RCT of Timolol Maleate Gel for Superficial Infantile Hemangiomas … · 2015. 3. 8. · jection;...

DOI: 10.1542/peds.2012-3828; originally published online May 6, 2013;Pediatrics

Hsien Chan, Catherine McKay, Susan Adams and Orli Wargon24-Week-Olds

RCT of Timolol Maleate Gel for Superficial Infantile Hemangiomas in 5- to

http://pediatrics.aappublications.org/content/early/2013/04/30/peds.2012-3828

located on the World Wide Web at: The online version of this article, along with updated information and services, is

of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

at University of Manitoba Libraries on May 9, 2013pediatrics.aappublications.orgDownloaded from

http://pediatrics.aappublications.org/content/early/2013/04/30/peds.2012-3828http://pediatrics.aappublications.org/

RCT of Timolol Maleate Gel for Superficial InfantileHemangiomas in 5- to 24-Week-Olds

WHAT’S KNOWN ON THIS SUBJECT: The systemic nonselectiveb-blocker propranolol hydrochloride is increasingly used as first-line management for infantile hemangiomas. Superficialnonulcerating lesions do not require systemic medications. Caseseries have suggested the efficacy of timolol; however, its safetyhas been questioned.

WHAT THIS STUDY ADDS: This randomized controlled trialindicates that timolol maleate 0.5% gel is a well-tolerated, safe,and effective treatment of superficial infantile hemangiomas.

abstractOBJECTIVE: Timolol maleate 0.5% gel is a safe and effective medica-tion for treating superficial infantile hemangiomas (IHs) in infantswith a median age of 9 weeks.

METHODS: Forty-one infants who had superficial IHs without ulcerationand not near mucosal surfaces were recruited and randomly assignedto placebo and treatment (timolol maleate 0.5% gel) groups. Efficacywas assessed by performing blinded volume measurements at weeks0, 1, 2, 3, 4, 8, 12, 16, 20, and 24 and blinded investigator photographscoring at weeks 0, 12, and 24. Safety was assessed by measuringheart rate and systolic and diastolic blood pressure at weeks 0, 1,2, 3, 4, 8, 12, 16, 20, and 24.

RESULTS: Fifteen of the 19 infants receiving treatment and 17 of the 22infants receiving placebo completed the study. Significant color changeon the blinded photographic scores was noted at week 24 of the study(P = .003). There was a significantly higher proportion of treated IHsthat reduced in size by .5% at weeks 20 and 24 (P , .02). Thepredicted proportion of IH volume change was also significantly lessfor treated IHs from week 16 onward when compared with placebo(P , .05). There was no significant variation in blood pressure andheart rate between the groups.

CONCLUSIONS: Topical timolol maleate 0.5% gel with a maximum doseof 0.5 mg per day is a safe and effective option for small superficial IHsthat have not ulcerated and are not on mucosal surfaces. Pediatrics2013;131:1–9

AUTHORS: Hsien Chan, MBBS,a Catherine McKay, MBBS,a

Susan Adams, FRACS,b and Orli Wargon, FACDa

Departments of aPediatric Dermatology and bPediatric Surgery,Sydney Children’s Hospital, Randwick, Australia

KEY WORDSinfantile hemangioma, timolol/adverse effects, randomizedcontrolled trial

ABBREVIATIONSCI—confidence intervalDBP—diastolic blood pressureIH—infantile hemangiomaSBP—systolic blood pressure

Drs Chan and McKay participated in the acquisition of data,analysis and interpretation of data, drafting and revising thearticle for important intellectual content, and approval ofthe final manuscript as submitted; Dr Adams participated in thestudy concept and design, critical revision of the article, andapproval of the final manuscript as submitted; and Dr Wargonparticipated in the study concept and design, analysis andinterpretation of data, critical revision of the article forimportant intellectual content, and final approval of the finalmanuscript as submitted.

This trial has been registered with the Australian and NewZealand Clinical Trials Registry at www.anzctr.org.au (identifierACTRN12610001069044).

www.pediatrics.org/cgi/doi/10.1542/peds.2012-3828

doi:10.1542/peds.2012-3828

Accepted for publication Feb 6, 2013

Address correspondence to Hsien Chan, MBBS, Sydney Children’sHospital, High St, Randwick, New South Wales 2031, Australia.E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2013 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

FUNDING: A Sydney Children’s Hospital Foundation grantprovided support for statistical analysis of the results. TheTouched by Olivia Foundation funded the Vascular BirthmarkResearch Fellowship position.

