Decemnen 2013 Covvnic Vouume 12 + Issue 12 1 OF Daves 1 DERMATOLOGY Full-Face Injections of Variable Total Doses of Abobotulinum Toxin Type A: A Randomized, Phase IV Clinical Trial of Safety and Efficacy Doris Hexsel MD,"* Cristiano Brum MD Ms,* Manoela D. Porto MD," Mariana Soirefinann MD Ms,“ Carolina Siega BSc,* Juliana Schilling Souza BPharm,’ and Ticiana C. Rodrigues MD PhD“ ‘Brazilian Center for Studies in Dermatology, Porto Alegre, Brazil ‘Cosmetic Dermatology, Department of Dermacology, Pontificia Univ dade Catolica do Rio Grande do Sul, Porto Alegre, Brazil *Complexo Hospitalar Sanea Casa, Porto Alegre, Brazil ‘Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil ‘on single or multiple facial reas. Objective: To evaluate the safety and efficacy of fulHlace trestmer vith various total doses of abobotulinum toxin A (ABO). | Methods: total of 90 participants were enrolled. Subjects had atleast two indications for BoN'FA treatments on each third of the face (up- | ‘ber, middle and lower. They were randomized into 3 groups, with pre-defined total dose renge of ABO, varying from 120 to 250 U | Results: Most of the subjects were women (96.5%). The statistically significant improvement from baseline lasted for more than 24 \weeks for glabellar lines, and more than 16 weeks for forehead wrinkles and crow’s feet, all P<0.001, with no differences between Sroups. The most frequent adverse event (excessive perioral weakness) was related to high dose in the perioral area, Conclusions: This is the fir study to compare safety and efficacy of different dases of ABO administered to the entire face simultane- ‘ously. As long as the recommended doses are used, concomitant injections of ABO are safe and efficient, with no increase in adverse: events, J Drugs Dermatol. 2013;12(12):1956-1362 Botvertiresneiccemesar treet ‘dynamic wrinkles and for other cosmetic indications.’ The Gil beefts cau thn twee er njoson, thon svrap uraton oS mena Comet entne ih BON Zhar boon ited in sf or mul xl reas, cording fo patent nec" Sevrl ais have show elescy af BONTA Ieee inspec reas of he upper ace" awl os mie ender fac Whon rut ndeatns tor SONA se prs onthe flac approach recommended Angeles opcns be done tar etme ely toa dye me” Although this full-face approach has been used frequently on dermatologic practice, there is no available data on the litera- ture about the efficacy and safety when multiple indications in ‘more than two thirds of the face are treated in a single session with BONT-A. Moreover, no studies have evaluated the optimal total and consensus doses of BoNT-A in the full-face approach, This study evaluated the safety and efficacy of full-face treat- ‘ments with three different total doses of abobotulinum toxin A (ABO) (Dysport®, Ipsen Biopharm Ltd,, Wrexham, UK). Study Design and Subjects This was @ prospective, single-center, randomized, open-label study of full-lace injections of three different doses of ABO. It wes conducted at the Brazilian Center for Studies in Dermatol ogy, in Porto Alegre, Brazil, and was approved by the ethics committee of Hospital Moinhos de Vento (ClinicalTrials.gov iden- tifier: NCT01032954). All subjects were fully informed about the study in accordance with the applicable regulations and GCP/ICH guidelines and provided written informed consent prior to the study. The main inclusion criterion was the presence of at least ‘wo indications for BONA treatment on each third of the face (upper, middle and lower). Eligible subjects were 30 to 60 years old, naive to BONTA or had not received BoNTA treatment in the previous six months, and agreed not to undergo other cos- metic or dermatologic procedures during the study, The main exclusion criteria were pregnancy, presence of scars or other dermatological conditions that could interfere with the evalua- tion of the results, and muscular or neurological diseases. The randomization list was generated by a statistician and subjects were sequentially allocated into 3 groups in a 1:1:1 proportion, with pre-defined total dose ranges of ABO: group1357 ‘JouRNAT OF Drucs 1x DERMATOLOGY Deceasen 2013 + Vorume 12 * Issue 12 1 from 120 to 165 U, group 2 from 166 to 205 U and group 3 from 206 to 250 U."