Mechanisms of Pain Hypersensitivity in a Human Skin Inflammation Model

NCT07092215 | Completed Early Phase 1

• 1 other identifier: EK1692/2024
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

The main goal of this double-blind, randomized, placebo-controlled crossover study is to understand the molecular mechanisms of inflammation-induced increased pain sensitivity (hyperalgesia). These mechanisms are studied using a recently established human model of skin inflammation that mimics aspects of skin infection. A localized inflammatory response in the skin of healthy volunteers is elicited by locally injecting a small, safe dose of Lipopolysaccharide (LPS), a major component of gram-negative bacteria. The study addresses three key research questions:

• Role of RAGE: To investigate if certain inflammatory effects of LPS, which contribute to hyperalgesia, are mediated by a signaling pathway involving the RAGE receptor.
• Pain Sensitization: To examine how skin inflammation affects pain caused by acidic stimuli, and to differentiate this from purely mechanical pain.
• Role of TRPV1: To determine if the contribution of the TRPV1 ion channel to acid-induced pain is different in inflamed skin. Participants will undergo an experimental session 4.5 hours after LPS injection to measure skin blood flow (using laser speckle imaging), mechanical pain sensitivity (using specialized tweezers), and pain induced by injecting a solution, of which the pH is gradually decreasing (acid-induced pain). The study has minimal risks due to the small, safe doses of substances used ('microdosing') and aims to lay the groundwork for developing new treatments for inflammatory pain conditions.

Conditions

Pain

Keywords

Inflammation; Skin; Pain model; Hyperalgesia; RAGE; Azeliragon; TLR4; Resatorvid; TRPV1; BCTC

Outcome Measures

Primary Outcomes (1)

• Skin Perfusion

  The degree of hyperemia, quantified by laser speckle imaging, will be analyzed using ImageJ. The following steps describe the protocol for analyzing the (non-)inflamed spots of one forearm of a subject. To determine the volume under the surface (VUS, in analogy to an area under the curve, but for a 2-dimensional signal) of the flux change, for each of the previously injected skin spots a ROI covering the flow increase is adapted. The flux change (Δflux) is determined by subtracting from the average of the ROI the average signal of the surrounding forearm, and multiplying this with the ROI area. Any widespread or systemic change, which is not expected to occur, would be present in both the test site and the surrounding forearm and would therefore be corrected for by the chosen analysis approach. The analyzing person will be blinded concerning the type of injection. The variable is measured in arbitrary units (A.U.).

  4.5h after the (non-)LPS injections

Secondary Outcomes (1)

• Pain AUC

  Between 4.5h and 5.5h after the (non-)LPS injections

Study Arms (10)

Sequence #01

EXPERIMENTAL

Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows: 1. SIF (neutral pH) 2. SIF (acidic pH) 3. LPS + RES (acidic pH) 4. SIF (acidic pH + BCTC) 5. LPS + RES (neutral pH) 6. LPS (neutral pH) 7. LPS + AZE (acidic pH) 8. LPS (acidic pH) 9. LPS + AZE (neutral pH) 10. LPS (acidic pH + BCTC)

Drug: Synthetic interstitial fluid (SIF) / SIF neutral pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng / SIF neutral pH; Drug: LPS 5 ng / SIF acidic pH; Drug: LPS 5 ng / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH; Drug: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH

Sequence #03

EXPERIMENTAL

Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows: 1. SIF (acidic pH + BCTC) 2. LPS (neutral pH) 3. SIF (acidic pH) 4. LPS (acidic pH) 5. SIF (neutral pH) 6. LPS (acidic pH + BCTC) 7. LPS + RES (acidic pH) 8. LPS + AZE (neutral pH) 9. LPS + RES (neutral pH) 10. LPS + AZE (acidic pH)

Drug: Synthetic interstitial fluid (SIF) / SIF neutral pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng / SIF neutral pH; Drug: LPS 5 ng / SIF acidic pH; Drug: LPS 5 ng / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH; Drug: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH

