38313 Azaleicacid vs Metrogel

7/29/2019 38313 Azaleicacid vs Metrogel

1/7

A Comparison of 15% Azelaic Acid Gel and0.75% Metronidazole Gel in the Topical Treatmentof Papulopustular Rosacea

Results of a Randomized Trial

Boni E. Elewski, MD; Alan B. Fleischer, Jr, MD; David M. Pariser, MD

Objective: To compare the efficacy and safety of a novelformulation of 15% azelaic acid gel (Finacea; Berlex Labo-ratories, Inc, Montville, NJ) with 0.75% metronidazolegel (MetroGel; Galderma Laboratories LP, Fort Worth,Tex) as topical therapy for moderate, papulopustular fa-cial rosacea.

Design: Multicenter,double-blind, randomized, parallel-

group study.

Setting: Thirteen US centers.

Patients: A total of 251 patients with papulopustularrosacea with persistent erythema and telangiectasia.

Interventions: Patients were randomized to receive az-elaic acid gel or metronidazole gel twice daily for 15 weeks.

Main Outcome Measures: Nominal and percentchange in inflammatory lesion count, change in ery-thema and telangiectasia severity ratings, investigatorsglobal assessment of rosacea, and investigators and pa-

tients overall improvement ratings.

Results: Azelaic acid gel was superior to metronida-

zole gel in reduction of mean nominal lesion count (12.9vs 10.7, respectively) (P =.003) and mean percent de-crease in inflammatory lesions (72.7% vs 55.8%, re-spectively) (P.001). With respect to erythema sever-ity, 56% of azelaic acid geltreated patients were ratedimproved vs 42% of metronidazole geltreated patients(P =.02). The effectiveness of metronidazole gel on thesevariables seemed to plateau after week 8, whereas az-

elaic acid gel demonstrated progressive improvementthrough week 15. Neither treatment had a clinically ap-preciable effect on telangiectasia. Both the investigatorsglobal assessment (P=.02) and overall assessment of im-provement (P=.005) showeda significant therapeutic ad-vantage for azelaic acid gel. Azelaic acid gel also scoredhigher on the patientsoverall assessment of efficacy.Bothtreatments were rated as having high cosmetic accept-ability. No serious or systemic treatmentrelated ad-verse events were reported in either group.

Conclusion: Use of 15% azelaic acid gel twice daily for15 weeks demonstrated significant superiority over us-ing 0.75% metronidazole gel in improving principal signs

of rosacea (inflammatory lesions and erythema).

Arch Dermatol. 2003;139:1444-1450

ROSACEA IS a chronic derma-tosis characterized by facialflushing, erythema, telangi-ectasia, inflammatory epi-sodes with papules andpus-

tules, and, in severe cases, rhinophyma.1,2

It most commonly becomes manifest in pa-tientsbetween the agesof30and 60years.3,4

Previously, 3 stages of rosacea were de-

scribed: stage 1, characterized by transienterythema lasting several hours or days andearly telangiectasia; stage 2, characterizedby papules, pustules and persistent ery-thema, and telangiectasia; and stage 3,characterized by large inflammatory nod-ules and tissue hyperplasia, including phy-mas.5 Recently, another classification sys-tem of rosacea has been introduced thatdistinguishes 4 different subtypes (erythe-matotelangiectatic, papulopustular, phy-

matous, andocular rosacea),describing themost common patterns of signs.6 The eti-ology of rosacea is not understood; patho-physiologic findings include lack of tissuesupport andwidening of dermal vessels, in-flammation, and fibromatous proliferationin the dermis.1,2

Whereas no phar macologic treat-ment of the vascular component of rosa-cea is known, inflammatory papules andpustules and, to some extent, persistenterythema of stage 2 rosacea react favor-ably to select topical antimicrobials. Theirmechanism of action in rosacea is notknown, since no microbiologic cause of ro-sacea has conclusively been identified.7

CME course available online

at www.archdermatol.com

STUDY

From the Departments of

Dermatology, University ofAlabama at Birmingham(Dr Elewski), Wake ForestUniversity, Winston-Salem, NC(Dr Fleischer), and irginiaMedical School, Norfolk(Dr Pariser). The authorsreceived financial compensationfrom Berle x Laboratories, Inc,Montville, NJ, for serving asprincipal investigators for thisstudy.