** Study Product Reconstitution of the product (ABO 500 U per vial) was done immediately prior to the injections (visit 1). Each dilution was, made with 2 mL of 0.9% sterile saline, resulting in 250 UimL of 2.5 U/0.01 mL of the reconstituted product: Injections were performed with BD Ultra-fine ll 0.3cc syringes, with 2 29G short needle, 0.5 cm in length. Subjects were instructed not to touch ‘or massage the zones subsequent to the injections. After ad- ministration, immediate side effects were recorded, ‘A dermatologist experienced in the use of ABO (DH) performed all the injections according to the indications of each patient and to the randomization group, aiming to obtain the best results. [At loast two indications of each third of the face were injected in each patient. The randomization group determined the total amount of units that was injected for each patient. Besides, the doses for each indication were standardized according to the consensus recommendations." Doses for indication could have a variation of 10% according to the subjects needs. Table 1 shows the total doses for each indication. The patients received the same doses for each indication, thus the difference between {groups was the number of treated areas. Crow's feet (periobital) wrinkles 70U Glabelta 50U Forohead 40U Lower eyelid 5U Nasal wrinklos 200 Malar wrinkles 10U. Perioral wrinkles 15) 10U" Asymmetric smile or gummy smile 5u Cellulitic ehin 20U Marionette lines 25U * The dese forthe pariora area was changed during the study Four weeks after the procedure all the patients received a touch up of a standard dose of 25 U of ABO, distributed on the treated areas according to individual patient needs. After treatment of the first 20 subjocts, the occurrence of side effects related to the perioral wrinkles treatments caused study protocol to amend and reduce the maximal dose from 15 to 10 U of ABO for this indication. D. Hessel, C, Brum, M.D. Porto, etal. Assessments ‘There were @ total of7 visits in the study: baseline, injection, and weeks 4, 5, 16,20, and 24 after the injections. Demographic data, medical, surgical and cosmetic procedures history, dermatologi- cal assessment, physical examination, and prior concomitant medications were evaluated at the baseline visit. A pregnancy test was performed for female subjects of childbearing age at baseline and at the end of the study. Standardized photographs and rating of wrinkles severity by validated scales were also per- formed at baseline. For the purposes of this article, only safety and efficacy data obtained in this trial will be presented. Dermatological evaluation, recording of concomitant medication and adverse events, and wrinkle severity assessments were per formed 4, 16, 20 and 24 weeks after the first injection. Standardized photographs were taken at baseline, week 5, 16, 20, and 24 Clinical 0-3 scoring for glabellar frown lines,® Photonumeric Atlas forthe Assessment of Crow's Feet Severity," Photonumerical Atlas for the Assessment of Forehead Wrinkle Severity; and Marionette Lines Grading Scale® were used for wrinkle assessment in these areas. For the remaining areas, efficacy of BONTA was assessed by the percentage (0%, 25%, 50%, 75% and 100%) of improvement obtained with the treatment, with 0% defined as no improvement from the baseline, and 100% as the optimal improvement. Statistical Methods ‘Simple (n} and relative (%) frequency were used to describe categorical variables and mean and standard deviation were used to describe quantitative variables. Kruskal-Wallis test was used to compare baseline data among the three groups, ANOVA repeated measures with correction for Bonferroni was used for efficacy evaluations with Validated Scales Assess- ment over time and General Linear Model and Mauchly’s Test of Sphericity for comparisons between groups. Efficacy results for other indications were assessed based on the improve- ments from baseline and described as percentages. ANOVA for repeated measures was used to compare the occurrence of immediate side effects and adverse events between groups. Chi-square or Fisher test was used to check if there was associ- ation between variables for the adverse events in perioral area before and after