PEDIATRICS Volume 131, Number 6, June 2013 1

ARTICLE


http://www.anzctr.org.aumailto:[email protected]://pediatrics.aappublications.org/

Infantile hemangiomas (IHs) are amongthe most common tumors of infancy,with ∼4% of infants affected.1–3 Khanet al4 reported that IHs arise fromCD133+ stem cells, which can differenti-ate into several cell lineages includingadipocytes. The mechanisms that con-trol the proliferation and involution ofthese lesions are not as yet fully un-derstood. Focal IHs are rarely presentat birth and exhibit a characteristicgrowth phase typically up to the age of 9months.5 A gradual involution phasetakes place over the subsequent 2 to 10years1,5; however, recently, Couto et al6

suggested that most IHs do not sub-stantially further improve after 3.5years of age. Increasingly, nonselectiveb-blockers, including propranolol hy-drochloride, have replaced or been usedin conjunction with previously recom-mended treatments such as systemiccorticosteroids and vincristine for thetreatment of IHs to prevent ulcerationand disfigurement and for systemic in-volvement.7,8 The mechanism via whichb-adrenergic receptor antagonists in-hibit the growth of IHs remains tobe fully elucidated. Whereas the side-effect profile of propranolol hydrochlo-ride is favorable,8,9 the potential forhypoglycemia, bronchial hyperactivity,and hypotension makes it difficult tojustify its use for less severe IHs.

For small, superficial focal lesions with-out features necessitating propranololor other systemic agents, the use oftopical imiquimod 0.5%10 and potenttopical corticosteroids11 has also beenreported. Topical timolol solution isa nonselective b-adrenergic receptorinhibitor that was approved in 1978 forthe treatment of glaucoma and has beensafely used as first-line therapy for pe-diatric glaucoma for .30 years.12,14 Anumber of case reports and case serieshave observed the efficacy of timololmaleate 0.5% gel for the treatment ofIHs15–22; however, concern has beenraised regarding its safety.12

This blinded, randomized, placebo-controlledstudy aims to begin to answer thesequestions relating to the safety andefficacy of topical timolol maleate 0.5%gel in the setting of small, superficialfocal IHs in infants aged 5 to 24 weeks.

METHODS

A randomized, double-blind, placebo-controlled, parallel-group trial wasconducted in a single institution be-tweenMarch2011andSeptember2012.Approval was obtained from the insti-tutional review board of the South East-ern Sydney and Illawarra Area HealthService, Northern Hospital Network Hu-man Research Ethics Committee. Writteninformed consentwas obtained from thechildren’s parents after a discussion ofthe risks and benefits of participating.

Eligibility of Patients

Patients were recruited at a single ter-tiary center from neonatal, pediatricophthalmology, general pediatric, andpediatric surgery clinics from March2011 to April 2012 (Fig 1). Participationwas offered to infants between the age

5 and 24 weeks with small, focal super-ficial IHs not requiring systemic therapy.Exclusion criteria included hypersensi-tivity to timolol maleate, wheezing, car-diac rhythm disturbances or congenitalheart disease, or large, ulcerated, mu-cosal, or subcutaneous IHs. During thetrial, proliferation of the lesion, ulcera-tion, or parental desire to commencesystemic therapy resulted inwithdrawalfrom the trial and institution of systemicmedications.

Study Design

Patients were enrolled in the trial by 1of 2 study physicians and randomlyassigned (by using a method of mini-mization)23 by the clinical trials phar-macist into 4 groups: age between 5and 15 weeks or between 16 and 24weeks and size of lesion, or.25mm.Participants, caregivers, and physicianswere blinded to group status. Baselinescreening comprised a cardiovascu-lar examination, including blood pres-sure and heart rate, as well as clinicalphotography and 2 hemicircumferencemeasurements of the IH, 90° apart. The

FIGURE 1Flow diagram of trial participants.

2 CHAN et al at University of Manitoba Libraries on May 9, 2013pediatrics.aappublications.orgDownloaded from

http://pediatrics.aappublications.org/

study medication was dispensed in a ra-tio of 1:1 as placebo or timolol maleate0.5% gel (5.0 mg of timolol/6.8 mg oftimolol maleate in 1 mL; gellan gum,trometamol, mannitol, and water for in-jection; 0.0012% benzododecinium bro-mide added as a preservative.)13 Theparents were instructed to apply witha fingertip part of 1 drop of the gel ontothe surface of the IH (enough to just coatthe lesion) twice a day, and to gentlyrub it in. One drop of timolol maleate0.5% gel has been estimated to contain0.25 mg of timolol.12 The first applica-tion was conducted in the outpatientdepartment, and blood pressure andheart rate were measured just beforeapplication and 1 hour after applica-tion of placebo or timolol maleate 0.5%gel. Heart rate and blood pressuremeasurements were compared withage-related reference ranges.24 Twohemicircumference measurements 90°apart were taken of the IH in questionbefore the first application of placebo ortimolol maleate 0.5% gel. Repeat hemi-circumference measurements, as wellas blood pressure and heart rate, weretaken at weeks 0, 1, 2, 3, 4, 8, 12, 16, 20,and 24 after commencement of studyparticipation. In addition, photographswere taken by a clinical photographeratbaseline, week 12, and week 24. After 24weeks, participation in the trial ceasedand subjects were given the option ofoff-label use of timolol maleate 0.5% gelfor ongoing treatment of the IH. Interimblinded statistical analysis was carriedout at the study midpoint to confirmwhether the trial should be continuedor ceased.