(REPRINTED) ARCH DERMATOL/ VOL 139, NOV 2003 WWW.ARCHDERMATOL.COM1444

2003 American Medical Association. All rights reserved.at University of Washington Libraries, on August 1, 2011www.archdermatol.comDownloaded from
http://www.archdermatol.com/http://www.archdermatol.com/http://www.archdermatol.com/http://www.archdermatol.com/


2/7

Metronidazole preparations are most commonly used asmonotherapy or in combination with oral tetracy-clines.7,8 Additionally, other topical antibiotics and sul-facetamide have been used to treat stage 2 rosacea.3 Dueto the chronic nature of rosacea, there is a continuingneedfor efficacious treatments that provide sustained re-lief of its principal signs.

Azelaic acidis a naturallyoccurring dicarboxylic acid(HOOC-[CH2]7-COOH). It is currently used as a topical

20% cream to treat mild to moderate forms of acne vul-garis; its antibacterial and comedolytic activity is respon-sible mainly for its beneficial effects. However, con-trolled comparisons with either placebo9,10 or topicalmetronidazole11 have indicated that 20% azelaic acidcream also hastherapeutic effects in rosacea. A directanti-inflammatory effect of azelaic acid, by inhibition of neu-trophil-generated reactive oxygen radicals, may ac-count for this beneficial effect.12,13

A novel 15% gel formulation of azelaic acid has re-cently been developed that optimizes galenical propertiesfor greater drugdeliveryand improved bioavailability. Thescope of the present study was to investigate the efficacy,safety, and tolerability of the newly developed 15% az-

elaic acid gel (Finacea; Berlex Laboratories, Inc, Mont-ville, NJ) in the treatmentof papulopustular rosacea (stage2 rosacea) by comparison with 0.75% metronidazole gel(MetroGel; Galderma Laboratories LP, Fort Worth, Tex).

METHODS

STUDY DESIGN AND PATIENTS

This 15-week, randomized, double-blind, parallel-group studywas conducted at 13 centers in the United States. Male and fe-male patients, 18 years and older, with moderate facial papu-lopustular rosacea (stage 2 rosacea) were eligible for inclusionin the study if they exhibited 10 to 50 inflamed facial papulesand/or pustules, persistent erythema, and telangiectasia. Pa-

tients were excluded if they met the following criteria: mild ro-sacea (stage 1 disease) with only transient erythema and/or ab-sence of lesions, severe rosacea (stage 3 disease, with phymas,rosacea conglobata, and rosacea fulminans), marked ocularmanifestations, steroid rosacea, dermatoses that may have in-terfered with the evaluation or diagnosis of rosacea, or a his-tory of hypersensitivity to any ingredient of the study medica-tion. In addition, due to label restrictions on infant exposureto metronidazole, breastfeeding mothers were excluded fromstudy participation. Beforeenrollment, all patients provided writ-ten informed consent, and institutional review board approvalwas obtained from each participating center.

Patients were required to complete a washout period of 2weeks for topical therapy with antibiotics, retinoids, cortico-steroids, or nonsteroidal anti-inflammatory drugs (NSAIDs);

4 weeks for systemic therapy with antibiotics, corticosteroids,or NSAIDs; 6 weeks for facial laser or light therapy; and at least6 months for oral isotretinoin. A total of 251 patients were ran-domly assigned to receive 15 weeks of treatment with eitherazelaic acid gel (n =124) or metronidazole gel (n =127), ap-plied twice daily,in themorning andevening,to theentire face.

A computer-generated blockwise randomization methodwas used to ensure balance between the 2 treatment groups.Assignment occurred by the physician in ascendingorder, witheach newly accepted patient receiving study medication withthelowest randomization number available in thecenter. A mini-mum of 12 patients was enrolled in each center. To preserve

blinding, study medication was dispensed and collected onlyby a study nurse or assistant not involved with selection andassessment of patients. Patients were not permitted to receiveany concurrent therapy that could potentially affect the courseof rosacea during the study.

Efficacy and safety variableswere evaluated at baseline andevery 4 weeks until the final 15-week visit. To ensure consis-tency, patient assessments were conducted by the same inves-

tigator throughout the entire treatment period.