Sequence #04

EXPERIMENTAL

Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows: 1. LPS (neutral pH) 2. LPS (acidic pH) 3. SIF (acidic pH + BCTC) 4. LPS (acidic pH + BCTC) 5. SIF (acidic pH) 6. LPS + AZE (neutral pH) 7. SIF (neutral pH) 8. LPS + AZE (acidic pH) 9. LPS + RES (acidic pH) 10. LPS + RES (neutral pH)

Drug: Synthetic interstitial fluid (SIF) / SIF neutral pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng / SIF neutral pH; Drug: LPS 5 ng / SIF acidic pH; Drug: LPS 5 ng / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH; Drug: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH

Sequence #05

EXPERIMENTAL

Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows: 1. LPS (acidic pH) 2. LPS (acidic pH + BCTC) 3. LPS (neutral pH) 4. LPS + AZE (neutral pH) 5. SIF (acidic pH + BCTC) 6. LPS + AZE (acidic pH) 7. SIF (acidic pH) 8. LPS + RES (neutral pH) 9. SIF (neutral pH) 10. LPS + RES (acidic pH)

Drug: Synthetic interstitial fluid (SIF) / SIF neutral pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng / SIF neutral pH; Drug: LPS 5 ng / SIF acidic pH; Drug: LPS 5 ng / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH; Drug: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH

Sequence #06

EXPERIMENTAL

Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows: 1. LPS (acidic pH + BCTC) 2. LPS + AZE (neutral pH) 3. LPS (acidic pH) 4. LPS + AZE (acidic pH) 5. LPS (neutral pH) 6. LPS + RES (neutral pH) 7. SIF (acidic pH + BCTC) 8. LPS + RES (acidic pH) 9. SIF (acidic pH) 10. SIF (neutral pH)

Drug: Synthetic interstitial fluid (SIF) / SIF neutral pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng / SIF neutral pH; Drug: LPS 5 ng / SIF acidic pH; Drug: LPS 5 ng / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH; Drug: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH

Sequence #07

EXPERIMENTAL

Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows: 1. LPS + AZE (neutral pH) 2. LPS + AZE (acidic pH) 3. LPS (acidic pH + BCTC) 4. LPS + RES (neutral pH) 5. LPS (acidic pH) 6. LPS + RES (acidic pH) 7. LPS (neutral pH) 8. SIF (neutral pH) 9. SIF (acidic pH + BCTC) 10. SIF (acidic pH)

Drug: Synthetic interstitial fluid (SIF) / SIF neutral pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng / SIF neutral pH; Drug: LPS 5 ng / SIF acidic pH; Drug: LPS 5 ng / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH; Drug: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH

Sequence #08

EXPERIMENTAL

Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows: 1. LPS + AZE (acidic pH) 2. LPS + RES (neutral pH) 3. LPS + AZE (neutral pH) 4. LPS + RES (acidic pH) 5. LPS (acidic pH + BCTC) 6. SIF (neutral pH) 7. LPS (acidic pH) 8. SIF (acidic pH) 9. LPS (neutral pH) 10. SIF (acidic pH + BCTC)

Drug: Synthetic interstitial fluid (SIF) / SIF neutral pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng / SIF neutral pH; Drug: LPS 5 ng / SIF acidic pH; Drug: LPS 5 ng / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH; Drug: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH

Sequence #09

EXPERIMENTAL

Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows: 1. LPS + RES (neutral pH) 2. LPS + RES (acidic pH) 3. LPS + AZE (acidic pH) 4. SIF (neutral pH) 5. LPS + AZE (neutral pH) 6. SIF (acidic pH) 7. LPS (acidic pH + BCTC) 8. SIF (acidic pH + BCTC) 9. LPS (acidic pH) 10. LPS (neutral pH)

Drug: Synthetic interstitial fluid (SIF) / SIF neutral pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng / SIF neutral pH; Drug: LPS 5 ng / SIF acidic pH; Drug: LPS 5 ng / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH; Drug: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH

