Gita Gupta, MD1,2; Deanne Daigle, MSc;2; Aditya K. Gupta, MD, PhD, FRCPC2,3; Linda Stein Gold, MD4
1Wayne State University, Detroit, MI, USA
2Mediprobe Research Inc., London, ON, Canada
3Department of Medicine, University of Toronto School of Medicine, Toronto, ON, Canada
4Henry Ford Medical Center, Department of Dermatology, Detroit, MI, USA
The etiology of papulopustular rosacea (PPR) is not well understood yet appears to involve both the innate and adaptive immune response in addition to possible infestation with Demodex mites. Current treatments for PPR consist mainly of antibiotics. Ivermectin cream 1%, a new topical treatment for PPR, possesses both anti-inflammatory and anti-parasitic properties. After 12 weeks of treatment, subjects treated with ivermectin cream 1% had significantly greater reductions in PPR symptoms and enhanced diseaserelated quality of life improvements compared to subjects who received vehicle. Furthermore, PPR symptoms continued to improve with prolonged treatment (40 weeks). Ivermectin cream 1% offers a multi-pronged approach to combat the complex pathophysiology of rosacea.
anti-parasitic, avermectin, Demodex, erythema, inflammation, insecticide, papulopustular rosacea, Rosiver®, Soolantra®,
Rosacea is a chronic inflammatory condition affecting the central facial skin of the cheeks, nose, chin and forehead. Rosacea typically affects females approximately 30 years of age and increases in severity throughout the lifespan.1 The exact cause of rosacea is unknown and its pathogenesis is not well understood.2,3 Innate and adaptive immune responses, vascular abnormalities, dermal microorganism imbalances, and environmental factors may interact to produce chronic inflammation and the development of fibrosis.2 Four subtypes of rosacea have been identified: 1) erythematotelangiectatic rosacea, 2) papulopustular rosacea (PPR), 3) phymatous rosacea, and 4) ocular rosacea2; yet, whether these represent a distinct variation or a continuum of disease severity remains a matter of debate.2 PPR, previously known as acne rosacea, is characterized by erythema, telangiectasia, papules, pustules, edema, and sometimes pain, stinging or burning.4 Patients report that symptoms are a cause of low self-esteem, as they are a source of shame, embarrassment, and physical discomfort.5 Treatment is strongly encouraged to moderate the detrimental effect on patient quality of life (QoL) and to prevent the condition from worsening. Few therapeutic alternatives exist for the treatment of PPR. There is some evidence supporting the efficacy of azelaic acid, topical metronidazole and sub-antimicrobial dose doxycycline in the treatment of moderate to severe rosacea, although it remains unclear which agent is most effective.6
Ivermectin is derived from avermectin, a class of broadspectrum anti-parasitic agents isolated from the fermentation of Streptomyces avermitilis.7 Ivermectin possesses both antiparasitic and anti-inflammatory properties and has been shown to reduce the number of Demodex mites in demodicidosis and blepharitis and to inhibit the production of lipopolysaccharide inflammatory cytokines, such as tumor necrosis factor-alpha and interlukin (IL)-1b, while upregulating the production of the anti-inflammatory cytokine IL-10.8 Because PPR is recognized as an inflammatory condition whose pathogenesis may involve parasitic infestation with Demodex mites, vehicle-controlled and active comparator trials were undertaken to evaluate the efficacy and safety of topical ivermectin 1% cream in the treatment of PPR.
Pivotal Phase 3 Studies
Two pivotal phase 3 trials assessed the efficacy and safety of ivermectin cream 1% for moderate to severe PPR.9 These trials were part of a larger study comprised of a second long-term active comparator trial10 and a 4 week follow-up safety study. The pivotal phase 3 studies were identically designed multicenter, randomized, double-blind, vehicle-controlled trials that enrolled participants aged 18 years or older with moderate to severe PPR and 15-70 inflammatory facial lesions.9 Subjects were randomized in a 2:1 ratio to receive either ivermectin 1% cream or vehicle cream for 12 weeks. Participants were instructed to apply their respective cream to the face once daily at bedtime while avoiding the upper and lower eyelids and lips. Participants were also asked to avoid known rosacea triggers, such as specific foods and environments, whenever possible. Evaluations occurred at baseline and at weeks 2, 4, 8 and 12. Co-primary efficacy outcomes for this study included the percentage of participants who achieved an Investigator Global Assessment (IGA) of “clear” or “almost clear” and mean change in inflammatory lesion counts between groups at week 12. Other efficacy outcomes were percent change in inflammatory lesion counts from baseline, subjective assessment of rosacea improvement, and QoL scores on the Dermatology Life Questionnaire Index (DLQI) and the Rosacea Quality of Life Index (RosaQoL™). Adverse events (AEs) and laboratory parameters (hematology and blood chemistry) were also monitored.
