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Jurnal Kulit Kelamin Asli B.ing

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Abstract and IntroductionAbstract

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 075%) 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 075% 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 075% (n = 484). At week 16, IVM 1% was significantly superior to MTZ 075% in terms of reduction from baseline in inflammatory lesions (830% vs. 737%; 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%: 849% vs. 754%, 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 075% 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.[14] 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) 075% cream in subjects with PPR, after 16 weeks of topical treatment.Materials and MethodsStudy Design

This was an investigator-blinded, randomized, parallel group study comparing the efficacy and safety of IVM 1% cream vs. MTZ 075% cream with a 16-week period A, and an ongoing 36-week period B to study recurrence; period A is discussed herein. The study took place in 64 centres from 10 European countries from April 2012 to April 2013. Study visits were as follows: a screening visit, and at baseline, weeks 3, 6, 9, 12 and 16.Subjects

Eligible subjects were 18 years or older, with moderate or severe PPR as noted by an Investigator Global Assessment (IGA) score of 3 ('several small or large papules/pustules, moderate erythema') or 4 ('numerous small and/or large papules/pustules, severe erythema'), and presenting with 1570 facial inflammatory lesions (papules and pustules).Sample Size

In a previous study, IVM 1% cream once-daily showed an estimated reduction in lesion counts at week 12, of 911% above that of MTZ 075% cream, in terms of median, mean or first quartile. In order to detect a 10% difference in lesion counts between products in the present study and assuming a SD of 45%, 960 subjects needed to be randomized (480 per group) and included in the intention to treat (ITT) analysis, with 93% power.Randomization and Blinding

Prior to the start of the study, a randomization list was generated by the statistician and was secured with restricted access. Treatment assignment was balanced into consecutive blocks in a 1 : 1 ratio and kit numbers were assigned sequentially in chronological order. The study design was investigator-blinded. The integrity of the blinding was ensured by packaging the products in identical tubes, not allowing the investigator and subject to discuss study treatments, and requiring a third party other than the investigator to dispense the medication.Treatment

Subjects were randomized in a 1 : 1 ratio to receive either IVM 1% cream (once daily, at bedtime) or MTZ 075% cream (twice daily, as per labelling at morning and bedtime) for 16 weeks. Study drugs were to be applied in a thin film on the entire face (right and left cheeks, forehead, chin and nose), avoiding the upper and lower eyelids, lips, eyes and mouth. The subjects were instructed to maintain a consistent lifestyle throughout the study regarding rosacea triggers (i.e. avoiding known offending environmental factors and foods, and excessive sun exposure).Assessments

Efficacy assessments at each visit were inflammatory lesion counts (papules and pustules) counted on five facial regions (forehead, chin, nose, right cheek, left cheek), and the Investigator's Global Assessment (IGA) of disease severity as shown in Table 1.

Safety assessments included adverse events (AEs) throughout the study, local tolerance parameters (stinging/burning, dryness, itching) at each visit evaluated on a 4-point scale [from 0 (none) to 3 (severe)], and laboratory parameters measured at baseline, weeks 9 and 16.

Other assessments included the subject's evaluation of rosacea improvement compared with their condition at baseline, with a global 5-point scale (worse, no improvement, moderate, good or excellent) and the subject's appreciation questionnaire at the end of the study (regarding satisfaction with the study drug). Lastly, a quality of life questionnaire [Dermatology Life Quality Index (DLQI)][19] was completed at baseline and at the end of the study (week 16).Statistical Methods

The ITT population included all subjects who were randomized and to whom the study drug was administered. The safety population included all subjects who received the study medication. The primary efficacy endpoint, percentage change in inflammatory lesion counts from baseline to week 16, was analysed using the Cochran-Mantel-Haenszel (CMH) test stratified on centre, with ridit (relative to an identified distribution integral transformation) analysis and row mean score difference statistic. Secondary efficacy endpoints included success rate [percentage of subjects with IGA rated 0 ('clear') or 1 ('almost clear') analysed by CMH test stratified on centre using general association statistic], IGA and absolute change in lesion counts (analysed using ancova, including treatments and analysis centre as factors, and baseline as covariate). Last Observation Carried Forward (LOCF) was the primary method for imputation of missing data, and multiple imputations (MI) method was used for sensitivity. Other variables were descriptively analysed.Ethical Considerations

