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JAMA Dermatology | Brief Report
Efficacy and Safety of Topical Timolol for the Treatment
of Infantile Hemangioma in the Early Proliferative Stage
A Randomized Clinical Trial
Fania Z. Muñoz-Garza, MD; Mónica Ríos; Esther Roé-Crespo, MD; José Bernabeu-Wittel, MD, PhD;
María Teresa Montserrat-García; Luís Puig, MD, PhD; Ignasi Gich, MD, PhD; Eulalia Baselga, MD, PhD
Visual Abstract
IMPORTANCE Treatment of infantile hemangioma (IH) with topical timolol in the first
2 months of life (early proliferative phase) may prevent further growth and the need for
treatment with oral propranolol. To our knowledge, no studies have determined whether
beginning early treatment with timolol for IH is better than in other proliferative stages.
Supplemental content
OBJECTIVE To evaluate the efficacy and safety of timolol maleate solution, 0.5%, for the
early treatment of IH in infants younger than 60 days.
DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, double-blind,
placebo-controlled, phase 2a pilot clinical trial included patients aged 10 to 60 days with
focal or segmental hemangiomas (superficial, deep, mixed, or minimal/arrested growth).
Patients were randomly assigned to treatment with topical timolol maleate solution, 0.5%,
or placebo twice daily for 24 weeks. Changes in lesion size (volume, thickness) and color
were evaluated from photographs taken at 2, 4, 8, 12, 24, and 36 weeks. Vital signs and
adverse effects were recorded at each visit. The study was carried out from November 2015
to January 2017, and data analyses were completed in September 2019.
MAIN OUTCOMES AND MEASURES The primary outcome of complete or nearly complete IH
resolution and the secondary outcomes of changes in lesion thickness, volume, and color
were evaluated by a blinded investigator.
RESULTS Of the 69 patients recruited, the mean (SD) age was 48.4 (10.6) days; 55 (80%)
were female; and 51 (74%), 11 (16%), 6 (9%), and 1 (1%) had superficial, mixed, abortive,
or deep IHs, respectively. The IHs were localized, segmental, or indeterminate in 60 (87%),
7 (10%), and 2 (3%) patients, respectively. The IHs were located on the head and/or neck
(n = 23 [33%]) or other body sites (n = 46 [67%]). The study was completed by 26 of 33
(79%) patients receiving timolol and 31 of 36 (86%) receiving placebo. There were no
significant differences between timolol and placebo for complete or nearly complete IH
resolution at 24 weeks (n = 11 [42%] vs n = 11 [36%]; P = .37). The odds ratio of complete or
almost complete response vs no response at week 24 was 1.33 (95% CI, 0.45-3.89). There
were no between-group differences in IH size (volume, thickness). An improvement in color
was observed at week 4 in the timolol group, and timolol was well tolerated with no systemic
adverse effects.
CONCLUSIONS AND RELEVANCE In this randomized clinical trial, results demonstrated that
topical timolol is well tolerated for the treatment of early proliferative IH but provides limited
benefit in lesion resolution when given during the early proliferative stage.
TRIAL REGISTRATION EudraCT Identifier: 2013-005199-17
JAMA Dermatol. 2021;157(5):583-587. doi:10.1001/jamadermatol.2021.0596
Published online April 7, 2021.
Author Affiliations: Dermatology
Service, Hospital de la Santa Creu i
Sant Pau, Barcelona, Spain
(Muñoz-Garza, Ríos, Roé-Crespo,
Puig, Baselga); Hospital Universitario
Virgen del Rocío, Seville, Spain
(Bernabeu-Wittel,
Montserrat-García); Department of
Clinical Epidemiology, CIM-Caiber-IIb
Sant Pau, Barcelona, Spain (Gich);
Now with Dermatology Service,
Hospital Sant Joan de Déu, Esplugues
de Llobregat, Spain (Baselga).
Corresponding Author: Eulalia
Baselga, MD, PhD, Dermatology
Service, Hospital Sant Joan de Déu,
Passeig Sant Joan de Déu 2, 08950
Esplugues de Llobregat, Spain
(ebaselga@sjdhospitalbarcelona.
org).
