Clinical trial NCT01026064: Cantharidin-induced Skin Blister for Testing Anti-inflammatory Effects of Macrolides
Official title: Utility of the Cantharidin-induced Skin Blister Assay for Evaluation of Anti-inflammatory Effects of Macrolides in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Inflammation
Keywords: Macrolides
Inflammation
Azithromycin
Cantharidin induced skin blister model
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-12-04
Enrollment: 44
Sex: MALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to investigate the utility of the cantharidin-induced skin blister assay for evaluation of the anti-inflammatory effects of macrolides in healthy male volunteers.

Detailed description: The study will consist of 3 parts. Part A of the study will assess the feasibility of different cantharidin blister induction/sampling timepoints (challenge options) ranging from 16/16 hours to 48/48 hours, including the ability to evaluate the acute and resolving phase of acute inflammation. In Part A, 4 to 8 healthy male volunteers will be included. This will be followed by Part B (in up to 12 subjects), aimed to select the optimum challenge option based on the reproducibility of read-outs across two challenge sessions. This option will be applied in Part C in up to 24 subjects in order to evaluate the utility of the assay to demonstrate anti-inflammatory effects of a standard macrolide (azithromycin). Part C is designed as a double-blind, placebo-controlled, parallel group trial. Following the first cantharidin challenge and blister evaluation, subjects will be randomised in a 1:1 ratio to receive azithromycin or placebo. Skin blister induction and assessment will be repeated immediately after treatment completion and, potentially, approximately 3 weeks later. The inflammatory response to cantharidin and its modulation by azithromycin will be evaluated by total and differential cell counts in blister fluid, monocyte/macrophage phenotyping and the measurement of selected inflammation mediators in blister fluid and serum.

Eligibility criteria: Inclusion Criteria:

* Healthy as determined by a responsible and experienced physician.
* Male between 18 and 65 years of age inclusive, at the time of signing the informed consent.
* The subject has a body weight of more than or equal to 50 kg and a BMI 18.5 to 30 kg/m2.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

* Subjects with very fair skin type.
* Presence on either forearm of tattoos, naevi, scars, keloids, hyperpigmentation, excessive hair or any skin abnormalities that may, in the opinion of the investigator, interfere with study assessments.
* Subjects with a history of keloids, skin allergy, hypersensitivity or contact dermatitis, including previous reactions to dressings to be used in the study.
* Subjects with a history of lymphangitis and/or lymphoedema.
* Subjects with a history of HIV infection, hepatitis B or C.
* A positive pre-study drug/alcohol screen.
* Use of prescription or non-prescription drugs, including ergot derivatives e.g. dihydroergotamine (Dihydergot), vitamins, herbal and dietary supplements (including St John's Wort) within whichever is the longer period of 14 days or 5 half-lives (if known) prior to the first challenge day, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the dosing day in the current study: 90 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56-day period.

For part C only:

* QTcB or QTcF \>450 msec, based on average QTc value of triplicate ECGs obtained over a brief recording period, if the first measurement shows abnormal QTc value.
* History of sensitivity to azithromycin, macrolide/ketolide antibiotics or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.

Primary outcomes:
measure: Tolerability and safety of cantharidin-induced skin blister assay (as determined by AEs, pain intensity, systemic inflammatory response, healing time, and cosmetic appearance of blister area)
timeFrame: Study duration
measure: Total cell count, neutrophil count and monocyte/macrophage count in blister fluid.
timeFrame: Part C: end of treatment and potentially 3 weeks later
Secondary outcomes:
measure: Monocyte/macrophage phenotype in blister fluid.
timeFrame: Part C: end of treatment and potentially 3 weeks later
measure: Inflammatory mediators in blister fluid.
timeFrame: Part C: end of treatment and potentially 3 weeks later
measure: Markers of neutrophil activation.
timeFrame: Part C: end of treatment and potentially 3 weeks later
measure: Inflammatory mediators in serum.
timeFrame: Part C: end of treatment and potentially 3 weeks later
measure: PK parameters for azithromycin in plasma and whole blood following the last dose of azithromycin, as well as azithromycin concentration in PMNs and, if possible, in peripheral blood mononuclear cells at selected time points.
timeFrame: Part C: end of treatment and potentially 3 weeks later
measure: Exploratory Outcome: Additional inflammatory mediators of interest may be determined.
timeFrame: Part C: end of treatment and potentially 3 weeks later
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
state: Cambridgeshire
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Pene Dumitrescu T, Anic-Milic T, Oreskovic K, Padovan J, Brouwer KL, Zuo P, Schmith VD. Development of a population pharmacokinetic model to describe azithromycin whole-blood and plasma concentrations over time in healthy subjects. Antimicrob Agents Chemother. 2013 Jul;57(7):3194-201. doi: 10.1128/AAC.02430-12. Epub 2013 Apr 29.