Superiority of Ivermectin 1% Cream Over Metronidazole 0·75% Cream in Treating Inflammatory Lesions of Rosacea

A Randomized, Investigator-Blinded Trial

A. Taieb; J.P. Ortonne; T. Ruzicka; J. Roszkiewicz; J. Berth-Jones; M.H. Peirone; J. Jacovella

Disclosures

The British Journal of Dermatology. 2015;172(4):1103-1110. 

In This Article

Abstract and Introduction

Abstract

Background Few therapeutic alternatives currently exist in the treatment of papulopustular rosacea (PPR).

Objectives To demonstrate superiority of once-daily ivermectin 1% cream (IVM 1%) once daily vs. twice-daily metronidazole (MTZ 0·75%) cream, regarding percentage reduction of inflammatory lesions in subjects with moderate to severe PPR.

Methods In this Phase 3, investigator-blinded, randomized, parallel-group study, subjects received IVM 1% once daily, or MTZ 0·75% twice daily over 16 weeks. Efficacy assessments were inflammatory lesion counts and Investigator's Global Assessment (IGA). Safety assessments included incidence of adverse events (AEs) and local tolerance parameters. Subjects evaluated their disease following a 5-grade scale and completed questionnaires.

Results A total of 962 subjects were randomized to receive IVM 1% (n = 478) or MTZ 0·75% (n = 484). At week 16, IVM 1% was significantly superior to MTZ 0·75% in terms of reduction from baseline in inflammatory lesions (83·0% vs. 73·7%; P < 0.001), observed as early as week 3 (Last Observation Carried Forward, LOCF). IGA results (subjects 'clear' or 'almost clear') also favoured IVM 1%: 84·9% vs. 75·4%, respectively (P < 0.001). Incidence of AEs was comparable between groups and local tolerability was better for IVM 1%. More subjects receiving IVM rated their global improvement as 'excellent' or 'good.'

Conclusions Ivermectin 1% cream was significantly superior to MTZ 0·75% cream and achieved high patient satisfaction.

Introduction

Rosacea is a highly prevalent, chronic inflammatory skin condition. Rosacea mainly affects adults around 30 years of age, and classically predominates in females and increases with age. Published prevalence data vary greatly from one study to another, depending on the populations studied and the methods used. In Europe and the U.S.A. prevalence ranges from less than 1% to more than 22% of the adult population.[1–4] The associated chronic inflammation and vascular dysfunction can lead to a multitude of signs and symptoms ranging from papules and pustules, frequent flushing and transient or persistent erythema, to ocular symptoms or rhinophyma. Papulopustular rosacea (PPR) is a subtype which is characterized by papules, pustules, and persistent facial erythema, associated with great psychological distress.[5] Facial blemishes (with one of the causes being rosacea) have been found to significantly impair health-related quality of life.[6]

The pathogenesis of rosacea is not yet completely understood. Its a etiology is multifactorial and in addition to exogenous factors including UV light, it may be secondary to parasitic involvement (particularly Demodex folliculorum mites).[7,8] Such factors activate neurovascular and/or immune responses, and consequently inflammatory cascades. Intermittent flares may contribute to the chronicity of rosacea as they are associated with prolonged inflammation. In addition, skin affected by rosacea is highly sensitive and prone to irritation,[9] making it difficult to treat.

There are only a few current anti-inflammatory treatment options for rosacea, and not many alternatives exist with high efficacy and once-daily dosing. A recent Cochrane review noted that it is unclear which is most effective, but some evidence supports the efficacy of topical metronidazole, azelaic acid and subantimicrobial-dose doxycycline in the treatment of moderate to severe rosacea.[10]

Ivermectin (IVM), a macrocyclic lactone derivative with dual anti-inflammatory and anti-parasitic properties, has been approved for the treatment of onchocerciasis, strongyloidiasis and scabies in humans by the oral route, and recently for topical head lice treatment.[11,12] Oral IVM has been demonstrated to be effective as an anti-parasitic agent in reducing the number of Demodex mites in demodicidosis and in blepharitis.[13,14] Ivermectin has also been shown to exert anti-inflammatory effects by inhibiting lipopolysaccharide-induced production of inflammatory cytokines, including tumour necrosis factor alpha and interleukin (IL)-1b, while increasing the anti-inflammatory cytokine IL-10.[15] Its therapeutic effect in rosacea is thought to be chiefly due to its anti-inflammatory properties, similar to that of other macrolides.[16,17]

Recent Phase 3 pivotal studies demonstrated that IVM 1% cream was superior to vehicle cream in terms of reduction in inflammatory lesions of PPR, with a better overall safety profile.[18] The objective of this Phase 3 study was to demonstrate superiority regarding the percentage reduction of inflammatory lesions counts of IVM 1% cream vs. metronidazole (MTZ) 0·75% cream in subjects with PPR, after 16 weeks of topical treatment.

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