EFFICACY VARIABLES

Efficacy variables were aimed at assessing the effect of treat-ment on the 3 principal symptoms of facial papulopustular ro-sacea andproviding overallassessment of treatment effect. Theprimary efficacy end point was the change in inflammatory le-sion count (sum of facial inflammatory papules and pustules)from baseline to last available visit. Secondary efficacy vari-ables includedpercent change in inflammatory lesion count andchangein severity rating forerythemaand telangiectasia. In ad-dition, an investigators global assessment (IGA) of rosacea andinvestigators and patients overall improvement ratings wereevaluated, and patients opinions of the cosmetic acceptabilityof the treatments were recorded.

The severity of erythema wasrated on a 4-point scale (none,mild, moderate, severe) (Table 1). Improvement in ery-thema severity was defined as a decrease of at least 1 point. Tel-angiectasia was assessed with the same method. The IGA wasperformed using a recently developed 7-point, static scoringsystem, ranging from 0 (clear) to 6 (severe) ( Table 2). Thisdescriptive score provides an integrated assessment of stage 2rosacea based on the severity of the principal symptoms: in-flammatory lesions, erythema, and telangiectasia.

The investigators and patients ratings of overall improve-ment were based on a comparison of the rosacea severity frombaseline to each visit (investigator only) and at the last availablevisit. The investigators rating was measured on a 6-point scale,reflecting the degree of clearance of disease signs andsymptoms,from 1 (complete remission) to 6 (deterioration). The patients

rating reflected a subjective impression of improvement based a5-point score, with 1 indicatingexcellent improvement and5 de-notinga worsening of rosacea severity. Additionally, patients ratedthecosmeticacceptability of thestudy medicationson a scale from1 to 4, with 1 being very good and 4 being poor.

SAFETY AND TOLERABILITY

Rosacea patients frequently report highly sensitive skin and lackof tolerance to cosmetic products. Therefore, pretreatment signsand symptoms of any untoward cutaneous events, such as burn-ing, stinging, or dryness, were recorded at baseline in all eligible

Table 1. Assessment of Overall Erythema Severity

NumericalScore Rating Description

0 None Either no visible erythema or minimalresidual erythema

1 Mild Slight erythema, either centrofacial orgeneralized to whole face

2 Moderate Pronounced erythema, eithercentrofacial or generalized to wholeface

3 Severe Severe erythema with a red to purplehue, either centrofacial or generalizedto whole face




3/7

patients. Treatment emergent adverse events (AEs) were re-

corded throughout the entire study period, including all cutane-ousand systemic eventsobserved by the investigator and all sub-

jective skin symptoms reported by patients. For all AEs, theduration,intensity,seriousness,and causal relationship to thestudymedication wereassessed by theinvestigator. Adverseevents wereclassified into 3 groups: facial skin signs and symptoms similarto pretreatment skinsigns and symptoms(burning, stinging, itch-ing, dry skin, rash, facial edema), other cutaneous AEs, and sys-temic AEs by body system. The pattern of facial skin signs andsymptoms (every dose, intermittent, continuous) was also as-sessed. The term transient was used to describe events that werereported as every dose. In addition, patient opinion of local tol-erabilityof therapy wasevaluated at the last visit based on 4 pos-sible ratings (good, acceptable despite minor irritation, less ac-ceptable due to continuous irritation, and nonacceptable).

STATISTICAL ANALYSIS

Efficacy and safety analyses were performed on the intent-to-treat (ITT) population, which included all randomized pa-tients who received study medication. Analysis of efficacy endpointswas based on thelast observation carried forwardmethod,in which data from the last available visit of each patient wereused to evaluate each efficacy variable. All statistical tests were2-sided using a .05 level of significance.

Analysis of mean and percent change in inflammatorylesion count was performed using an analysis of covariance

model, which included factors for treatment and study centerand the covariate number of lesions at baseline. For all otherend points, treatment differences were compared using anextended Mantel-Haenszel test, controlling for centers andusing modified ridit scores (van Elteren test). SAS statisticalsoftware (SAS Institute Inc, Cary, NC) was used to performthese analyses.

The incidence of all treatment-related AEs reported in theITT population was tabulated and classified by intensity, du-ration, and pattern. Differences in the patients overall rating

of tolerability between the 2 treatments were analyzed usingthe same method as for other secondary end points (ie, ex-tended Mantel-Haenszel test controlling for centers and usingmodified ridit scores [van Elteren test]).