|Study 1||Study 2|
|Ivermectin 1% cream (n=451)||Vehicle (n=232)||Ivermectin 1% cream (n=459)||Vehicle (n=229)|
|IGA ‘clear’ or ‘almost clear’||38.4%†||11.6%||40.1%†||18.8%|
|Reduction in inflammatory lesion count from baseline||76.0%†||50.0%||75.0%†||50.0%|
|Subjective rosacea improvement ‘excellent’ or ‘good’||69.0%†||38.6%||66.2%†||34.4%|
|Table 1. Efficacy endpoints for the pivotal phase 3 trials of ivermectin 1% cream vs. vehicle IGA = Investigator global assessment; †P|
Study 1 enrolled 683 participants and Study 2 enrolled 688 participants, the majority of whom were female (Study 1: 68.2% and Study 2: 66.7%) and approximately 50 years of age on average. Participants in Study 1 had an average of 30.9 lesions, while subjects in Study 2 had an average 32.9 inflammatory lesions at baseline. The proportion of participants with an IGA of ‘severe’ was 18% and 24.1% in Studies 1 and 2, respectively. There were no differences in DLQI scores between treatment groups at baseline.
Efficacy results are presented in Table 1. In both studies, a significantly higher percentage of participants who received ivermectin 1% had an IGA of ‘clear’ or ‘almost clear’ at week 12 compared to vehicle (P<0.001) and the significant difference between active and control arms was noted at week 4 (10.9% and 11.8% vs. 5.6% and 5.7%, respectively; P The mean difference in inflammatory lesion counts between ivermectin 1% and vehicle from baseline to week 12 was -8.13 and -8.22 for Studies 1 and 2, respectively (ivermectin 1% vs. vehicle, both P<0.001). There was also a significant difference in the median reduction in lesion count from baseline between the ivermectin 1% and vehicle groups (both studies P<0.001) observed as early as week 2. In both studies, a significantly higher proportion of participants who received ivermectin 1% cream reported improvement of their rosacea symptoms as ‘excellent’ or ‘good’ compared to participants who received vehicle (P<0.001). QoL scores also improved in the ivermectin 1% groups compared to vehicle at the end of 12 weeks. In both studies, a significantly greater proportion of participants in the ivermectin 1% group (approximately 53%) than the vehicle group (approximately 35%) considered their rosacea had no effect on their QoL (P<0.001). Improvement in RosaQoL scores was also significantly higher for ivermectin 1% compared to vehicle (-0.64 ± 0.7 and -0.60 ± 0.6 vs. -0.35 ± 0.5 in both vehicle groups; P=0.001 for Studies 1 and 2).
For Studies 1 and 2, no serious treatment-related AEs were reported in either the ivermectin 1% cream or vehicle groups. Burning (1.8% for ivermectin 1% cream and 2.6% for vehicle) was the most commonly reported treatment-related AE in Study 1, while pruritus and dry skin were the most commonly reported treatment-related AEs in Study 2 (pruritus: 0.7% vs. 0% and dry skin: 0.7% vs. 0.9% for ivermectin 1% cream vs. vehicle). Furthermore, treatment-related AEs with active drug were less than with vehicle alone. Laboratory tests showed no clinically significant abnormalities.