Outcome Measures

Response to therapy was measured by(1) blinded predicted volume estima-tion25 at weeks 0, 1, 2, 3, 4, 8, 12, 16, 20,and 24 and (2) blinded scoring of clinicalphotographs at 0, 12, and 24 weeks. Forvolume estimation, 2 measurements ofthe IH hemispheric diameter were taken90° apart and the estimated hemispheric

volume was calculated by the formula0.073m3 wherem is the mean of the 2hemispheric measurements.25 The pho-tographs at 0, 12, and 24 weeks werescored by 1 blinded investigatoras 0 if noredness was observable, 1 if the lesionwas ∼50% red, or 2 if the lesion wascompletely red.

With regard to safety data, heart rate,systolic blood pressure (SBP), and di-astolic blood pressure (DBP) were mea-suredbefore administering thefirst doseof placeboordrug, aswell as 1 hourafterthe initial dose, and then at every visit.

Statistical Analysis

The datawere analyzed by a statisticianblinded to group status. Descriptivestatistics arepresentedaspercentages(%) of the group, means and SD, ormedians and interquartile range.

The number of children with redness asindicated by the photo score at visits 1,12, and 24 and the percentage witha categorized lesion size at each timepoint were investigated by using conti-nuity corrected x2 or Pearson’s x2 test.

A linear mixed model with an autore-gressive covariance structure wasused to examine whether there weresignificant differences in volume andpercentage change in volume, heartrate, SBP, or DBP between the groupsover time. The autoregressive covari-ance structure was used to allow vol-umes close together in time to bemore correlated than those fartherapart. A time-by-group interaction wasincluded to allow the groups to varydifferently by time. Post hoc compar-isonswith a least significant differencewere used to determine whether therewas a significant difference betweengroups at each visit.

RESULTS

A total of 41 children were enrolled inthe study; 19 were randomly assignedto treatment and 22 were randomly

assigned to placebo. There were nosignificant differences in gender ratios,age, and site of lesion between thegroups (Table 1). Although we plannedto recruit and analyze subjects in 2 agegroups (5–15 weeks and 16–24 weeksold), only 3 of 41 individuals were in theolder age group category and subjectswere consequently not stratified on thebasis of age in the results analysis.Similarly, subjects were also initiallystratified on the basis of an IH meandiameter being , or .25 mm (vol =1094 mm3). However, only 4 of 41 sub-jects had IH lesions with a mean di-ameter .25 mm. Thus, in the resultsanalysis all subjects were consideredin 1 group regardless of lesion size.Whereas all IH lesions analyzed com-menced asmacular lesions, volumetricapproximation and analysis were re-quired because a significant number oflesions developed a height of at least 5mm, thusmakingmean diameter a lessaccurate measure of IH lesion size.Comparisons of predicted absolutevolume of IH lesions between treatmentand placebo groups were made at eachtime point (Table 2). To gauge whetherthere was a significant reduction inpredicted absolute volume between

TABLE 1 Baseline Characteristics ofSubjects

Treatment Placebo

n 19 22Gender, %Male 26 33Female 74 67

Age, mean (SD), mo 2.1 (0.8) 3 (0.9)Site of lesion, %Face 47 50Neck 16 14Torso 11 —Thigh 11 5Upper limb 11 9Back 5 14Hand — 9

Volume, median (IQR),mm2

60 (180.4) 26.8(179.5)

,10 mm2, % 21 3210–50 mm2, % 21 3250–1000, % 53 32.1000 mm2, % 5 5

IQR, interquartile range; —, indicates 0%.

ARTICLE

PEDIATRICS Volume 131, Number 6, June 2013 3 at University of Manitoba Libraries on May 9, 2013pediatrics.aappublications.orgDownloaded from


treatment and placebo, a comparisonwasmadewith regard to the number ofIH lesions that decreased in predictedabsolute volume by $5% in the treat-ment and placebo groups (Table 3).Because 5- to 24-week-old infants growrapidly, most IH lesions also correspond-ingly increased in size. A comparisonwas thusmade between relative changein predicted absolute volume of IH le-sions between treatment and placebo(Fig 2). This comparison was addition-ally stratified on the basis of initialpredicted absolute volume of IH lesions(Fig 3).

There was no significant difference inpredicted absolute volume size be-tween the treatment and placebogroups at baseline or at any of the in-dividual time points. There was a mar-ginally significant difference in the sizeof the IH lesions atweeks 12and16,withthe lesions being smaller in the treat-ment group (Table 2; P = .05). In termsof relative reduction in size of IHs (Ta-ble 3), there was a significantly higherproportion of IH lesions with at leasta 5% volume reduction in the treat-ment group compared with placebo atweek 8 (P = .04), week 20 (P = .02), andweek 24 (P = .01; Table 3). Because 5- to24-week-old infants grow rapidly andhence their nonproliferating IHs in-crease in size relatively, a measure-ment of the proportional change ingrowth compared between groups wasalso analyzed (Fig 2). Before week 12

there was no significant differencebetween predicted percentage changein volume between treatment and pla-cebo (P. .05). Subsequent to week 16,there was a significantly lower pre-dicted percentage volume increase inthe treatment group compared withthe placebo group (P , .01).