Sequence #10

EXPERIMENTAL

Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows: 1. LPS + RES (acidic pH) 2. SIF (neutral pH) 3. LPS + RES (neutral pH) 4. SIF (acidic pH) 5. LPS + AZE (acidic pH) 6. SIF (acidic pH + BCTC) 7. LPS + AZE (neutral pH) 8. LPS (neutral pH) 9. LPS (acidic pH + BCTC) 10. LPS (acidic pH)

Drug: Synthetic interstitial fluid (SIF) / SIF neutral pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng / SIF neutral pH; Drug: LPS 5 ng / SIF acidic pH; Drug: LPS 5 ng / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH; Drug: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH

Sequence #02

EXPERIMENTAL

Participants receive 10 intradermal injetions at time point -4.5h, of which 3 contain no substance (SIF), 3 contain LPS, 2 contain LPS + AZE and 2 contain LPS + RES. This is followed by laser speckle imaging (all skin spots), mechanical stimulation (all skin spots) and injection of neutral OR acidic solutions, containing OR not containing BCTC (stated in parantheses) at time point 0. The order is as follows: 1. SIF (acidic pH) 2. SIF (acidic pH + BCTC) 3. SIF (neutral pH) 4. LPS (neutral pH) 5. LPS + RES (acidic pH) 6. LPS (acidic pH) 7. LPS + RES (neutral pH) 8. LPS (acidic pH + BCTC) 9. LPS + AZE (acidic pH) 10. LPS + AZE (neutral pH)

Drug: Synthetic interstitial fluid (SIF) / SIF neutral pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH; Drug: Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng / SIF neutral pH; Drug: LPS 5 ng / SIF acidic pH; Drug: LPS 5 ng / SIF acidic pH + BCTC 1 µM; Drug: LPS 5 ng + Azeliragon 100 µM / SIF neutral pH; Drug: LPS 5 ng + Azeliragon 100 µM / SIF acidic pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF neutral pH; Drug: LPS 5 ng + Resatorvid 10 µM / SIF acidic pH

Interventions

Synthetic interstitial fluid (SIF) / SIF neutral pH DRUG

Intradermal injection of SIF at time point -4.5h, followed by laser speckle imaging, mechanical stimulation and intradermal injection of SIF with neutral pH (pH 7.4)

Sequence #01; Sequence #02; Sequence #03; Sequence #04; Sequence #05; Sequence #06; Sequence #07; Sequence #08; Sequence #09; Sequence #10

Synthetic interstitial fluid (SIF) / SIF acidic pH DRUG

Intradermal injection of SIF at time point -4.5h, followed by laser speckle imaging, mechanical stimulation and intradermal injection of SIF with acidic pH (pH 7.4 to pH 5.7)

Sequence #01; Sequence #02; Sequence #03; Sequence #04; Sequence #05; Sequence #06; Sequence #07; Sequence #08; Sequence #09; Sequence #10

Synthetic interstitial fluid (SIF) / SIF acidic pH + BCTC 1 µM DRUG

Intradermal injection of SIF at time point -4.5h, followed by laser speckle imaging, mechanical stimulation and intradermal injection of SIF with acidic pH (pH 7.4 to pH 5.7), containing BCTC 1 µM

Sequence #01; Sequence #02; Sequence #03; Sequence #04; Sequence #05; Sequence #06; Sequence #07; Sequence #08; Sequence #09; Sequence #10

LPS 5 ng / SIF neutral pH DRUG

Intradermal injection of LPS 5 ng at time point -4.5h, followed by laser speckle imaging, mechanical stimulation and intradermal injection of SIF with neutral pH (pH 7.4)

Sequence #01; Sequence #02; Sequence #03; Sequence #04; Sequence #05; Sequence #06; Sequence #07; Sequence #08; Sequence #09; Sequence #10

LPS 5 ng / SIF acidic pH DRUG

Intradermal injection of LPS 5 ng at time point -4.5h, followed by laser speckle imaging, mechanical stimulation and intradermal injection of SIF with acidic pH (pH 7.4 to pH 5.7)