This study was conducted in accordance with the ethical principles derived from the Declaration of Helsinki and ICH (International Conference on Harmonization) Good Clinical Practices and in compliance with local regulatory requirements, and was reviewed and approved by local ethics committees for these institutions. All subjects provided their written informed consent before entering the study. The study is registered with EudraCT (https://eudract.ema.europa.eu/), no. 2011-004791-11.ResultsSubject Disposition and Baseline CharacteristicsA total of 1034 subjects were screened and 962 randomized to receive IVM 1% cream (n = 478) or MTZ 075% cream (n = 484); 902 (938%) completed the study (Fig. 1). Treatment groups were comparable at baseline in terms of demographics and baseline disease characteristics, with about 32 inflammatory lesions on average and the majority having moderate rosacea (833% with an IGA of 3) (Table 2). As expected, the daily quantity of product applied in the MTZ 0.75% group (twice-daily applications) was nearly twice as much as the product applied in the IVM 1% group (once-daily application), with a mean of 131 g vs. 072 g, respectively. Figure 1.Study population and causes for withdrawal. ITT, intention-to-treat; IVM 1%, ivermectin 1% cream (once-daily application); MTZ 0.75%, metronidazole 0.75% cream (twice-daily application).EfficacyRegarding the primary endpoint, at week 16 (ITT-LOCF), IVM 1% cream was significantly superior to MTZ 075% cream in terms of percentage reduction from baseline in inflammatory lesion counts (830% vs. 737%; P < 0.001; Fig. 2). This difference was observed as early as week 3 (ITT-LOCF) (as soon as week 6 with ITT-MI), and this continued through week 16 (all P-values 0.04). Similar results were found for the IGA success rate (subjects rated 'clear' or 'almost clear' as defined in Table 1): 849% for IVM 1% cream vs. 754% for MTZ 075% cream at week 16 (ITT-LOCF) (P < 0.001). As illustrated in Figure 3, the difference in IGA was the highest at week 12 (149% superior for IVM).

Figure 2.Mean percentage change from baseline in inflammatory lesion counts and 95% CI (intention-to-treat Last Observation Carried Forward, ITT-LOCF).

Figure 3.Success rate based on the IGA of 'clear' or 'almost clear'.About 13% more subjects were rated as completely clear (IGA = 0) for IVM 1% than MTZ 075% (349% vs. 217%, respectively). Furthermore, in a subgroup analysis of success rate according to IGA severity, about 20% more subjects with severe rosacea at baseline in the IVM 1% group achieved success (825% vs. 630%). Efficacy results according to severity (IGA 3 or 4) are detailed in Figure 4. Additionally, photographs of two subjects before and after treatment are shown in Figures 5, 6.

Figure 4.Success rate based on Investigator's Global Assessment (IGA) of 'clear' or 'almost clear', according to baseline severity.

Figure 5.Photographs of female patient at (a) baseline with IGA = 3 and 22 inflammatory lesions; (b) after 16 weeks of ivermectin treatment with IGA = 0 and 0 inflammatory lesions.

Figure 6.Photographs of female patient at (a) baseline with IGA = 3 and 22 inflammatory lesions; (b) after 16 weeks of ivermectin treatment with IGA = 1 and 5 inflammatory lesions.SafetyThe incidence of adverse events (AEs) was similar between groups (324% vs. 331% of subjects in the IVM 1% and MTZ 075% groups, respectively), as well as for related AEs (23% vs. 37%). Furthermore, a comparably low number of subjects experienced a related dermatological AE [nine subjects (19%) in the IVM 1% group and 12 (25%) in the MTZ 075% group]. The most common related AE was skin irritation [three subjects (06%) vs. four subjects (08%) for IVM 1% and MTZ 075%, respectively]. Thirteen subjects reported serious but unrelated AEs. A total of three subjects (06%) in the IVM 1% group experienced related adverse events leading to discontinuation (due to skin irritation and hypersensitivity), compared with 10 (21%) subjects in the MTZ 075% group [due to skin irritation, allergic dermatitis, aggravation of rosacea, erythema, pruritus and general disorders (feeling hot)].In terms of local tolerance, the incidence of worsening from baseline was higher in the MTZ 075% group for stinging/burning (155% vs. 111%), dryness (128% vs. 100%) and itching (114% vs. 88%). Laboratory tests did not demonstrate clinically significant abnormalities.