With regard to which IHs may be moreamenable to topical timolol maleate0.5% gel treatment, the impact of IHvolume on treatment efficacy wasconsidered. Therewere 12 IHs thatwere,100mm3 (mean diameter = 11.3mm)in volume at baseline in the treatmentgroup and 16 in the placebo group. ForIHs with a baseline volume of ,100mm3 (Fig 3), the predicted percentageincrease in mean IH volume was sig-nificantly less in the treatment groupfromweek 8 onward (P, .003). For IHswith a baseline volume.100mm3, therewas no significant difference in pre-dicted percentage change in IH volumebetween treatment and placebo at anytime point (weeks 1–16, P. .2; week 20,P = .09; week 24, P = .06). In addition,a receiver operating characteristic curveplotted for IH lesions in the treatmentgroup indicated that a cutoff of 65 mm3

for baseline volume predicts whethervolume will decrease by$5% (area un-der the curve = 0.88, P = .02).

The clinical appearance of IH lesions asdetermined by blinded photo scorewasalso compared between treatment andplacebo groups at baseline, week 12,

and week 24. Representative photos ofIHs treated successfully with topicaltimolol maleate 0.5% gel are shownalong with images of IHs in the placebogroup in Fig 4. A score of 0 indicated noredness, a score of 1 indicated the le-sion was 50% red, and a score of 2indicated the lesion was completelyred. As shown in Table 4, no significantdifference in score distribution was seenat baseline or at 12 weeks. At 24 weeks,there was a significant difference inblinded photo score distribution betweentreatment and placebo groups. The pro-portion of photo scores of 0 (no redness)was significantly greater in the treatmentgroup (47%) than in the placebo group(6%). Conversely, the proportion of photoscores of 2 (completely red) was signifi-cantly less in the treatment group (6%)compared with the placebo group (55%;Pearson’s x2, P = .003).

With regard to side effects of topicaltimolol maleate gel, there were nocases of bradycardia or hypotensiveepisodes. Comparisons of mean heartrate (treatment mean heart rate = 147beats per minute; 95% confidence in-terval [CI]: 140–154; placebo meanheart rate = 147 beats per minute; 95%CI: 140–154; P = .81), mean SBP (treat-ment mean SBP = 89 mm Hg; 95% CI:86–93; placebo mean SBP = 84 mm Hg;95% CI: 80–89; P = .28), and mean DBP(treatment mean DBP = 43 mm Hg; 95%CI: 36–51; placebomeanDBP=38mmHg;95% CI: 33–43; P = .40) indicated no

TABLE 2 Volume in Categories by Time

Week Treatment Placebo P

n ,10 mm2 10–50 mm2 50–1000 mm2 .1000 mm2 n ,10 mm2 10–50 mm2 50–1000 mm2 .1000 mm2

1 19 21 21 53 5 22 32 32 32 5 .582 17 24 18 53 6 22 32 32 32 5 .563 17 18 18 59 6 22 36 27 32 5 .364 19 21 21 53 5 21 33 24 38 5 .798 19 37 5 53 5 19 21 32 42 5 .2012 18 33 11 50 6 18 11 50 28 11 .0516 15 40 7 47 7 18 11 44 33 11 .0520 14 36 7 50 7 18 11 39 39 11 .1324 15 33 7 53 7 18 17 33 39 11 .24

Data are percentages (%) of the group or n. There was a borderline significant difference at weeks 12 and 16 with more small lesions in the treatment group.



significant difference between treatmentand placebo groups (Table 5).

In total, there were 9 dropouts from thestudy (4 in the treatment group and 5 inthe placebo group) (Fig 1). Reasons forwithdrawal are summarized in Table 6.

DISCUSSION

Efficacy

IH growth cessation occurring as earlyas 48 hours after commencement oforal propranolol hydrochloride has

been described previously.7,26–29 Thisrelatively rapid onset of action forsystemic therapy most likely encour-ages compliance.30 In comparison,topical timolol maleate gel has beenassociated with growth arrest anda slower reduction in redness andthickness within the first 2 to 4 weeksof use as seen in 2 noncontrolledstudies of the use of topical timololmaleate gel for IHs.20,21 Chamberset al22 reported a significant improve-ment with topical 0.25% timolol male-ate gel compared with placebo forperiocular IHs after 8 weeks of treat-ment. The results presented from thisstudy indicate a therapeutic onset ofaction after 12 to 16 weeks of therapy,with a significant increase in thenumber of IH lesions decreasing insize by.5% and a significant decreasein proportional growth rate noted inthe treatment group compared withthe placebo group. This later onset ofaction compared with oral proprano-lol hydrochloride may be related toa lower dose being used in this study

and may explain withdrawals due tosubject-observed lack of efficacy. With-drawal may also be attributed to pa-rental anxiety as well as the inability topredict the appropriateness of the le-sion to topical treatment and the riskof ulceration. Despite the withdrawal of9 subjects from a relatively small sam-ple size, intention-to-treat analysis stillrevealed a significant difference in mea-sured outcomes as described above.From a practical perspective, it wouldbe suggested that any lesion consideredbeing at risk of ulceration or developingsigns of early ulceration would be moresuitable for systemic therapy.