(Reprinted) 583
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Research Brief Report
Efficacy and Safety of Topical Timolol for Infantile Hemangioma in the Early Proliferative Stage
I
nfantile hemangiomas (IHs) are the most common benign
tumors of infancy.1 They exhibit a rapid growth before
8 weeks of age, and most growth is complete by 5 months
of age.2,3 Most IHs regress spontaneously without treatment,
but complications needing treatment arise in approximately
10% to 15% of cases.4-6
In recent years, timolol maleate, a nonselective β-adrenergic drug, has been used as a topical agent to treat superficial
IHs. A recent meta-analysis7 concluded that topical timolol
is an effective and safe agent for treatment of superficial
IHs, although the quality of evidence was assessed as low to
moderate, with only 1 small randomized clinical trial (RCT)8
included in the analysis. Consequently, there is very little
guidance on the use of topical timolol for IH in clinical
practice.7
We hypothesized that the use of topical timolol in the early
proliferative phase would be even more effective for preventing hemangioma growth and the need for oral propranolol
treatment. This pilot RCT aimed to analyze the efficacy
and safety of timolol maleate solution, 0.5%, for treating IM
during the first 60 days of life.
Methods
This was a prospective, randomized, double-blind, placebocontrolled, phase 2a clinical trial approved by all participating centers’ institutional review boards (Hospital de la Santa
Creu i Sant Pau in Barcelona, Spain, and Hospital Universitario Virgen del Rocío in Seville, Spain) and executed in accordance with the Declaration of Helsinki. The Consolidated
Standards of Reporting Trials (CONSORT) reporting guidelines
were used.
Patients aged 10 to 60 days with focal or segmental IHs
(superficial, deep, mixed, or minimal/arrested growth) were
recruited. Written informed consent was obtained from all par-
Key Points
Question Does the use of topical timolol in the first
2 months of life prevent further infantile hemangioma (IH)
growth?
Findings In this randomized clinical trial of 69 patients younger
than 60 days, there were no significant differences between
use of timolol and placebo for complete or nearly complete IH
resolution at 24 weeks. A significant improvement in lesion color
was observed at week 4 in the timolol group, and topical timolol
was well tolerated.
Meaning Topical timolol appears well tolerated in the
treatment of early proliferative IH but provides limited benefit
in the resolution of lesions when given during the early
proliferative stage.
ents. Full inclusion and exclusion criteria are provided in the
trial protocol in Supplement 1.
Participants were randomized through a computergenerated process to receive either 2 drops of timolol maleate solution, 0.5%, administered topically every 12 hours
for 24 weeks or 2 drops of a saline-based placebo (Figure 1).
Clinical photographs of the IHs taken at 0, 2, 4, 8, 12,
24, and 36 weeks were used to assess the degree of resolution of the IHs, which were assessed qualitatively as complete, almost complete, or not resolved (Figure 2) by the
study investigator (F.Z.M.) and a blinded evaluator (J.B.).
Lesion volume was assessed using 2 perpendicular hemicircumferential measurements of the IHs. 9 Coloration was
assessed using a semiquantitative scale (1, barely noticeable; 2, red with central clearing; 3, dull red; 4, bright red).
Systemic effects were assessed by measuring systolic blood
pressure, diastolic blood pressure, and heart rate at baseline, 1 hour after the initial dose of timolol or placebo, and at
Figure 1. CONSORT Diagram
215 Assessed for eligibility
145 Excluded
102 Declined to participate
25 Other reasons
18 Did not meet inclusion criteria
69 Randomized
584
33 Randomized to receive timolol
33 Received allocated intervention
36 Randomized to receive placebo
36 Received allocated intervention
7 Lost to follow-up (parents noticed lack of efficacy and
withdrew consent or refusal to complete the study)
2 Discontinued intervention (withdrew due to risk of
ulceration and commenced propranolol)
5 Lost to follow-up (parents noticed lack of efficacy and
withdrew consent or refusal to complete the study)
5 Discontinued intervention (withdrew due to risk of
ulceration and commenced propranolol)
26 Analyzed
7 Excluded from analysis (lost to follow-up)
31 Analyzed
5 Excluded from analysis (lost to follow-up)
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Efficacy and Safety of Topical Timolol for Infantile Hemangioma in the Early Proliferative Stage
weeks 2, 4, 8, 12, and 24. Adverse effects were reported at
every visit.