Patient-reported OutcomesAt the end of period A of this study, 855% of subjects in the IVM 1% group rated their global improvement as 'excellent' or 'good' compared to 748% in the metronidazole 075% group. Furthermore, more subjects receiving IVM 1% reported an 'excellent' improvement (523% vs. 370%, respectively; Fig. 7). Regarding the subject's appreciation questionnaire, more subjects in the IVM 1% group were satisfied with the study drug (760% vs. 613% in the MTZ 075% group). In addition, more subjects treated with IVM 1% tended to consider the product easy to use and that the time needed for application was satisfactory, whereas more subjects found MTZ 075% to be irritating (data not shown).

Figure 7.Subjects' rating of rosacea improvement.At baseline, the mean DLQI scores were similar between groups (693 for IVM 1% and 605 for MTZ 075%, respectively). Patients treated with IVM 1% showed a higher numerical reduction in their DLQI score than patients treated with MTZ 075% (518 vs. 392; P < 0.01), indicating a greater improvement in quality of life. At the end of the study after 16 weeks of treatment, 71% of patients treated with IVM 1% reported that their disease had no deleterious effect at all on their quality of life (vs. 64% for MTZ 075%). Concerning the appreciation questionnaire, the study drugs diverged in favour of IVM 1% in the subjective item subscale (level of itching, soreness, pain or stinging: 'not at all' for 787% vs. 630% in the MTZ 075% group; how embarrassed or self-conscious: 'not at all' for 703% vs. 601%, respectively).Discussion

Topical MTZ 075% has been one of the most frequently used therapies in the treatment of PPR. In our study, IVM 1% cream was significantly superior to MTZ 075% cream in terms of percentage reduction from baseline in inflammatory lesion counts, with an onset of efficacy (first difference vs. MTZ 075%) as early as 3 weeks that continued through 16 weeks. Our findings show that IVM is more efficacious than MTZ, with a tendency to show an increased efficacy even in patients with higher severity (Fig. 4). In addition based on the IGA score at week 16, a marked difference was shown in favour of IVM 1% cream over MTZ 075% as about 13% more subjects were evaluated as completely clear. As shown in Figure 3, there was no plateau for the level of efficacy at week 16 for either drug; results of a long-term 1-year study are awaited.

An overall good safety profile was observed for IVM, and it was well-tolerated in comparison with MTZ. It is not surprising that for both products, patients experienced a similarly low number of related adverse events, particularly since the tolerability of MTZ is known to be satisfactory. Metronidazole's higher incidence of worsening from baseline concerning stinging/burning, dryness and itching may be attributed to the usual signs and symptoms of rosacea. Nevertheless, this worsening appeared to negatively affect the level of quality of life as measured by the DLQI, as more patients in the MTZ group reported itching, soreness, pain or stinging.

Patient-reported outcomes for IVM 1% cream were consistent with its superior efficacy results. More patients using IVM indicated that the product was easy to use and that the time needed for application was satisfactory, implying that the daily application is more convenient than MTZ's twice-daily regimen. Rosacea negatively impacts quality of life. Indeed, the Rosacea International Expert group emphasizes the need for a comprehensive triad of rosacea care: patient education involving psychological and social aspects, as well as proper skin care and treatment.[20] However, in 58 studies evaluated in a recent Cochrane review regarding the management of rosacea, only two evaluated quality of life using validated instruments.[10] Our study is thus one of the few to examine rosacea's impact on quality of life, and future studies are warranted in this domain. The improvement in quality of life observed among patients in our study along with the convenience of IVM 1% cream's daily dosing can theoretically lead to a better compliance with treatment.

A limitation of our study is that it was only investigator-blinded due to the obvious difference in treatment regimens. However, as mentioned in the 'Materials and methods' section above, multiple measures were implemented to mitigate the risk of potential unblinding.

The efficacy of IVM 1% cream in the treatment of inflammatory lesions of rosacea could be linked to both the anti-inflammatory and anti-parasitic properties of the medication. Several in vitro and in vivo studies suggest that IVM has anti-inflammatory properties. In one study, IVM improved the survival rate of mice challenged with lipopolysaccharide (LPS), and was hypothesized to block the nuclear factor-B pathway and therefore inhibit the LPS-induced production of inflammatory cytokines.[21] In addition, the structure of IVM is similar to that of the macrolide antibiotics, which are known to exert an anti-inflammatory effect.[22] Ivermectin also causes death of parasites, primarily through binding selectively with high affinity to glutamate-gated chloride channels.[23] Although the exact role of parasites (namely Demodex) in the pathogenesis of rosacea is not fully understood, the proliferation of mites are hypothesized to trigger immune reactions which can result in the papules and pustules of rosacea.[24] Medications with both anti-inflammatory and anti-parasitic activity have not yet been developed for rosacea treatment.