Ivermectin 1% Cream vs. Azelaic Acid 15% Gel
Ivermectin 1% cream was then evaluated against azelaic acid 15% gel in a 40 week extension study.10 In this continuation of the pivotal phase 3 trials, participants with PPR originally assigned to ivermectin 1% cream once daily in the 12-week study continued to be treated as such and participants initially randomized to vehicle were switched to azelaic acid 15% gel twice daily for 40 weeks. Efficacy was assessed at 4 week intervals using the IGA. Safety assessments were comprised of documentation of AEs, tolerability signs and symptoms, and laboratory tests.
Six hundred and twenty-two and 683 participants enrolled in the 40-week extension studies (see previous section for participant demographics). The efficacy of ivermectin 1% cream increased over time as IGA scores of ‘clear’ and ‘almost clear’ increased from 38.4% to 71.1% by the end of Study 1 and from 40.1% to 76% by the end of Study 2; 59.4% and 57.9% of participants who received azelaic acid had an IGA of ‘clear’ or ‘almost clear’ by the end of Studies 1 and 2, respectively. No statistical comparisons were made because of the differing treatments lengths between the ivermectin 1% and azelaic acid 15% groups. Furthermore, because the ivermectin group had already been treated with ivermectin for 3 months, while the azaleic acid group had previously received vehicle, baseline factors may not have been comparable between groups.
The incidence of treatment-related AEs in the ivermectin 1% cream and azelaic acid 15% gel groups was 1.9% vs. 6.7% and 2.1% vs. 5.8% in Studies 1 and 2, respectively. No severe or serious AEs were deemed related to ivermectin 1% cream in Studies 1 or 2 and no serious AEs were considered related to azelaic acid 15% gel in either study; however, 1 severe case of skin irritation was considered related to azelaic acid in Study 2. In Study 1, 4 participants in the azelaic acid group and 5 in the ivermectin group discontinued the study as a result of AEs. In Study 2, 5 participants in the azelaic acid group and 3 in the ivermectin group discontinued the study due to AEs. None of the AEs in either study were considered related to ivermectin 1% cream; however, in the azaleic acid group, 3 AEs in Study 1 and 4 AEs in Study 2 were considered related to azaleic acid (Study 1: skin irritation, eye and skin irritation, and skin pain and burning; Study 2: skin irritation, skin burning, skin discomfort, and skin burning and pruritus).
|Ivermectin 1% cream (n=478)||Metronidazole 0.75% cream (n=484)|
|IGA ‘clear’ or ‘almost clear’||84.9%†||75.4%|
|Reduction in inflammatory lesion count from baseline||83.0%†||73.7%|
|Table 2. Efficacy endpoints for the phase 3 trial of ivermectin 1% cream vs. metronidazole 0.75% cream IGA = Investigator global assessment; †P|
Ivermectin 1% Cream vs. Metronidazole 0.75% Cream
Another phase 3, investigator-blinded, randomized trial conducted in Europe explored the efficacy and safety of ivermectin 1% cream compared to metronidazole 0.75% cream for the treatment of moderate to severe PPR (Table 2).1 Nine-hundred and sixty-two participants age 18 years or older with moderate or severe PPR and presenting with 15-70 facial lesions were randomized 1:1 to receive either ivermectin 1% cream (n=478) once daily or metronidazole 0.75% gel (n=484) twice daily for 16 weeks. Treatments were applied to the entire face, avoiding the upper and lower eyelids and lips. Participants were also asked to avoid known rosacea triggers. Study visits were at baseline and at weeks 3, 6, 9, 12 and 16. Efficacy endpoints included inflammatory lesion counts, the IGA, participants’ subjective evaluation of rosacea improvement, and the DLQI. The safety evaluation consisted of AE assessments over the course of the study, as well as local tolerance and laboratory parameters.