Sequence #01; Sequence #02; Sequence #03; Sequence #04; Sequence #05; Sequence #06; Sequence #07; Sequence #08; Sequence #09; Sequence #10

LPS 5 ng / SIF acidic pH + BCTC 1 µM DRUG

Intradermal injection of LPS 5 ng at time point -4.5h, followed by laser speckle imaging, mechanical stimulation and intradermal injection of SIF with acidic pH (pH 7.4 to pH 5.7), containing BCTC 1 µM

Sequence #01; Sequence #02; Sequence #03; Sequence #04; Sequence #05; Sequence #06; Sequence #07; Sequence #08; Sequence #09; Sequence #10

LPS 5 ng + Azeliragon 100 µM / SIF neutral pH DRUG

Intradermal injection of LPS 5 ng + Azeliragon 100 µM at time point -4.5h, followed by laser speckle imaging, mechanical stimulation and intradermal injection of SIF with neutral pH (pH 7.4)

Sequence #01; Sequence #02; Sequence #03; Sequence #04; Sequence #05; Sequence #06; Sequence #07; Sequence #08; Sequence #09; Sequence #10

LPS 5 ng + Azeliragon 100 µM / SIF acidic pH DRUG

Intradermal injection of LPS 5 ng + Azeliragon 100 µM at time point -4.5h, followed by laser speckle imaging, mechanical stimulation and intradermal injection of SIF with acidic pH (pH 7.4 to 5.7)

Sequence #01; Sequence #02; Sequence #03; Sequence #04; Sequence #05; Sequence #06; Sequence #07; Sequence #08; Sequence #09; Sequence #10

LPS 5 ng + Resatorvid 10 µM / SIF neutral pH DRUG

Intradermal injection of LPS 5 ng + Resatorvid 10 µM at time point -4.5h, followed by laser speckle imaging, mechanical stimulation and intradermal injection of SIF with neutral pH (pH 7.4)

Sequence #01; Sequence #02; Sequence #03; Sequence #04; Sequence #05; Sequence #06; Sequence #07; Sequence #08; Sequence #09; Sequence #10

LPS 5 ng + Resatorvid 10 µM / SIF acidic pH DRUG

Intradermal injection of LPS 5 ng + Resatorvid 10 µM at time point -4.5h, followed by laser speckle imaging, mechanical stimulation and intradermal injection of SIF with neutral pH (pH 7.4 to pH 5.7)

Sequence #01; Sequence #02; Sequence #03; Sequence #04; Sequence #05; Sequence #06; Sequence #07; Sequence #08; Sequence #09; Sequence #10

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age between 18 and 70 years
• Full legal capacity

You may not qualify if:

• Participant of another study, ongoing or within the last four weeks
• Current medication intake (except hormonal contraception) or drug abuse
• Female subjects: Positive pregnancy test or breastfeeding
• Body temperature above 38°C, diagnostically verified
• Known allergic diseases, in particular asthmatic disorders and skin diseases
• Sensory deficit, skin disease or hematoma of unknown origin in the physical examination of the test site
• Symptoms indicating respiratory tract infection

Sponsors & Collaborators

• Stefan Heber: lead

Study Sites (1)

Medical University of Vienna

Vienna, Vienna, 1090, Austria

Location

Related Publications (12)

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• Bretag AH. Synthetic interstitial fluid for isolated mammalian tissue. Life Sci. 1969 Mar 1;8(5):319-29. doi: 10.1016/0024-3205(69)90283-5. No abstract available.

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• Heber S, Ciotu CI, Hartner G, Gold-Binder M, Ninidze N, Gleiss A, Kress HG, Fischer MJM. TRPV1 antagonist BCTC inhibits pH 6.0-induced pain in human skin. Pain. 2020 Jul;161(7):1532-1541. doi: 10.1097/j.pain.0000000000001848.

