Efficacy and Safety of Ivermectin 1% Cream in Treatment of Papulopustular Rosacea: Results of Two Randomized, Double-Blind, Vehicle-Controlled Pivotal Studies

treatments are indicated for the reduction of inflammatory lesions of rosacea, including two topical treatments. A recent Cochrane review noted some evidence supporting the effectiveness of topical metronidazole and azelaic acid in the treatment of moderate to severe rosacea,⁸ yet it is clear that not all patients respond to these medications. In a national survey of current rosacea medication users, 46% of patients had previously changed medications, usually due to a lack of improvement.⁹ These factors underscore the need for new effective PPR treatments.

Ivermectin is a member of the avermectin class, which has been shown in immunopharmacological studies to exert anti-inflammatory effects by inhibiting lipopolysaccharide-induced production of inflammatory cytokines, such as tumor necrosis factor alpha and interleukin (IL)-1b, while upregulating the anti-inflammatory cytokine IL-10.¹⁰ Since ivermectin is a macrocyclic lactone derivative,its therapeutic effect is thought to be prominently due to its anti-inflammatory properties, similar to that of other macrolides.^11-12 In addition to its anti-inflammatory mode of action, it possesses antiparasitic properties. Its predecessor, avermectin, is an antiparasitic agent of agricultural importance first isolated in 1974.¹³ Ivermectin is 22-23 dihydro-avermectin B₁, modified from its parent compound avermectin, and judged to be superior to naturally occurring avermectins B₁ and B₂. Since then, several studies support ivermectin’s role in the effective oral treatment of cutaneous demodicidosis (in combination with topical permethrin cream) and scabies, as well as topical treatment of head lice.^14-16

The objective of the studies described herein was to evaluate the efficacy and safety of once-daily ivermectin 1% cream in subjects with moderate to severe PPR after 12 weeks of treatment.

Two phase 3 multicenter, randomized, double-blinded, parallel-group, vehicle-controlled trials of identical design (hereafter designated Study 1 and Study 2) were conducted in the United States and Canada from December 2011 to July and August, 2013, respectively. The studies had a duration of 12 weeks, and were the first part of a three-part study, the second being active- controlled vs azelaic acid 15% gel over 40 weeks, and the third part lasting 4 weeks as a safety follow-up phase (without treatment). Both studies were conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practices, and in compliance with local regulatory requirements. The studies were reviewed and approved by institutional review boards. All subjects provided their written informed consent prior to entering the studies. Study visits were as follows: screening visits, baseline, and weeks 2, 4, 8, and 12.

Eligible subjects were 18 years or older, with moderate or severe papulopustular rosacea based on Investigator Global Assessment (IGA; Table 1) and with 15-70 facial inflammatory lesions (papules and pustules). Eligible subjects were randomized by an Interactive Web Registration System (IWRS) in a 2:1 ratio to receive either ivermectin 1% cream (once daily every day at bedtime) or vehicle cream (once daily every day at bedtime) on the entire face for 12 weeks, and were instructed to apply a thin film of cream on the entire face (right and left cheeks, forehead, chin and nose), avoiding the upper and lower eyelids, lips, eyes and mouth. Cleansers and moisturizers were not provided. Subjects were also instructed to avoid rosacea triggers, such as sudden exposure to heat, certain foods, and excessive sun exposure.

Randomization lists were generated prior to study initiation by a statistician, and were then sent to the clinical supply group, and only the personnel directly involved with labeling and packaging (not site personnel) had access. The integrity of the blinding was ensured by packaging the topical creams in identical tubes with no visible difference between the creams, and requiring a third party other than the investigator to dispense the medication.

Efficacy assessments at each visit were the Investigator’s Global Assessment (IGA) of disease severity, and inflammatory lesion counts (papules and pustules) on each of the five facial regions (forehead, chin, nose, right cheek, left cheek). Safety assessments included adverse events (AEs) throughout the study, local tolerance parameters (stinging/burning, dryness, itching) at each study visit evaluated on a 4-point scale [from 0 (none) to 3 (severe)], and laboratory parameters (hematology and biochemistry) measured before and after treatment. Other assessments included the subject’s evaluation of their rosacea improvement at the end of the study (week 12) compared to their condition at baseline, and two quality of life (QoL) questionnaires [a dermatology-specific instrument, the Dermatology Life Quality Index (DLQI)],¹⁷ and a rosacea-specific instrument, the RosaQoL^â„¢18 completed at baseline and week 12.