Previous studies have suggested thatsuperficial19,22 and plaque-like IHs aremore amenable than nodular and deeplesions20 to topical timolol maleate geltreatment; hence, this study excludeddeep lesions. By using a receiver op-erating characteristic analysis andstratifying the data on the basis of IHvolume, a significant difference wasnoted in drug efficacy for lesions,100mm3 in volume (mean hemisphericdiameter ,11.3 mm) from week 8 on-ward. Lesions .100 mm3 treated withtopical timolol maleate gel appeared tohave no significant difference in growthcompared with lesions of a similar vol-ume in the placebo group at any timepoint. Because a fixed dose of topicaltimolol maleate gel (1 drop twice a day)regardless of lesion size was applied,one might predict that smaller lesions,due to their higher surface area to vol-ume ratio, aremore amenable to topicaltherapies. The lack of different dosagesused and the small number of largelesions in the present study make itdifficult to predict the optimal manage-ment of large IH lesions with topical ti-molol maleate gel. With regard to theinfluence of site of IH lesion on topicaltimolol maleate gel efficacy, whereas itis predicted that IHs in areas in whichthe epidermis is thinner (eg, the eye-lids) would be more responsive to

TABLE 3 Infants With IH Volume Reduced by$5%

Week Treatment Placebo P

n Percentage ofGroup

n Percentage ofGroup

2 19 32 22 18 .533 19 26 22 5 .134 19 26 21 5 .148 19 37 20 5 .04*12 18 39 19 16 .2316 16 38 18 22 .5520 15 47 18 6 .02*24 15 60 18 11 .01*

* Significant difference at weeks 8, 20, and 24 with morelesions reduced by $5% in the treatment group.

FIGURE 2Percentage change in predicted volume for all IHs in treatment and placebo groups. P for group = .050.Post hoc group comparisons at each time point: weeks 0–4, P. .20; week 8, P = .07; week 12, P = .05;week 16, P = .01; week 20, P = .002; week 24, P = .002.

ARTICLE



topical timolol maleate gel, the safetyconcern and paucity of existing dataof systemic absorption at these sitesprevented a direct analysis of thisprediction.

Although it was anticipated that sub-jects in 2 age groups (5–15 weeks and16–24 weeks old) would be recruited,only 3 individuals were in the 16- to24-week-old age group category. Theoverall mean age of participants was 9to 10 weeks. Other studies of topicaltimolol maleate gel for the treatment ofIH have involved subjects between theages of 5 and 30 weeks21 and 12 and 68weeks20 and cohorts with mean ages of19 weeks22 and 32 weeks.19 The efficacyof topical timolol maleate gel in therelatively young age group of the pres-ent study supports previously notedobservations that timolol maleate gelmay be more effective during the earlyproliferation stage.20 The safety datafrom this study indicate that even in thisyounger cohort, a limited volume oftopical timolol maleate gel has a favor-able side-effect profile.

The sustained effect of the 24-weekcourse of topical timolol maleate gelhas not directly been considered inthis study. Posttrial follow-up of themajority of study candidates, however,has provided the investigators with theimpression that no significant reboundof IHs occurred in those successfullytreated with topical timolol maleate gelonce the medication ceased. This find-ing is supported in other studies inwhich no significant IH rebound at 4weeks after 8 to 30 weeks of treat-ment,21 at 4 months after 6 months oftreatment,20 and at 3 to 6 months aftera mean treatment duration of 3.46 2.7months19 was described.

Safety

The specific pharmacokinetics of ti-molol maleate gel are not well defined;however, 1 study of the systemic ab-sorption of topically applied 5% timololvia 0.2-mg/cm2 transdermal patchesindicated that plasma concentrationswere undetectable in 3 of 4 patients 48hours after application.31 This finding

is mirrored by the fact that safety datafrom studies of the use of topical ti-molol maleate to treat IH have gener-ally been favorable.19,20,22 However,concern has been voiced regardingthe potential systemic absorption andside effects that may arise from topicaltimolol maleate gel and what specificmonitoring requirements are neededwhile receiving therapy. McMahon et al12

estimated that 1 drop of 0.5% timololgel-forming solution may equate to 2 to8 mg of oral propranolol hydrochloride.As a comparison, oral propranolol hy-drochloride is generally used at a doseof 1 mg/kg 2 to 3 times a day. In thepediatric ophthalmology literature,systemic bioavailability of timolol so-lution applied to mucosal surfaces hasbeen estimated to be as high as 60% to80%32 and has been attributed to casesof apnea, asthma, bradycardia, dizzi-ness, and dissociated behavior.12 Inthe studies of timolol maleate solutionfor the treatment of IHs, a case reportof a 4-month-old girl developing ble-pharoptosis after treatment of a thin-plaque IH on the upper eyelid with 0.5%timolol solution has been described.16

The systemic absorption of timololmaleate gel formulation is consideredto be significantly less than that of ti-molol maleate solution and hence hasbeen favored in more recent studies.33

With regard to the gel formulation, ina study in 73 individuals treated withtimolol maleate 0.1% or 0.5% gel, 1case of significant sleep disturbancenecessitating treatment cessation hasbeen reported as well as local site-of-application side effects such as burn-ing, stinging, and irritant reactions.19

In a study in 25 individuals aged 12 to68 weeks using topical timolol 1%gel, no adverse events were noted.20

Similarly, no adverse effects were de-scribed in a retrospective, consecutive,nonrandomized cohort study of twice-daily timolol maleate 0.25% gel forthe treatment of periocular IHs.22 Inthe present study, which used timolol

FIGURE 3Percentage change in predicted volume for small lesions only (,100 mm3 at baseline). P for group =.003. Post hoc group comparisons at each time point: weeks 0–4, P. .20; week 8, P = .003; week 12, P =.001; weeks 16–24, P , .0001.



