A randomized, placebo-controlled, evaluator-blinded, study to assess the anti-inflammatory effects of topical erythromycin and clindamycin in patients with inflammatory facial acne

Acne vulgaris (AV) is a cutaneous disease of the pilosebaceous follicles. In
adolescents it is very common, the prevalence ranges from 35 to over 90% (1,
2). Acne vulgaris typically affects the face, neck, chest, upper back and upper
arms. Clinical features include non-inflammatory lesions (closed and/or open
comedos) and inflammatory lesions (papules, pustules and nodules). When
becoming extensive, inflammatory lesions can lead to scarring and
post-inflammatory hyperpigmentation and it is known that acne can have a
significant impact on patients self-esteem and social life (3).
Four factors are involved in the pathophysiology of AV, i) follicular
hyperkeratinisation, ii) increased sebum production, iii) Propionibacterium
acnes (P. acnes) colonization within the follicle and iv) inflammation. The
exact role of P. acnes in acne is an ongoing debate, however P. acnes is able
to stimulate the immune system in several ways: stimulation of Toll-like
receptors 2 and 4, direct stimulation of T lymphocytes, and the activation of
the NRLP3-inflammasome via various NLRs, Figure 1 (4). Furthermore recent
investigations suggest that the pro-inflammatory cytokine IL-1beta may play an
important role in the development of inflammation in AV (5, 6).
Antibiotics including erythromycin (a macrolide antibiotic) and clindamycin (a
lincosamide antibiotic) via topical and systemic administration route play a
major role in the treatment of AV. Both erythromycin and clindamycin are
bacteriostatic by reversibly binding to the P site on the 50S subunit of
bacterial ribosomes. Furthermore, anti-inflammatory and immuno-modulating
properties of these antibiotics have been described in vitro and in vivo,
mostly in the field of respiratory medicine. A recent in-vitro study showed
that erythromycin reduces IL-1beta in LPS stimulated PMBCs (7).
However, currently there is no mechanistic evidence of those anti-inflammatory
properties in vivo in skin diseases such as acne. Therefore, the objective of
this study is to assess the anti-inflammatory and immunomodulatory properties
of topical erythromycin and clindamycin in patients with inflammatory acne.

* To evaluate the effects of topically applied erythromycin and clindamycin in
patients with facial AV
* To explore skin and faecal microbiota in patients with AV;
* To evaluate the effects of topically applied erythromycin and clindamycin on
skin and faecal microbiota;

This is a randomized, open-label, placebo-controlled, evaluator-blinded study.

Investigational drug
Erythromycin 4% topical gel formulation
Erythromycin is a bacteriostatic antibiotic that belongs to the macrolide group
of antibiotics. Macrolides act as antibacterial by reversibly binding to the P
site on the 50S subunit of bacterial ribosomes. A topical gel formulation with
hyprolose and ethanol.
Clindamycin 1% topical lotion formulation:
Clindamcin is a bacteriostatic antibiotic that belongs to the lincosamide group
of antibiotics. Lincosamides act as bacteriostatic by reversibly binding to the
P site on the 50S subunit of bacterial ribosomes. An aqueous topical lotion
formulation with ethanol.
Comparative drug
Seventy (70) % topical ethanol solution will serve as placebo.

The overall aim of this study is to evaluate the anti-inflammatory and
immunomodulatory properties of topical erythromycin and clindamycin in acne
patients. Treatment with topical erythromycin and clindamycin is known to be
safe and well tolerated. We refer to the SmPC in D2. of the submission dossier
for more information. Two (2) mm biopsies will be taken from a facial lesion,
this is minimal invasive with a rapid healing and low risk of scarring and
therefore justified.