The sample size calculation was based on results for thelesion count. A difference of 5 lesions in mean lesion countfor the 2 treatments was considered to be medically relevant.Assuming a common SD of 12 for the number of inflamma-tory lesions at the end of treatment, 92 patients per groupwould be sufficient to detect a difference of 5 in mean lesioncount between the 2 treatments with a power of 80% and a.05 2-sided significance level. Accounting for dropouts, it wasplanned to include a total of 204 patients (102 per treatment)in this study.

RESULTS

PATIENT CHARACTERISTICS AND DISPOSITION

Study enrollment occurred from October 29, 2001, toJanuary 31, 2002. Because of the fast enrollment rate, thestudy overenrolled 47 patients before all recruiting ef-forts in the centers could be stopped. At baseline, pa-tient demographic characteristics and signs and symp-toms of rosacea were comparable in the azelaic acid geland metronidazole gel groups (Table 3).

Table 2. Investigators Global Assessment of Rosacea:7-Point Static Score

NumericalScore Definition Description

0 Clear Almost no rosacea (ie, no papulesand/or pustules); no or residualerythema; mild to moderatedegree of telangiectasia may bepresent

1 Minimal Rare papules and/or pustules;residual to mild erythema; mild tomoderate degree of telangiectasiamay be present

2 Mild Few papules and/or pustules; milderythema; mild to moderatedegree of telangiectasia may bepresent

3 Mild to moderate Distinct number of papules and/orpustules; mild to moderateerythema; mild to moderatedegree of telangiectasia may bepresent

4 Moderate Pronounced number of papulesand/or pustules; moderateerythema; mild to moderate

degree of telangiectasia may bepresent

5 Moderate to severe Many papules and/or pustules,occasionally with large inflamedlesions; moderate erythema;moderate degree of telangiectasiamay be present

6 Severe Numerous papules and/or pustules,occasionally with confluentareas of inflamed lesions;moderate to severe erythema;moderate to severe degree oftelangiectasia may be present

Table 3. Patient Demographics and Baseline Characteristics(Intent-to-Treat Population)

Characteristic

Azelaic AcidGel*

(n = 124)

MetronidazoleGel

(n = 127)P

Value

Age, mean (range), y 49 (23-83) 46 (18-82) .15

Sex, % female 68 66 .79

Ethnicity, %

White 94 93African American 2 3

Hispanic 4 3 .79

Asian 0 1

Other 1 0

Mean previous durationof rosacea, y

7.8 7.5 .75

Mean inflammatory lesioncount

18 19 .25

Erythema intensity, %

Mild 28 26

Moderate 65 68 .78

Severe 8 6

Telangiectasia intensity, %

Mild 53 49

Moderate 45 45 .17

Severe 2 6

*Finacea; Berlex Laboratories, Inc, Montville, NJ.MetroGel; Galderma Laboratories LP, Fort Worth, Tex.




4/7

The disposition of patients is summarized inFigure 1. Overall, approximately 90% of patients com-pleted the study, with a slightly higher completion ratein the metronidazole gel group. The discontinuationrateswere 11% and 8% in the azelaic acid gel and metronida-zole gel groups, respectively.

EFFICACY

Inflammatory Lesion Count

Patients in the azelaic acid gel group experienced a con-tinuous decline in mean inflammatory lesion counts

throughout 15 weeks of treatment, from 18.1 lesions atbaseline to 4.5 lesions at week 15 (Figure 2). In the met-ronidazole gel group, the mean number of lesions also de-creased from baseline (19.4 lesions) through week 8 (7.7lesions). However, after week 8, lesion counts leveled off,with no further reduction seen through week 15 (7.6lesions). No such leveling off in efficacy was observed inthe azelaic acid gel group. At the last available visit, themean inflammatory lesion counts with azelaic acid gelandmetronidazole gel were 5.1 and 8.7, respectively.

The mean decrease in the number of facialinflammatory papules and pustules from baseline tothe last available visit was significantly greater withazelaic acid gel (12.9) than metronidazole gel (10.7)

(P =.003). Also, a significantly greater mean percentreduction in inflammatory lesions from baseline to lastavailable visit was achieved with azelaic acid gel(72.7%) compared with metronidazole gel (55.8%)(P.001) (Table 4).