amendment. Data were analyzed with SPSS 18.0 sofware (Chicago, IL) and significance level was 5%. See nea eae tien fee rk1358 Jounnat oF Daucs in Dimaaxorocy Decenmen 2013 + Vowume 12 + Issue 12 Mean age was 48.3 + 7.2 (range: 30 - 60 years) and most of the subjects were female (n=82, 96.5%), Caucasian 92.9% (n=79), non-smokers (62.4%, n=53}, naive for botulinum toxin use (60%, n=61), and for previous treatment with dermal fillers (635%, 4). Most of them were phototypes Il Il, and IV (176%, n=15; 48.2%, n=41, and 31.8%, n=27, respectively). Mean age was com- parable among groups. The severity scores of the glabellar lines, forehead wrinkles, crows feet and marionette lines also showed »o significant differences among the three groups. Table 2 shows the percentage of subjects who received troat- ment for each indication. Among the possible 11 indications, all subjects received treatment of glabellar lines, crow’s feet, hhasal wrinkles, lower eyelids and chin; perioral wrinkles and forehead lines were also frequently treated. Of note, these in- ications were not present or always treated for all patients. In some cases, mainly for those subjects randomized for groups ‘and 2, some indications were not treated. This is because the investigator hed to choose only some areas to keep total the dose (used for the treatment of the whole face) under the limit established for each randomization group. The mean doses by Group were 16624, 194212 and 214211 (groups 1, 2 and 3 re- spectively, P<0,0001), Overall, regardless of the randomization group, the doses for the same areas were similar among the groups, except for glabella area: group 1 had lower doses than groups 2 and 3 (484 vs 5223 and 5242, respectively), TABLE 2. Percentage of Subjects Treated With ABO Injections for the eee er Cr Ear) ee) Frontal (forehead) 384-828 96.7 Glabella 100.0 100.0 100.0 Periorbital {erow's feet) 100.0 100.0 100.0 Malar wrinkles : : 33 Nasal wrinkles 100.0 100.0 100.0, Lowor eyelid 100.0 100.0 100.0, wrinkles 923 897 © 900 100.0 100.0 100.0, Asymmetric Smile : aes Gummy Smite see 33 Marionette lines 154 207267 Efficacy A total of four indications were evaluated using validated scales with photonumeric guides. Statistically significant reductions in the wrinkle scores were seen only at 16 weeks for forehead and row’s feet wrinkles (all P<0.001, with no difference between the groups), elthough clinical effects were still seen at 24 weeks (Fig- D. Hessel, C. Bram, M.D, Porto, etal. tres 1a-c and 2a-c) Statistically significant improvement was seen in glabellar lines, with results lasting more than 24 weeks (Figure 32-b) (all P<0.001, with no difference between the groups). Figures: 40 6 show wrinkle severity grading for these three areas, Reduc- tion in the severity of marionette lines was observed between baseline and week 4 only when considering the entire group. Lower eyelid wrinkles, nasal wrinkles, perioral wrinkles and chin wore assessed based on improvement from baseline. Four weeks after the injections, most of the subjects presented at least 50% improvement for all four areas, and a few individuals had sus- tained results at 16 wooks (Figure 7a-c). At week 16, more than 15% of the subjects maintained at least 50% improvernent in low- ‘ereyelid wrinkles, and more than 50% of the subjects maintained at least 25% improvement in nasal and lower eyelid wrinkles. At week 20, 18% of the subjects maintained at least 25% improve- ‘ment in nasal wrinkles and 28% of the subjects maintained at least 25% improvement in lower eyelid wrinkles. Figure 8 shows the average of the percentages of improvement according to investi- {gator’s opinion for each indication and for each group. Safety Safety assessments included the occurrence of immediate side effects and other adverse events. Immediate side effects were ‘mainly related to the injections, and occurred as listod: 57 (67%) subjects had erythema, 24 (27%) bruising, 11 (13%) edema, two (2.4%) reported pain, pruritus and burning and four (4.7%) had ‘some bleeding. Only one (1.2%) subject reported a sensation of heaviness in the eyelids.This symptom was transitory and did not lead to eyelid ptosis. After the touch up tfour weeks after intial injections}, 