Thus, IVM appears to be adapted to the complex aetiology of rosacea, and in our study, IVM 1% cream demonstrated superiority to MTZ 075% cream in terms of inflammatory lesion reduction. As noted in the afore-mentioned Cochrane review, few robust studies have compared topical MTZ with another rosacea treatment and in three identified studies, topical metronidazole was either non-significantly different or less effective than azelaic acid.[10]

In conclusion, while MTZ 075% cream has been the standard treatment for the papulopustular lesions of rosacea, its efficacy is now surpassed by that of IVM along with the advantage of once-daily dosing and high patient satisfaction. Longer-term studies are needed to address relapse time and a maintenance regimen.References1. Chosidow O, Cribier B. Epidemiology of rosacea: updated data. Ann Dermatol Venereol 2011; 138 (Suppl. 3):S17983.2. Berg M, Lid_en S. An epidemiological study of rosacea. Acta Derm Venereol 1989; 69:41923.3. McAleer MA, Fitzpatrick P, Powell FC. Papulopustular rosacea: prevalence and relationship to photodamage. J Am Acad Dermatol 2010; 63:339.4. Augustin M, Herberger K, Hintzen S et al. Prevalence of skin lesions and need for treatment in a cohort of 90880 workers. Br J Dermatol 2011; 165:86573.5. Wilkin J, Dahl M, Detmar M et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol 2002; 46:5847.6. Balkrishnan R, McMichael AJ, Hu JY et al. Correlates of health-related quality of life in women with severe facial blemishes. Int J Dermatol 2006; 45:11115.7. Del Rosso JQ, Gallo RL, Tanghetti E et al. An evaluation of potential correlations between pathophysiologic mechanisms, clinical manifestations, and management of rosacea. Cutis 2013; 91 (Suppl 3):18.8. Holmes AD. Potential role of microorganisms in the pathogenesis of rosacea. J Am Acad Dermatol 2013; 69:102532.9. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol 2004; 51:499514.10. 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; 165:76081.11. Shimose L, Munoz-Price LS. Diagnosis, prevention, and treatment of scabies. Curr Infect Dis Rep 2013; 15:42631.12. Pariser DM, Meinking TL, Bell M, Ryan WG. Topical 0.5% ivermectin lotion for treatment of head lice. N Engl J Med 2012; 367:168793.13. Damian D. Demodex infestation in a child with leukemia: treatment with ivermectin and permethrin. Int J Dermatol 2003; 42:7246.14. Filho PA, Hazarbassanov RM, Grisolia AB et al. The efficacy of oral ivermectin for the treatment of chronic blepharitis in patients tested positive for Demodex spp. Br J Ophthalmol 2011; 95:8935.15. Ci X, Li H, Yu Q et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin Pharmacol 2009; 23:44955.16. Yanagihara K, Kadoto J, Kohno S. Diffuse panbronchiolitis- pathophysiology and treatment mechanisms. Int J Antimicrob Agents 2001; 18 (Suppl. 1):S837.17. Ianaro A, Ialenti A, Maffia P et al. Anti-inflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther 2000; 292:15663.18. 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; 13:31623.19. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) a simple practical measure for routine clinical use. Clin Exp Dermatol 1994; 19:21016.20. Elewski BE, Draelos Z, Dr_eno B et al. Rosacea global diversity and optimized outcome: proposed international consensus from the Rosacea International Expert Group. J Eur Acad Dermatol Venereol 2011; 25:188200.21. Zhang X, Song Y, Ci X et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res 2008; 57:5249.22. Jain A, Sangal L, Basal E et al. Anti-inflammatory effects of erythromycin and tetracycline on Propionibacterium acnes induced production of chemotactic factors and reactive oxygen species by human neutrophils. Dermatol Online J 2002; 8:2.23. Wolstenholme AJ, Rogers AT. Glutamate-gated chloride channels and the mode of action of the avermectin/milbemycin anthelmintics. Parasitology 2005; 131 (Suppl):S8595.24. Forton FMN. Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link. J Eur Acad Dermatol Venereol 2012; 26:1928.


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