Erythema

Overall facial erythema improved over time in both treat-ment groups. However, at the last available visit, azelaicacid gel demonstrated a statistically significantly greater

reduction in overall facial erythema than metronidazolegel (P =.02). An improvement in erythema severity wasobserved in 56% of patients in the azelaic acid gel groupvs 42% of patients in the metronidazole gel group. Ery-thema continued to improve during the 15 weeks of treat-

ment in the azelaic acid gel group but remained steadyafter week 8 in the metronidazole gel group (Figure 3).

Telangiectasia

No clinically relevant improvement in telangiectasia se-verity occurred in either treatment group. The telangi-ectasia rating remained unchanged in 73% and 76% ofpatients in the azelaic acid gel and metronidazole gelgroups, respectively. A total of6% ofpatients in each groupexperienced a worseningof telangiectasiaduring thestudy.

251 PatientsWere Randomized

127 (100%)

Received

Metronidazole Gel

124 (100%)

Received

Azelaic Acid Gel

110 (89%)

CompletedTreatment

14 (11%)

DiscontinuedTreatment

117 (92%)

CompletedTreatment

10 (8%)

DiscontinuedTreatment

0 Patients

(0%) Discontinued Owing to

Adverse Events

2 (2%) Discontinued Owing to

Lack of Efficacy

2 (2%) Deviated From Protocol

3 (2%) Withdrew Consent

3 (2%) Discontinued for

Other Reasons

5 Patients

(4%) Discontinued Owing to

Adverse Events

1 (1%) Discontinued Owing to

Lack of Efficacy

3 (2%) Deviated From Protocol

3 (2%) Withdrew Consent

2 (2%) Discontinued for

Other Reasons

Figure 1. Patient disposition.

25

15

20

10

5

00 4 8 12 15

Week

LesionCount

Metronidazole Gel

Azelaic Acid Gel

Last Available

Visit (LOCF)

Figure 2. Reduction in inflammatory lesion count at each visit and lastavailable visit with 15% azelaic acid gel (Finacea; Berlex Laboratories, Inc,Montville, NJ) vs 0.75% metronidazole gel (MetroGel; Galderma LaboratoriesLP, Fort Worth, Tex) (intent-to-treat population) (mean and 95% confidenceintervals). LOCF indicates last observation carried forward.

Table 4. Percent Change of Inflammatory Lesion CountsFrom Baseline

Week

Azelaic AcidGel*

(n = 124)

MetronidazoleGel

(n = 127)P

Value

4 44.5 38.8 .13

8 61.1 60.3 .65

12 68.0 61.3 .0915 75.7 61.3 .002

Last availablevisit (LOCF)

72.7 55.8 .001

Abbreviation: LOCF, last observation carried forward.*Finacea; Berlex Laboratories, Inc, Montville, NJ.MetroGel; Galderma Laboratories LP, Fort Worth, Tex.




5/7

Investigators Global Assessment

Beforetreatment, approximately92% of all patients in bothtreatment groups were classified as having a mild, mild-to-moderate, or moderateratingof rosacea ontheIGA staticscore of stage 2 papulopustular rosacea. (No patients were

rated clear or minimal.) At the last available visit, success,as defined by an IGA rating of clear, minimal, or mild, wasachieved in a significantly greater proportion of patientstreated with azelaic acid gel (69%) compared with metro-nidazole gel (55%) (P=.02) (Table 5). Nearly twice asmany azelaic acidtreated patients (11%) received an IGAscore of clear at the last availablevisit compared with met-ronidazole gel (6%). By contrast, more than twice as manypatients in the metronidazole gel group (19%) had a scoreof moderate, moderate to severe, or severe disease com-pared with the azelaic acid gel group (9%).

Investigators Rating of Overall Improvement

An overall improvement in rosacea occurred over time inboth treatment groups. Nearly half of azelaic acid geltreated patients (48%) experienced excellent improve-ment or complete remission, whereas slightly more thanone third (35%) of metronidazole geltreated patients re-ceived these ratings. More patients in the metronidazolegel group (6%) experienced deterioration of their rosaceacompared with theazelaic acid gel group (1%). At thelastavailablevisit, thedifferencebetween treatmentgroupswasstatistically significant (P=.005). This difference reachedstatistical significance at week 12 (P=.006).