15 subjects had immediate side effects [11 [13%) re- ported erythema, three (3.5%) bruising and one subject had some bleeding]. No significant statistical differences in the immediate side effects were observed among the three groups (P>0.05) ‘There were no serious adverse events reported in the study, and alll reported adverse events were mild. The most frequent adverse events related to the product and doses used in this study were excessive perioral weakness (30 subjects out of the 77 injected for perioral area, 39.0%|, and lip asymmetry (three subjects: two subjects injected for perioral area and one injected for gummy smile). These adverse events were also mild, No significant sta- tistical differences were observed among groups (P+0.05). The relatively high frequency of adverse events in the perioral region was linked to the injection dose in the area. Of note, 15 out of 20, subjects (75.0%) injected with the initial proposed dose of 15 U before the amendment presented excessive perioral weakness, whereas 15 out of 57 (26.3%| subjects injected with a lower dose {total of 10U) after the amendment reported this adverse event {Table 3). Correspondingly, the mean doses injected in the sub- jects with this adverse event (11.6 U) were significantly higher than those presenting no adverse events in the perioral area (9.0 U), P= 0.004 (equal variances assumed).SURNAL oF Dues iN Dexwarorocy ] D. Hexsel, C. Brum, M. D. Porto, etal FIGURE 1. Same subject ata) baseline; b) 16; and c) 24 weeks after treatment FIGURE 2. Same subj FIGURE 3. Same subject t a) baseline and b) 24 weeks after treatment1360 JourNat or Dnucs 1N Dexmarorocy | D. Hexsel, C. Bram, M.D Porto, etal Drcenmer 2013 + Vorum 12 Issue 12 FIGURE 4. Mean values of the scores of Photonumerical Atlas inthe FIGURE 7. Same subject at ) baseline; b) five weeks after treatment; and ¢} 18 weeks after tr th little effec. Assessment of Forehead Wrinkle Severity FIGURE §. Clinical scores (0-3) or glabellar frown lines. FIGURE 6. Photonumaric Atlas for the Assessment of Crow's Feet Wrinkles Severity ISCUSSION The present study is the first to compare safety and efficacy and marionette lines. More than 0% of subjects had at least 50% hree different total doses of ABO administered to upper, improvement from baseline in nasal wrinkles, lower eyelid wrin middle and lower face (at least 6 indications) simultaneously. _Kles, perioral wrinkles and chin, regardless of tho total injected dose on face. The best performance was observed for the glabt Abobotulinum toxin A was efficient in reducing wrinkles: less se- lar area, where the improvement in wrinkles with ABO treatment vere wrinkles were observed for glabella, forehead, crow's feet, _was significant up to 24 weeks after initial inj1361 ‘JouRNAL OF Davos iN DenmaroLocy DeceMmen 2013 + Vowue 12 + Issue 12 FIGURE 8, Percentage of improvement from baseline for a) nasal ‘wrinkles; b) lower eyelid wrinkles; e) perioral wrinkles; and d) chin. : 2 Ma. Ms. Botulinum toxin type-A treatments of two or more areas are rarely reported, although they are very common in clinical prac- tice. Carruthers and Carruthers* have compared three different, doses of BoNT-A for the treatment of three areas in the upper third of the face and the main difference observed between groups was the duration of the effects. A possible hypothesis for the longer duration of cosmetic results may be that with the treatment of multiple areas, there is 2 lower likelihood of ad- jacent muscle recruitment This hypothesis could also explain the similar duration of effects observed in the present study in the glabella, since most subjects had their glabellas and fore: heads treated simultaneously. ‘A retrospective study? reported the injection of BoNTA in more ‘than two areas simultaneously: 30.7% (n = 290) of the subjects received treatmentin the glabella, forehead, and lateral periorbital region. However, the results focused on the comparisons among ‘multiple treatment cycles instead of the concomitant treatments. ‘The effects of BoNT-A have been regularly reported to last up to 16 to 24 weeks on average.” The majority of the studies showed results of different commercially available toxins at 4 