The primary end point was the rate of complete or almost
complete resolution of the IH after 24 weeks of treatment with
timolol or placebo. Secondary outcomes were change in thickness, volume, and coloration of the IH at 24 weeks of treatment; persistence of efficacy, assessed at 36 weeks; and the
safety and tolerability of timolol.
To estimate the sample size, we hypothesized a 10% response rate for placebo and 40% response rate for timolol.
Based on these assumptions, with a 2-sided significance of
P = .05 and power of 0.8, a total sample size of 70 patients was
required with fewer than 10% withdrawals.
All analyses were conducted using SPSS, version 25.0
(IBM Corporation). Fisher exact test was used to evaluate response to treatment. Changes in lesion volume, thickness, and
color were analyzed through Wilcoxon test for paired data.
A threshold of P = .05 was used for statistical significance. For
more detailed descriptions of the statistics, see eMethods in
Supplement 2.
Brief Report Research
Figure 2. Degree of Infantile Hemangioma Resolution
A Eye lesion at baseline
B
C
Genital lesion at baseline
D Almost complete resolution at 24 wk
E
Skin lesion at baseline
F
Complete resolution at 24 wk
Results
Of the 69 patients included in the analysis, the mean (SD) age
was 48.4 (10.6) days, 55 (80%) were female, 33 (48%) were randomized to topical treatment with timolol and 33 (48%) to placebo. A total of 50 patients completed 24 weeks of treatment,
24 (48%) with timolol and 26 (52%) with placebo. Baseline
demographics and characteristics of the 69 patients evaluable by patient-reported outcome are summarized in eTable 1
in Supplement 2.
Not resolved at 24 wk
Efficacy Outcomes
At 24 weeks, 11 (42%) patients treated with timolol had complete or nearly complete resolution of IH compared with
11 (36%) in the placebo group, but this difference was not statistically significant (P = .37). In the per-protocol analysis
(n = 57), the odds ratio of complete or almost complete response vs no response was 1.33 (95% CI, 0.45-3.89) at 24 weeks;
in the intention-to-treat analysis (n = 69), there were no significant differences in response and the odds ratio was 1.36
(95% CI, 0.41-3.13).
We observed a decrease of IH volume in the timolol
group related to the time of evolution compared with the placebo group, although statistical significance was not
achieved (week 2, P < .51; week 4, P < .30; week 8, P < .30;
week 12, P < .40; week 24, P < .04; and week 36, P < .84; supporting data are reported in Figure 3A and eFigure in Supplement 2). Likewise, no statistically significant differences
were found in the decrease of IH mean thickness between
both groups (week 2, P < .99; week 4, P < .74; week 8, P < .59;
week 12, P < .48; week 24, P < .36; and week 36, P < .83; supporting data are reported in Figure 3B); however, in the timolol group, the decrease in thickness occurred earlier than in
the placebo group. In both groups, there was an improvement in color related to the time of evolution, which was
more pronounced in the timolol group but was only signifi-
Examples of degree of resolution in 3 hemangiomas treated with timolol and
assessed qualitatively as complete (A), almost complete (B), or not resolved (C)
after 24 weeks of treatment. Almost complete resolution was defined as a
minimum degree of telangiectasia, erythema, cutaneous thickening, soft tissue
swelling, and/or distortion of anatomical references.
cant at week 4 (week 2, P < .33; week 4, P < .01; week 8,
P < .09; week 12, P < .61; and week 24, P < .12; supporting
data are reported in Figure 3C).
Safety Outcomes
Comparison of baseline systolic blood pressure, diastolic
blood pressure, and heart rate with 1-hour posttreatment
levels showed no significant differences between both
groups (eTable 2 in Supplement 2). Posttreatment heart rate
was reduced in both treatment groups but failed to achieve
statistical significance. Three patients in the timolol group
had hypotension 1 hour posttreatment, and 1 patient had
bradycardia. All patients were asymptomatic during the
episodes.
Adverse events were noted in 16 patients across both
groups. Local xerosis from medication, ulceration, and infection of the IH were the most common adverse events,
although no events resulted in drug discontinuation.