FIGURE 4Clinical photos of IHs at baseline (left), 12 weeks (middle), and 24 weeks (right) after commencement of placebo or treatment. A, subject no. 131 (treatment);B, subject no. 104 (treatment); C, subject no. 111 (treatment); D, subject no. 202 (placebo); E, subject no. 125 (placebo); F, subject no. 102 (placebo).

ARTICLE



maleate 0.5% gel on intact skin, no ad-verse eventswere noted and there wereno significant differences in mean heartrate and mean SBP and DBP. Review ofthe use of topical timolol maleate forophthalmologic purposes also indicatesno significant differences in heart rateand blood pressure; however a redu-ction in exercise-induced increases inheart rate during the daytime has been

reported.34,35 Similarly, we would sug-gest that the likelihood of bradycardiaand hypotension due to the use of topi-cal timolol maleate gel for intact IHs isvery low. Exercise-induced differenceswould be less pronounced in the youn-ger age distribution of our presentstudy due to relatively low levels of ex-ercise, although continuous measure-ment of blood pressure and heart ratewould provide a more accurate as-sessment of this possibility. The safetyof topical timolol maleate gel for ulcer-ated, mucosal, or periorbital IHs alsorequires additional study.

Limitations

Although numbers were sufficient tocomparebloodpressure andheart ratebetween the groups, there were in-sufficient numbers to exclude rare andidiosyncratic adverse events. Continualblood pressure and heart rate moni-toring would provide additional insightswith regard to safety. Neither this study

nor previous studies showed significantcomparisons of efficacy on the basis ofthe IH site.19 A more sensitive scoringsystem incorporating other variablessuch as height/depth of IH with orwithout ultrasound imaging and a morecomprehensive photographic scalewouldhave improved the study.

CONCLUSIONS

This randomized placebo-controlled tri-al in infants aged5 to 24weeks indicatesthat up to 2 drops per day of topicaltimolol maleate 0.5% gel for 24 weeks’duration is a safe and effective therapyfor the treatment of IH not requiringsystemic treatment. The onset of ac-tion appears to be slower than oralpropranolol chloride with significantimprovements in absolute volume re-duction, proportional growth, andclinical appearance noted after only12 to 16 weeks. The efficacy of topicaltimolol maleate 0.5% gel appears tobe more pronounced for lesions witha mean diameter of ,11.3 mm (ie,,100mm3 in vol). The side-effect profileof topical timololmaleate 0.5% gel in the5- to 24-week age group is favorable,with no significant differences in heartrate, SBP, or DBP. Larger multicentertrials may provide insight into factorssuch as site-dependent efficacy as wellas additional safety, monitoring, dosing,duration-of-treatment, and age-group–specific data.

ACKNOWLEDGMENTSThe Vascular Birthmark Research Fellow-shipisfundedbytheTouchedbyOliviaFoun-dation. We thank Dr Jenny Peat, HonoraryProfessor of Statistics, Australian CatholicUniversity, for her assistance in the statis-tical analysis of the data; Ms Sarah Hill,Clinical Nurse Consultant, Department ofDermatology, Sydney Children’s Hospital,for assistance in the collection of subjectdata; and Ms Shelley Wang, University ofNew South Wales medical student, for herassistance in collection of subject data.

TABLE 4 Redness as Indicated by BlindedPhoto Score

Time andGroup

n Score0

Score1

Score2

P

Week 1Treatment 19 — 21 79 .17Placebo 21 — 41 59

Week 12Treatment 16 13 56 31 .49Placebo 17 6 44 50

Week 24Treatment 15 47 47 6 .003*Placebo 18 6 39 55

Data are percentages (%) or n of the group with photoscore as indicated. 2, completely red; 1, half red; 0, noredness. P values were determined by Pearson’s x2 test.—, indicates 0%.* P , .05.