months?22"** and, to the best of our knowledge, no studies pre- sented the duration of effects at 6 months follow-up in the main facial indications. In the present study, a significant improve- ment in wrinkles for frontal and periocular area up to 16 weeks after the injections was observed, while a significant improve ment in wrinkles for glabellar area was observed up to 24 weeks after the injections. This suggests that the consensus doses used in the treatment of these areas are proper and very efficacious. ‘There were no statistically significant differences regarding the occurrence of immediate side effects and other adverse D. Hessel, C. Brum, M.D. Porto, etal [erent subject received the injection | Pre-amendment (Total Ce) Corie eo 5 25.0% 15 75.0% <0 Post-amendment (Total Seoul 42 737% 15 263% 0.001 events among the three groups with varying total dose. This result suggests that, as long as the recommended doses for each indication are followed, concomitant injections of BONT- ‘Ain various facial areas can be performed with no increased safety concerns. ‘The unexpected high frequency of transient adverse events for the perioral area with the previously established dose (15 U), pushed the review and reduction of the doses for the treatment of this region. The initially proposed dose for perioral wrinkles was changed due to the occurrence of side effects; this action resulted in significantly fewer occurrences of excessive peri- oral weakness. Thus, this dose-dependent adverse event can be avoided by reducing the dose for the treatment of perioral wrin- les. A recent study on the use of onabotulinumtoxinA for the ‘treatment of hyperdynamic perioral lines also reported the in- cidence of adverse events for this area to be dose-dependent.” ‘The use of high doses of ABO, up to 250 U, in full-face treat- ment is safe and effective. In this approach, the ABO doses recommended by the consensus for the upper face were used ‘and showed to be very effective, producing long-lasting results that remained statistically significant up to 24 weeks or moro. However, differences in the duration of the effects were found in some areas. In the upper face, glabellar area had long last- ing results were seen in the (more then 24 weeks) compared to forehead and crow's feet lines (more than 16 weeks! ‘There wes low incidence of adverse events, and when occurred, their frequency was dose-related in the perioral area, and not due to the total dose administered. Lower doses in the perioral area are recommended to avoid complications, DINVeReNTe ess Dr. Hexsel has conducted clinical trials for Ipsen, Allergan, Gal- derma, and Medicis. The other authors have no relevant conflicts of interest to declare. This study was an Investigator Initiated Trial. Scientific grant was received from Galderma Inc., France. EFERENCES ‘Crrthers J, Carruthers A. Botulinum Tox in Facial Rejvenation: An Up fate, Dermat) Cn 200927181725,n. 4 20. 2. 23 24, 25 EA 2 1362 1D, Hexsel, C, Brum, M. D Porto, et al. Jounnat or Drucs wv Dinmarorocy Decempen 2013» Vorume 12 + Issur 12 Nestor MS, Ablon GR. Duraton of action af abobotuinumtoxine and ons botuinamtoxinaa randerzod, doubling study using «cotrleteral ron tals model J Cie Aesth Demato!201 891429. any 8, AstherB, Monnet G. Teatment of gabe ines with botulnurn toxin type A (Spevinced Uni clinical averwew, Eur Acad Dermatol Ue- nereol 201,281 1-14 CComahers 8 Caruthers JA single-center, dove-comperson pit study of botulinum neurotoxin type A in female patents wih uoper fecal yids safety and eficacy. Am Acad Dermatol 2008:6016) 372.3. Camuthers A Caruthers A singe center dose-comperson study of bon num neurotai type Ain females with upper faci yids: sosessing patents! porogpsion of restment outcomes. JDrigs Dermato!2009,810) 9249. Raary 8, DilMuler D, Grablowitz, at ak Reposted batuinur toxin A rc ‘ns for the tueatment of lines in the upper face: a rettospactve study of 4,108 reatmentsin 945 patents, Dermatol Sug 70073311 Spec No S125, Ascher 8, Zatine B. Kestemort Pe aA mulicente, randomized, dovble- bind, placsbo-conttoled studyaf eticacy and alety of 3 aoses of botulinum toxin dn the weatment of labor Ines, Acad Dermatol 2008'S 12.2259. CCouthers J, Caruthers