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• Nair M, Jagadeeshan S, Katselis G, Luan X, Momeni Z, Henao-Romero N, Chumala P, Tam JS, Yamamoto Y, Ianowski JP, Campanucci VA. Lipopolysaccharides induce a RAGE-mediated sensitization of sensory neurons and fluid hypersecretion in the upper airways. Sci Rep. 2021 Apr 16;11(1):8336. doi: 10.1038/s41598-021-86069-6.

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• Yamamoto Y, Harashima A, Saito H, Tsuneyama K, Munesue S, Motoyoshi S, Han D, Watanabe T, Asano M, Takasawa S, Okamoto H, Shimura S, Karasawa T, Yonekura H, Yamamoto H. Septic shock is associated with receptor for advanced glycation end products ligation of LPS. J Immunol. 2011 Mar 1;186(5):3248-57. doi: 10.4049/jimmunol.1002253. Epub 2011 Jan 26.

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• Buters TP, Hameeteman PW, Jansen IME, van Hindevoort FC, Ten Voorde W, Grievink HW, Schoonakker M, de Kam ML, Gilroy DW, Feiss G, Rissmann R, Jansen MAA, Burggraaf J, Moerland M. Clinical, Cellular, and Molecular Effects of Corticosteroids on the Response to Intradermal Lipopolysaccharide Administration in Healthy Volunteers. Clin Pharmacol Ther. 2022 Apr;111(4):964-971. doi: 10.1002/cpt.2516. Epub 2022 Jan 6.

  PMID: 34935141 BACKGROUND

• Buters TP, Hameeteman PW, Jansen IME, van Hindevoort FC, Ten Voorde W, Florencia E, Osse M, de Kam ML, Grievink HW, Schoonakker M, Patel AA, Yona S, Gilroy DW, Lubberts E, Damman J, Feiss G, Rissmann R, Jansen MAA, Burggraaf J, Moerland M. Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers. Br J Clin Pharmacol. 2022 Feb;88(2):680-690. doi: 10.1111/bcp.14999. Epub 2021 Aug 24.

  PMID: 34293819 BACKGROUND

MeSH Terms

Conditions

Pain; Inflammation; Hyperalgesia

Interventions

Lipopolysaccharides; azeliragon; ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Pathologic Processes; Somatosensory Disorders; Sensation Disorders; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Glycoconjugates; Carbohydrates; Polysaccharides, Bacterial; Polysaccharides; Lipids; Antigens, Bacterial; Antigens; Biological Factors; Endotoxins; Bacterial Toxins; Toxins, Biological

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: To ensure double-blind conditions, all solutions are prepared and numbered by an independent laboratory technician who is not involved in the experiment. Both the participants and the experimenter are blinded to the injected substances (LPS, Azeliragon, Resatorvid, BCTC) and to whether solutions contain neutral or acidic solutions for the acid-induced pain model. Familiarization injections are administered unblinded for safety and tolerability assessment. Blinding is maintained until the end of each subject's participation. Randomization sequences are generated and stored separately and are only accessible to unblinded personnel in case of emergency.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: The study is designed as a double-blind, randomized, placebo-controlled crossover study. The study design involves 10 groups. The low local dose, which does not spread to other test sites as well as the short duration of biological effects induced by pain, excludes biological carry over effects. To prevent bias from psychological carryover effects, multiples of 10 participants are tested using a Latin squares balanced design according to Williams (https://adsabs.harvard.edu/full/1949ausra...2..149w). For each participant, one of 10 pre- specified sequences is randomly selected and removed from the pool.

Study Record Dates

• First Submitted: June 11, 2025
• First Posted: July 29, 2025
• Study Start: June 17, 2025
• Primary Completion: July 11, 2025
• Study Completion: July 11, 2025
• Last Updated: July 29, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: IPD will be made available at the time of publication of the primary results article, as a supplementary file.
• Access Criteria: All individuals who have access to the published article will be able to access the individual participant data (IPD) and supporting information as supplementary material. No special request or data use agreement is required.

Locations

AU (1)