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Abstract and Introduction


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.

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

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

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 Methods

Study 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.

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.

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).

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 (, no. 2011004791-11.

Subject Disposition and Baseline Characteristics
A 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
Regarding 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 (intentionto-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.
The 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 Outcomes
At 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%,

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 antiinflammatory 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

1. 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;
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, vehiclecontrolled 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

24. Forton FMN. Papulopustular rosacea, skin immunity and Demodex: pityriasis
folliculorum as a missing link. J Eur Acad Dermatol Venereol 2012; 26:1928.