A. Betuinum Toxin Type A Trestment of Mutiple Upper Facial Sites: Patert-Reported Outccmes, Dermatol Surg 20073811 ‘Spor No S107 Hexsel D, Os!'Fomo T Type A Botulinum Tein inthe Upoer Aspect ofthe Face. Cini in Dermat 2003.2 48857 Pragor W, Wasmillor E, Kolhoest 8 etal. Cortparion of two botulinum toxin type A premaratons fo treating cows feet: splitace, double‘ing, roct-o-condeat study Dermatol Surg 2010364): 2 186-60 Caruthers A. Caruthers 4. Le! X, etal Onabotuinutoxina troatment of ld gabel tines in repose. Dermatol Surg 2010,2641-216871 Careuthers J, Carats A Satsnum toxin Ain the mid andl owe ac neck Dermal Cin 2004:22721 1518, Camuthers J, Caruthers A. Aestnete botuinum A toxin inthe mid and lower face and neck. Dermat Surg 2003 2918 468 76, Camthers J Comahore A, Menrot GD, Davis PS, Wdteenter,anderized ae ale-groun sty of orabotunumicxin§ ana yar ack dermal ies ng) ‘mY smoot, cohesie gal ane and in combination or ower fc rejuvenation satisfaction ard patentepored autcares. Darnto Surg 2010264 213545, Camutners A, Caruthers J, Monheit GD, etal Multicenter rondomzed, par Bile-grow study ofthe safety and afoctvenaas of anabotuinurntonnA on hyaluronic acid dermal files (mgm smooth cohesive gel alone ann ombinaton for lowe oc rejwenston Dermata Sur 2010:384)212138 Custs 1 Seyret 0, Carranza D, eta. Comparison of treatment of molo- ‘ental fold thyees with crosslinked tyalronic acid combined wth ne botuinamtoxina and crosslinked Myalronke ack alone Dermal Surg 70103601852. Hexse!D, Hersel CL. Gotutnum toxins. In: Robinson JK, Hanke CW Siegel DM, Frais A. ed. Surgery ofthe skin ~ rocadurl dvmatlogy, 2" Edinburgh: Elsevier, 2010p. 433-46, ‘Asche B,TalaeoS, Casuto Do a. ntematonal consensus recommender ‘ions onthe aesthetic usage ofboutoum toxn type. Saywood ui par "upper fail vaikles. J Eur Acas Dermatol Venereo! 201624111 127-88. Ascher 8 Talico 5, Cassuto D eta. Intemational consensus ecammon- "ations onthe aesthetic usage of totuliaum toxn type A (Speywcod ni) “par I: winks onthe middle and wer fece, rack and chest J Eur Acad Dorma! Venareo!2010;24/3) "20595, Honeck R Wess C. Starry W, ota. Reproducibility of 2 fourpoint cca ‘overt sores lor labeler frown ines. BJ Dormatl 2008149121206 10, Hund Ascher 8. Reany 8. Reproducisity of Two FourPoint Cincal Se- vwrty Scares for Lateral Corhal Lines (Crows Fee, Oetmate’ Sug 2008 32110125660, Caruthers, Caruthers J. Cohen JA Prospective, Double-Bind, Randomized, Paralle-Grouo, DoseFienging Stuy of Botulinum Tax fypo A a Ferole Sub pct with Horaontal Forehead yids. Dermat! Surg 2003 2015 46157 Carnaners A, Caruthers J, Hares Bot a Await grading scale for rar- ‘nete ines, Dermatol Surg 2008:34 Supp 2816772. Monten G, Caruthers A, Brandt = Rend Randomized, daubleblnd, place 'bo-conrolad study of botulinum takin ype A forth eaten of gabe Ines ‘eterminaion of opal ds, Dermat Sgery 20073 IISp0s No S61 ‘Ascher B, Zaire B,Kestermont Rt aA muticote, randomized, doubled, Boceto-contoled study of eficacy and salty of 3 dese of botulinum toxin A inthe treaent of gabel ines. JA Acad Darmata/ 200851 22322 Ascher B, ZakineB,Kestomont Fetal. Botulinum Ioxin inthe treatment of (abeta joes: scheduling the nest injection. Aasthet Surg J2005.25:365 78, Gemes PE, Stabaze D.A fourmont randomized, double bind evaluation ofthe efficacy of botinum toxin ype A Tor the treatment of glbeller lines in women with ske types andi. Dermatol Surg 2000,3513 425.5, sdscussion 4356, 28 Ea a Feary’ 8, Ascher B, Fata A. et al Eficacy and safety of -and injection pat- toms 90 and 80 Ul of botulinum xn Oyebor forthe treet nen of wares i the glabala anc the cena forohaad region. ich Dera 2008122082208, Baumann L, Brandt FS, Kare MA, Donato UV, An analysis of efficacy dat ‘rom four phase I studies of borin nauratoxn type ABO for he Cea ‘ment of labeler ines. Aesther Suro J 20002516 Supp S576 Lome NU, Ascher 8, Heckmann Me Double bind, randomied,placebo- controled, dose-esporee tudy of the salty and effeacy of botlinum ox type in subjects wit cow's feet. Dermatol Surg 2008 3148 257.82. Cohen Jt, Dayan SH, Cox SE, et al. Onabotuinumtoxind Dose angina ‘Study for Hyperdynamic Povoral Lines, Dermatol Surg 2012:281) 1697505, Doris Hexsel MD E-mail A corie@hexse..corn br