Patients Overall Rating of Improvement

The patients subjective impression of the overall im-provement achieved with study medications was consis-tent with that seen in the investigators rating. Excellentimprovement was noted in 40% of patients receiving az-elaic acid gel vs 34% of patients receiving metronida-zole gel. In the azelaic acid gel group, 78% of patientsrated their improvement as excellent or good comparedwith 64% of patients in the metronidazole gel group.

Patients Opinions of Cosmetic Acceptability

There was no significant difference in patients opinionof the cosmetic acceptability of the study medications,with both receiving favorably high ratings at the end ofthe study. A rating of very good or good was given by75% and 82% of patients in the azelaic acid gel and met-ronidazole gel groups, respectively.

SAFETY AND TOLERABILITY

Pretreatment, untoward facial skin signs and symp-toms, such as burning, stinging, itching, scaling, and dryskin, were observed in most patients in both treatmentgroups (85% and 91% with azelaic acid gel and metro-

nidazole gel, respectively). Skin dryness was reported byapproximately two thirds of patients, and more than halfcomplained of scaling. Other events cited by at least onethird of all patients were itching, edema, burning, andstinging, in descending order of frequency.

No serious or systemic AEs were reported ineither treatment group. There were no reports of pho-totoxic or photoallergic reactions. The investigatorsdetermined that most AEs causally related to the studymedication were facial or involved other cutaneoussigns and symptoms.

70

50

60

40

30

20

10

04 8 12 15

Week

PatientsImprove

d,

%

Azelaic Acid Gel

Metronidazole Gel

Last AvailableVisit (LOCF)

Figure 3. Improvement in erythema severity as measured by theinvestigators overall assessment of erythema at each visit and last availablevisit with 15% azelaic acid gel (Finacea; Berlex Laboratories, Inc, Montville,NJ) vs 0.75% metronidazole gel (MetroGel; Galderma Laboratories LP, FortWorth, Tex) (intent-to-treat population). LOCF indicates last observationcarried forward.

Table 5. Investigators Global Assessment of RosaceaScores at Baseline and Last Available Visit

TreatmentBaseline,No. (%)

Last AvailableVisit (LOCF),

No. (%)

Azelaic acid gel* (n = 124)

Clear 0 14 (11.3)

Minimal 0 37 (29.8)

Mild 11 (8.9) 35 (28.2)Mild to moderate 62 (50.0) 27 (21.8)

Moderate 42 (33.9) 8 (6.5)

Moderate to severe 9 (7.3) 3 (2.4)

Severe 0 0

Metronidazole gel (n = 127)

Clear 0 8 (6.3)

Minimal 0 38 (29.9)

Mild 14 (11.0) 24 (18.9)

Mild to moderate 50 (39.4) 33 (26.0)

Moderate 53 (41.7) 15 (11.8)

Moderate to severe 8 (6.3) 7 (5.5)

Severe 2 (1.6) 2 (1.6)

Abbreviation: LOCF, last observation carried forward.*Finacea; Berlex Laboratories, Inc, Montville, NJ.MetroGel; Galderma Laboratories LP, Fort Worth, Tex.




6/7

In total, 32 of 124 azelaic acid geltreated patients(26%) experienced facial skin signs and symptoms. Inmost of these patients (25/32), these events were tran-sient in nature. Furthermore, these events were of mild-to-moderate severity in most patients (25/32). In the met-ronidazole gel group, 9 (7%) of 127 patients experiencedfacial skin signs and symptoms. In 3 of these 9 patients,the events were transient. In all 9 patients, the severitywas mild to moderate. In addition, 1 incident of acne was

reported in the azelaic acid gel group.In the azelaic acid gel group, 4 patients discontin-ued treatment and 5 patients had their dose reduced dueto a treatment-related AE. In the metronidazole gel group,treatment-related AEs resulted in a dose reduction in 2patients.

At the end of treatment, patients gave both treat-ments favorable local tolerability ratings. In the pa-tients opinion of local tolerability, the treatments wereevaluated as good or acceptable despite minor irritationby 89% and 96% of patients in the azelaic acid gel andmetronidazole gel groups, respectively.