TABLE 5 Safety Data for Comparison of Mean Heart Rate, SBP, and DBP Between Treatment andPlacebo Groups

Treatment (95% CI) Placebo (95% CI) P

Mean heart rate, beats per minute 147 (140–154) 147 (140–154) .81Mean SBP, mm Hg 89 (86–93) 84 (80–89) .28Mean DBP, mm Hg 43 (36–51) 38 (33–43) .40

TABLE 6 Subjects Withdrawn From the Study

SubjectNumber

Treatment orPlacebo

Study WeekWithdrawn

Reason for Withdrawal From Trial

109 Placebo 4 Development of new subcutaneous periorbital IH;commenced receiving propranolol

115 Placebo 4 At risk of ulceration; commenced receivingpropranolol

121 Placebo 8 Withdrawn because of transfer to another tertiarycenter

128 Placebo 12 At risk of ulceration; commenced receivingpropranolol

135 Placebo 16 Voluntarily withdrawn124 Treatment 8 Voluntarily withdrawn; subsequently commenced

receiving propranolol201 Treatment 12 Developed small ulcer; commenced receiving

propranolol108 Treatment 16 At risk of ulceration; commenced receiving

propranolol119 Treatment 16 Small nonproliferating lesion; strong parental desire

to commence propranolol



REFERENCES

1. Jacobs AH. Strawberry hemangiomas; thenatural history of the untreated lesion.Calif Med. 1957;86(1):8–10

2. Dickison P, Christou E, Wargon O. A pro-spective study of infantile hemangiomaswith a focus on incidence and risk factors.Pediatr Dermatol. 2011;28(6):663–669

3. Kilcline C, Frieden IJ. Infantile hemangio-mas: how common are they? A systematicreview of the medical literature. PediatrDermatol. 2008;25(2):168–173

4. Khan ZA, Boscolo E, Picard A, et al. Multi-potential stem cells recapitulate humaninfantile hemangioma in immunodeficientmice. J Clin Invest. 2008;118(7):2592–2599

5. Chang LC, Haggstrom AN, Drolet BA, et al;Hemangioma Investigator Group. Growthcharacteristics of infantile hemangiomas:implications for management. Pediatrics.2008;122(2):360–367

6. Couto RA, Maclellan RA, Zurakowski D,Greene AK. Infantile hemangioma: clinicalassessment of the involuting phase andimplications for management. Plast ReconstrSurg. 2012;130(3):619–624

7. Léauté-Labrèze C, Dumas de la Roque E,Hubiche T, Boralevi F, Thambo J-B, Taïeb A.Propranolol for severe hemangiomas of in-fancy. N Engl J Med. 2008;358(24):2649–2651

8. de Graaf M, Breur JMPJ, Raphaël MF, VosM, Breugem CC, Pasmans SGMA. Adverseeffects of propranolol when used in thetreatment of hemangiomas: a case seriesof 28 infants. J Am Acad Dermatol. 2011;65(2):320–327

9. Janmohamed SR, de Laat PCJ, Madern GC,Dorresteijn EM, Jan Danser AH, Oranje AP.Treating hemangioma of infancy with beta-blockers: is there really a risk of hypo-tension? J Am Acad Dermatol. 2012;67(2):315–316, author reply 316–318

10. Ho NTC, Lansang P, Pope E. Topical imiqui-mod in the treatment of infantile heman-giomas: a retrospective study. J Am AcadDermatol. 2007;56(1):63–68

11. Garzon MC, Lucky AW, Hawrot A, Frieden IJ.Ultrapotent topical corticosteroid treat-ment of hemangiomas of infancy. J AmAcad Dermatol. 2005;52(2):281–286

12. McMahon P, Oza V, Frieden IJ. Topical ti-molol for infantile hemangiomas: puttinga note of caution in “cautiously optimistic”.Pediatr Dermatol. 2012;29(1):127–130

13. Timoptol-XE Product Information MerckSharp & Dohme (Australia) Pty Ltd:1–11.Available at: http://secure.healthlinks.net.au/content/msd/pi.cfm?product=mkptimxe.Accessed March 22, 2013

14. Coppens G, Stalmans I, Zeyen T, Casteels I.The safety and efficacy of glaucoma medi-cation in the pediatric population. J PediatrOphthalmol Strabismus. 2009;46(1):12–18

15. Pope E, Chakkittakandiyil A. Topical timololgel for infantile hemangiomas: a pilotstudy. Arch Dermatol. 2010;146(5):564–565

16. Guo S, Ni N. Topical treatment for capillaryhemangioma of the eyelid using beta-blocker solution. Arch Ophthalmol. 2010;128(2):255–256

17. Kunzi-Rapp K. Topical propranolol therapyfor infantile hemangiomas. Pediatr Der-matol. 2012;29(2):154–159

18. Khunger N, Pahwa M. Dramatic responseto topical timolol lotion of a large hemi-facial infantile haemangioma associatedwith PHACE syndrome. Br J Dermatol.2011;164(4):886–888

19. Chakkittakandiyil A, Phillips R, Frieden IJ,et al. Timolol maleate 0.5% or 0.1% gel-forming solution for infantile hemangio-mas: a retrospective, multicenter, cohortstudy. Pediatr Dermatol. 2012;29(1):28–31

20. Semkova K, Kazandjieva J. Topical timolol mal-eate for treatment of infantile haemangiomas:preliminary results of a prospective study[published online ahead of print]. Clin ExpDermatol. 2012; Mar;38(2):143–146

21. Moehrle M, Léauté-Labrèze C, Schmidt V,Röcken M, Poets C-F, Goelz R. Topical timololfor small hemangiomas of infancy [pub-lished online ahead of print]. Pediatr Der-matol. 2012; Mar;30(2):245–249