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Research Brief Report
Efficacy and Safety of Topical Timolol for Infantile Hemangioma in the Early Proliferative Stage
Figure 3. Volume, Thickness, and Color of Infantile Hemangioma
During Evaluation
Discussion
A Volume reduction
1750
1500
Mean volume, mm3
1250
1000
Placebo
750
Timolol
500
250
0
0
2
4
8
12
24
36
Weeks
B
Thickness reduction
2.2
Mean thickness, mm
2.0
1.8
Placebo
1.6
Timolol
1.4
1.2
0
2
4
8
12
24
This RCT assessed the efficacy and safety of topical timolol for
treatment of IH in the early proliferative phase. Difference in
resolution rate with use of timolol was not significant compared with placebo. There were also no significant differences
in IH volume and thickness, although volume measurements
were difficult and imprecise in patients with mainly superficial IMs. Treatment with timolol produced a statistically significant improvement in lesion color only at week 4. A retrospective, multicenter cohort study of topical timolol treatment
in patients with IHs aged 1 to 3 months (n = 454) showed similar results where color improvement (69.6%) was much greater
than improvement in size, extent, and volume (38.8%).10 The
rapid improvement observed in color may reassure parents
and even justify treatment for IHs in visible areas.
The use of timolol in the first weeks of life did not always
achieve hemangioma stabilization; therefore, patients treated
with timolol should be monitored closely. Owing to the risk of
ulceration, 7 patients were switched during the current study
to treatment with oral propranolol, the drug of choice for systemic treatment of IH.4,11
Although we found no safety concerns with use of timolol in the present study, detectable levels of timolol have been
reported in the urine and blood following topical treatment of
IHs.12-14 Special attention to avoid systemic absorption is advisable when using timolol in infants with low birth weight,
or an IH of more than 3-mm thickness, on the diaper area, or
near mucous membranes.15
36
Weeks
Limitations
C
The main limitations of this study were that the final sample
size was less than originally calculated and that there was
a higher rate of dropouts than expected. A larger number of
patients might have proven significance.
Color reduction
5
Color scale
4
3
Conclusions
2
Placebo
1
Timolol
0
0
2
4
8
12
24
Weeks
All error bars indicate an SD of 1.
ARTICLE INFORMATION
Accepted for Publication: February 11, 2021.
Published Online: April 7, 2021.
doi:10.1001/jamadermatol.2021.0596
Author Contributions: Drs Muñoz-Garza and
Baselga had full access to all the data in the study
and take responsibility for the integrity of the data
and the accuracy of the data analysis.
586
36
In this RCT, topical timolol solution, 0.5%, used twice daily for
24 weeks was not effective for the treatment of early proliferative IH. There was only improvement in lesion color at week 4,
but it was not significantly different than with use of placebo. This
early improvement may be highly desired for some families
for whom visible IHs may cause social stigma. There were no
noteworthy systemic adverse effects. Larger multicenter RCTs
may be needed to demonstrate the efficacy of this treatment.
Concept and design: Muñoz-Garza, Roé-Crespo,
Baselga.
Acquisition, analysis, or interpretation of data: Ríos,
Bernabeu-Wittel, Monserrat-García, Puig, Gich,
Baselga.
Drafting of the manuscript: Muñoz-Garza, Ríos,
Gich, Baselga.
Critical revision of the manuscript for important
intellectual content: Roé-Crespo, Bernabeu-Wittel,
Monserrat-García, Puig, Baselga.
Statistical analysis: Gich.
Administrative, technical, or material support:
Muñoz-Garza, Ríos, Bernabeu-Wittel,
Monserrat-García.
Supervision: Roé-Crespo, Bernabeu-Wittel, Puig,
Baselga.
Conflict of Interest Disclosures: Dr Baselga
reports receiving personal fees and nonfinancial
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Efficacy and Safety of Topical Timolol for Infantile Hemangioma in the Early Proliferative Stage
support from Pierre Fabre Dermatologie, receiving
other support from Venthera as a founder and
adviser, and serving on the executive committee of
the Spanish Academy of Dermatology. No other
disclosures were reported.
Funding/Support: Pierre Fabre Dermatologie
provided funding for preparation of the manuscript
with editorial support by Robert A. Furlong, PhD,
and David P. Figgitt, PhD, of Content Ed Net.
Role of the Funder/Sponsor: The funder had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: We thank the parents
of the pictured patients for granting permission to
publish this information.
Data Sharing Statement: See Supplement 3.
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