COMMENT

This randomized, double-blind study compared the effi-cacy and safety of a novel formulation of azelaic acid (15%gel) with a widely used topical therapy (0.75% metroni-dazole gel) over 15 weeks of twice-daily treatment in 251patients with moderate, facial papulopustular rosacea. Ef-ficacy as assessed by nominal and percent change of in-flammatory lesioncount from baseline to last availablevisitin the ITT population was statistically significantly supe-rior for azelaic acid gel. Thus, azelaic acid gel proved su-perior to metronidazole gel in reducing both the meannominal lesion count (12.9 vs 10.7, respectively)(P =.003) and the mean percent decrease in inflamma-tory lesions (72.7% vs 55.8%, respectively) (P.001).

Also, in the azelaic acid gel group, a higher number of pa-tients showed improvementof the erythema severity score(P=.02). In theazelaic acid gel group, 56% of patientswererated improved at the last available visit compared with42% of patients in the metronidazole gel group. Like-wise, the IGA, a static score describing the overall sever-ity of rosacea, and the investigators overall assessment ofimprovement showed a significant advantage for azelaicacid gel at the last available visit. According to patientsoverall assessment, azelaic acid gel scored numericallyhigher than metronidazole gel. Neither treatment had aclinically appreciable effect on telangiectasia. Thus, in thisstudy, azelaic acid gel demonstrated consistently and sig-nificantly superior efficacy over metronidazole gel on the

primary and most secondary efficacy end points.During the first 4 weeks of treatment, there was a

greater mean decrease in the number of inflammatory le-sions with azelaic acid gel, from 18.1 to 9.6 comparedwith a decrease of 19.4 to 11.9 with metronidazole gel.This suggests that azelaic acid gel may have a more rapidonset of action. The signs and symptoms of stage 2 ro-sacea continued to improve during the 15-week treat-ment course with azelaic acid gel. In contrast, in this study,the effect of metronidazole gel showed a plateau that oc-curred from week 8 on with regard to inflammatory le-

sion count and a slight worsening between weeks 8 and15 of the erythema severity score. Given the chronic na-ture of rosacea, further studies with longer treatment du-rations are needed to investigate the long-term effects ofazelaic acid gel.

The safety of topical azelaic acid has been estab-lished through many years of worldwide clinical use, in-cluding useduring pregnancy (pregnancy categoryB).Like-wise, metronidazole gel is considered to be a safe topical

treatment. The safety andtolerability of azelaic acid gel andmetronidazole gel were confirmed by this study. No seri-ous or systemic AEs considered to be drug related by theinvestigatorwere reported foreither treatment, andno pho-totoxic or photoallergic reactions occurred. The cutane-ous AEs observed withbothtreatments were similarto thoserecorded as pretreatment, untoward skin signs and symp-toms. Some degree of burning, stinging, itching, scaling,and dry skin was present in more than 85% of the patientsat baseline, perhaps a result of the sensitive skin associ-ated with rosacea. Themost frequent treatment-related AEsreported in both treatment groups were facial skin signsandsymptoms.In most patients,these eventswere of mild-to-moderate severity and transient in nature. However, a

higherincidenceof these eventswasseen in patients treatedwith azelaic acid gel. Overall, these events did not seem tobeofgreat concern to thepatientsin eithertreatmentgroup.Patients expressed overall satisfaction with the local toler-ability of both azelaic acid gel and metronidazole gel, with89% of the patients rating their treatment as good or ac-ceptable despiteminor irritation in theazelaicacidgel groupand 96% of the patients in the metronidazole gel group.

In conclusion, this study evaluatedtheefficacy,safety,and tolerability of a novel 15% azelaic acid gel comparedwith 0.75% metronidazole gel. Results showed that az-elaic acid gel was consistently superior to metronidazolegel in improving principal signs of rosacea(ie,reducingin-flammatory papules and pustules and reducing erythema

intensity). In addition, azelaic acidgel wassuperior to met-ronidazole gel in improving or resolving rosacea signs asmeasured by 2 distinct investigators assessments. Al-though the effectiveness of metronidazole gel plateaued af-ter week 8, azelaic acid gel continued to show progressiveimprovement through 15 weeks. Thus, these results sug-gest a beneficial effectof azelaic acid duringprolonged treat-ment periods, warranting further investigation of long-term treatment of rosacea with azelaic acid gel. The highsafety of both topical azelaic acid and metronidazole wasconfirmed. This study establishes 15% azelaic acid gel tobe a promising, new, safe, andtolerable therapy option forpatients with moderate papulopustular rosacea.