22. Chambers CB, Katowitz WR, Katowitz JA,Binenbaum G. A controlled study of topical0.25% timolol maleate gel for the treatmentof cutaneous infantile capillary hemangio-mas. Ophthal Plast Reconstr Surg. 2012;28(2):103–106

23. Wade A, Pan H, Eaton S, Pierro A, Ong E. Aninvestigation of minimisation criteria. BMCMed Res Methodol. 2006;6:11

24. National High Blood Pressure EducationProgram Working Group on High BloodPressure in Children and Adolescents. Thefourth report on the diagnosis, evaluation,and treatment of high blood pressure in

children and adolescents. Pediatrics. 2004;114(suppl 2):555–576

25. Tsang MW, Garzon MC, Frieden IJ. How tomeasure a growing hemangioma and as-sess response to therapy. Pediatr Derma-tol. 2006;23(2):187–190

26. Sans V, de la Roque ED, Berge J, et al.Propranolol for severe infantile hemangio-mas: follow-up report. Pediatrics. 2009;124(3). Available at: www.pediatrics.org/cgi/content/full/124/3/e423

27. Manunza F, Syed S, Laguda B, et al. Pro-pranolol for complicated infantile hae-mangiomas: a case series of 30 infants. BrJ Dermatol. 2010;162(2):466–468

28. Schiestl C, Neuhaus K, Zoller S, et al. Effi-cacy and safety of propranolol as first-linetreatment for infantile hemangiomas. Eur JPediatr. 2011;170(4):493–501

29. Holmes WJM, Mishra A, Gorst C, Liew SH.Propranolol as first-line treatment for rap-idly proliferating infantile haemangiomas.J Plast Reconstr Aesthet Surg. 2011;64(4):445–451

30. Hogeling M, Adams S, Wargon O. A random-ized controlled trial of propranolol for in-fantile hemangiomas. Pediatrics. 2011;128(2).Available at: www.pediatrics.org/cgi/content/full/128/2/e259

31. Kubota K, Yamada T, Kikuchi K, Koyama E,Ishizaki T. Pharmacokinetics and beta-blockingeffects of transdermal timolol. Eur J ClinPharmacol. 1993;44(5):493–495

32. Urtti A. Delivery of antiglaucoma drugs: ocularvs systemic absorption. J Ocul Pharmacol.1994;10(1):349–357

33. Shedden AH, Laurence J, Barrish A, Olah TV.Plasma timolol concentrations of timolol mal-eate: timolol gel-forming solution (TIMOPTIC-XE)once daily versus timolol maleate ophthalmicsolution twice daily. Doc Ophthalmol. 2001;103(1):73–79

34. Dickstein K, Hapnes R, Aarsland T. Com-parison of aqueous and gellan ophthalmictimolol with placebo on the 24-hour heartrate response in patients on treatment forglaucoma. Am J Ophthalmol. 2001;132(5):626–632

35. Nieminen T, Lehtimäki T, Mäenpää J, Ropo A,Uusitalo H, Kähönen M. Ophthalmic timolol:plasma concentration and systemic car-diopulmonary effects. Scand J Clin Lab In-vest. 2007;67(2):237–245

ARTICLE


http://secure.healthlinks.net.au/content/msd/pi.cfm?product=mkptimxehttp://secure.healthlinks.net.au/content/msd/pi.cfm?product=mkptimxehttp://pediatrics.aappublications.org/

DOI: 10.1542/peds.2012-3828; originally published online May 6, 2013;Pediatrics

Hsien Chan, Catherine McKay, Susan Adams and Orli Wargon24-Week-Olds

RCT of Timolol Maleate Gel for Superficial Infantile Hemangiomas in 5- to

ServicesUpdated Information &

/peds.2012-3828http://pediatrics.aappublications.org/content/early/2013/04/30including high resolution figures, can be found at:

Subspecialty Collections

cs_and_toxicologyhttp://pediatrics.aappublications.org/cgi/collection/therapeutiTherapeutics & Toxicologythe following collection(s):This article, along with others on similar topics, appears in

Permissions & Licensing

tmlhttp://pediatrics.aappublications.org/site/misc/Permissions.xhtables) or in its entirety can be found online at: Information about reproducing this article in parts (figures,

Reprints http://pediatrics.aappublications.org/site/misc/reprints.xhtml

Information about ordering reprints can be found online:

rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy of Pediatrics. All and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elkpublication, it has been published continuously since 1948. PEDIATRICS is owned, published, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

http://pediatrics.aappublications.org/content/early/2013/04/30/peds.2012-3828http://pediatrics.aappublications.org/cgi/collection/therapeutics_and_toxicologyhttp://pediatrics.aappublications.org/site/misc/Permissions.xhtmlhttp://pediatrics.aappublications.org/site/misc/reprints.xhtmlhttp://pediatrics.aappublications.org/

RCT of Timolol Maleate Gel for Superficial Infantile Hemangiomas … · 2015. 3. 8. · jection;...

Documents

Transcript of RCT of Timolol Maleate Gel for Superficial Infantile Hemangiomas … · 2015. 3. 8. · jection;...