clinically significant medical condition or abnormalities, as judged by the investigator. History of sepsis, cardiovascular disease or malignancy. History of trauma with likely damage to the spleen or surgery to spleen. History of alcohol or drug abuse. Any clinically significant febrile illness 30 days preceding study Day 1. History of serious bleeding. 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. Previous participation in a systemic (i.v./inhaled) LPS challenge trial within a year before the first study day. Have any current and / or recurrent pathologically, clinically significant skin condition at the lower forearms (i.e., atopic dermatitis) including tattoos. Antibiotic use, operation or intervention by surgeon/dentist within one month before the first study day. 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. 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. Any active inflammatory or infectious disease (e.g., periodontitis). Known immunodeficiency. Positive test results for Hepatitis B, Hepatitis C, HIV antibody. 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: POLB 001 30 mg<br> | Drug: POLB 001<br>* Investigational Medicinal Product<br>|
| Active Comparator: POLB 001 70 mg<br> | Drug: POLB 001<br>* Investigational Medicinal Product<br>|
| Active Comparator: POLB 001 150 mg<br> | Drug: POLB 001<br>* Investigational Medicinal Product<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Matching Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of intradermal LPS challenge | To evaluate the effect of POLB 001 on inflammatory responses following an intradermal LPS challenge in healthy volunteers Endpoints: Skin response by imaging - Erythema (multispectral imaging) (Clinician's Erythema Assessment (CEA) Scale) | 16 days | 
| Effect of intradermal LPS challenge | To evaluate the effect of POLB 001 on inflammatory responses following an intradermal LPS challenge in healthy volunteers Endpoints: Blister exudate analysis - Flow cytometry (neutrophils, monocyte subsets, T cells, B cells, NK cells, dendritic cells) (10*9/L) | 16 days | 
| Effect of intradermal LPS challenge | To evaluate the effect of POLB 001 on inflammatory responses following an intradermal LPS challenge in healthy volunteers Endpoints: Blister exudate analysis - Cytokines (IL-6, IL-8, TNF, IL-1β) (pg/mL) | 16 days | 
| Effect of intravenous LPS challenge | To evaluate the effect of POLB 001 on inflammatory responses following an intravenous LPS challenge in healthy volunteers Endpoints: Blood - Cytokines (IL-6, IL-8, IL-10, TNF, IL-1β) (pg/mL) | 16 days |