Accepted for publication March 11, 2002.We acknowledge the contribution of Jeanne Ferrigno,

BS, MT, senior study manager, and the other principal in-vestigators whowere involved in thisstudy: Leslie Capin, MD,Castle Rock, Colo; James Q. Del Rosso, DO, Las Vegas, Nev;JoLynne Herzog, MD, Birmingham, Ala; Terry Jones, MD,Bryan, Tex; Kean Lawlor, MD, Seattle, Wash; Thomas Ni-gra, MD, Washington, DC; Michael Maloney, MD, Denver,Colo; John Proffitt, MD, Shawnee, Kan; Alan B. Shalita, MD,Brooklyn, NY; and Diane M. Thiboutot, MD, Hershey, Pa.




7/7

Corresponding author and reprints: Boni E. Elewski,MD, Department of Dermatology, University of Alabamaat Birmingham, The Eye Foundation Professional Build-ing, 70018th St S, EFH 414, Birmingham, AL 35233 (e-mail:[email protected]).

REFERENCES

1. Dahl MV. Pathogenesis of rosacea. Adv Dermatol. 2001;17:29-45.

2. Wilkin JK. Rosacea: pathophysiology and treatment. Arch Dermatol. 1994;130:

359-362.

3. Zuber TJ. Rosacea. Prim Care. 2000;27:309-318.

4. Cohen AF, Tiemstra JD. Diagnosis and treatment of rosacea. J Am Board Fam

Pract. 2002;15:214-217.

5. Plewig G, Kligman AM. Acne and Rosacea. 3rd ed. Berlin, Germany: Springer-

Verlag; 2000:460.

6. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of

the National Rosacea Society Expert Committee on the Classification and Stag-

ing of Rosacea. J Am Acad Dermatol. 2002;46:584-587.

7. Rebora A. The management of rosacea. Am J Clin Dermatol. 2002;3:489-496.

8. Thiboutot DM. Acne and rosacea: new and emerging therapies. Dermatol Clin.

2000;18:63-71.

9. BjerkeR, FyrandO, GraupeK. Double-blindcomparisonof azelaicacid20% cream

andits vehiclein treatmentof papulopustular rosacea.ActaDerm Venereol.1999;

79:456-459.

10. Carmichael AJ, Marks R, Graupe KA, Zaumseil RP. Topical azelaic acid in the

treatment of rosacea. J Dermatol Treat. 1993;4(suppl 1):S19-S22.

11. Maddin S. A comparison of topical azelaic acid 20% cream and topical metro-

nidazole 0.75% cream in the treatment of patients with papulopustular rosacea.

J Am Acad Dermatol. 1999;40:961-965.

12. Akamatsu H, Komura J, Asada Y, Miyachi Y, Niwa Y. Inhibitory effect of

azelaic acid on neutrophil functions: a possible cause for its efficacy in treat-

ing pathogenetically unrelated diseases. Arch Dermatol Res. 1991;283:162-

166.

13. Passi S, Picardo M, Zompetta C, et al. The oxyradical-scavenging activity of az-

elaic acid in biological systems. Free Radic Res Commun. 1991;15:17-28.

ARCHIVES Web Quiz Winner

Congratulations to the winner of our August quiz, Pij B. Marko, MD, Department of Dermatology, Maribor TeachingHospital, Maribor, Slovenia. The correct answer to our August challenge was

desmoplastic melanoma. For a complete

discussion of this case, see the Off-Center Fold section in the September ARCHIVES (Calista D. Dome-shaped lesion of thenose. Arch Dermatol. 2003;139:1209-1214).

Be sure to visit the Archives of Dermatology World Wide Web site (http://www.archdermatol.com) to try your hand atthe Interactive Quiz. We invite visitors to make a diagnosis based on selected information from a case report or other featurescheduled to be published in the following months print edition of the A RCHIVES. The first visitor to e-mail our Web editorswith the correct answer will be recognized in the print journal and on our Web site and will also receive a free copy of theThe Art of JAMA II.



38313 Azaleicacid vs Metrogel

Documents

Transcript of 38313 Azaleicacid vs Metrogel