At baseline, the majority of participants had moderate rosacea (16.7% severe) with an average 32.5 inflammatory lesions. Participants had a mean age of 52 years and were primarily female (65.2%). In terms of efficacy at week 16, ivermectin was significantly more effective than metronidazole 0.75% cream in reducing the percentage of inflammatory lesions (83% vs. 73.7%; P<0.001) with a significant difference between the two treatments observed at week 3. The IGA of disease severity was also significantly better for ivermectin 1% cream compared to metronidazole 0.75%, with 84.9% of the ivermectin 1% cream and 75.4% of the metronidazole 0.75% cream groups rated as ‘clear’ or ‘almost clear’ at week 16 (P<0.001), with the greatest difference in IGA noted at week 12. Approximately 86% of the ivermectin group rated their global improvement as ‘excellent’ or ‘good’ compared to 74.8% in the metronidazole 0.75% group. Although the DLQI scores were similar between treatment groups at baseline (6.93 and 6.05 for ivermectin and metronidazole, respectively), participants treated with ivermectin 1% cream showed a greater improvement in QoL as indicated by a reduction in their DLQI scores (-5.18 vs. -3.92; P<0.01).
A similarly low proportion of participants experienced a treatment-related AE (1.9% in the ivermectin 1% cream group and 2.5% in the metronidazole 0.75% group). The most common treatment-related AE was skin irritation experienced by 3 and 4 participants in the ivermectin 1% cream and metronidazole 0.75% cream groups, respectively. Three participants in the ivermectin 1% cream group discontinued the study because of skin irritation and hypersensitivity, while 10 participants in the metronidazole 0.75% cream group discontinued the study due to skin irritation, allergic dermatitis, aggravation of rosacea, erythema, pruritus and feeling hot. Worsening of local tolerance parameters from baseline was more pronounced in
the metronidazole 0.75% group than the ivermectin 1% cream group for stinging/burning (15.5% vs. 11.1%), dryness (12.8% vs. 10%), and itching (11.4% vs. 8.8%). No clinically significant abnormalities in laboratory parameters were found.
Ivermectin 1% cream is markedly more effective than vehicle in reducing inflammatory lesions of rosacea as it results in a significant reduction in lesion counts after only 2 weeks of treatment and produces substantially greater improvements in IGA ratings of ‘clear’ or ‘almost clear’ as early as week 4.9 The efficacy of ivermectin 1% cream increases with prolonged treatment as evidenced in the 40 week trials.10 Also, when compared to the standard treatment for PPR, metronidazole 0.75% cream, topical ivermectin was markedly superior to metronidazole in terms of reducing inflammatory lesions and IGA ratings.1 Ivermectin 1% cream had a significantly greater positive impact on patient QoL compared to vehicle or metronidazole 0.75%.1,9 Ivermectin 1% cream was well-tolerated and demonstrated a favorable safety profile across phase 3 studies, with skin irritation being the most common treatmentrelated AE.
In phase 3 trials, ivermectin 1% cream produced greater objective and subjective outcomes and improvements in disease-specific QoL over vehicle and an active comparator. Topical ivermectin represents a novel approach to the treatment of PPR that appears to confer superior efficacy and tolerability as compared to current treatment options, while offering the added convenience of once daily dosing. Since ivermectin possesses both anti-parasitic and anti-inflammatory properties, its effectiveness in treating PPR may be attributed to its ability to combat several pathogenic factors linked to the condition. Further studies are needed to elucidate the contribution of the anti-parasitic versus the antiinflammatory modes of action of ivermectin.
- Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. 2015 Apr;172(4):1103-10.
- Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004 Sep;51(3):327-41.
- Diamantis S, Waldorf HA. Rosacea: clinical presentation and pathophysiology. J Drugs Dermatol. 2006 Jan;5(1):8-12.
- Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013 Dec;69(6 Suppl 1): S15-26.
- van der Linden MM, van Rappard DC, Daams JG, et al. Health-related quality of life in patients with cutaneous rosacea: a systematic review. Acta Derm Venereol. 2015 Apr 15;95(4):395-400.
- van Zuuren EJ, Kramer SF, Carter BR, et al. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. 2011 Oct;165(4):760-81.
- Merck & Co. Inc. Stromectal (ivermectin) tablets [Internet]. 2010 [cited 2015 Feb 20].
- Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogenactivated protein kinase activation pathway. Fundam Clin Pharmacol. 2009 Aug;23(4):449-55.
- Stein L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014 Mar;13(3):316-23.
- Stein Gold L, Kircik L, Fowler J, et al. Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled,investigator-blinded trials. J Drugs Dermatol. 2014 Nov;13(11):1380-6.