Conditions: Hemangioma
Keywords: Infantile hemangioma Propranolol Atenolol Efficacy Safety
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 377
Healthy volunteers: yes

Brief summary:
The purpose of this study is to compare the efficacy of orally administered propranolol versus atenolol in the treatment of potentially disfiguring or functionally threatening IHs.

Detailed description:
Currently, propranolol is the preferred treatment for problematic proliferating infantile hemangiomas (IHs). Although propranolol is clearly efficacious, rare side effects, such as hypoglycemia, may be life-threatening. The possibility of propranolol resistance and treatment failure is also important, and highlights the need for employing more established techniques in certain cases.

Nonselective β-adrenergic antagonists, such as propranolol and timolol, are competitive antagonists of catecholamines at the β1- and β2-adrenergic receptors (β-ARs). β2-AR blockade may result in hypoglycemia as a result of decreased glycogenolysis, gluconeogenesis, and lipolysis. Moreover, bronchial hyperreactivity is a direct effect of nonselective β-blockers, resulting in bronchospasms due to pulmonic β2-AR blockade. A solution to minimize many of the side effects of nonselective β-blocker therapy may be the use of more selective β1-blockers such as metoprolol or atenolol, which, at low dosages, have little β2 activity. Unfortunately, there is a paucity of clinical data comparing the efficacy of selective and non-selective β-blocker. Furthermore, because of the broad heterogeneity of IH (e.g., proliferating versus involuting), confounding with other pharmacologic exposures (e.g., corticosteroids), associated complications (e.g., ulceration) and comorbid medical anomalies (e.g., PHACE) that can influence efficiency after IH treatment, observational studies are unable to definitively establish the clinical utility of β-blockers in IH. Thus, questions regarding the efficacy of the subtypes of β-blockers must be answered in randomized controlled trials, which may provide the only way to overcome the selection and ascertainment bias.

The purpose of this study is to compare the efficacy of orally administered propranolol versus atenolol in the treatment of potentially disfiguring or functionally threatening IHs.

Arms:
arm 1: Propranolol arm 2: Atenolol

Interventions: intervention 1: Propranolol intervention 2: Atenolol
Intervention descriptions: intervention 1: Initiated at a dosage of 1 mg/kg per day divided 3 times daily for 1 week, and then increased to 2 mg/kg per day divided 3 times daily from weeks 2 to 24. intervention 2: Initiated at a dosage of 0.5 mg/kg per day in a single dose for 1 week, and then increased to 1 mg/kg per day in a single dose from weeks 2 to 24.

Protocol document:
Prot_SAP_000.pdf: 
Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
1 
 
Propranolol versus atenolol for problematic infantile hemangiomas: a 
randomized clinical trial (Version 1.3/Final version) 
 
Protocol outline 
Title 
Propranolol versus atenolol for problematic infantile 
hemangiomas: a randomized clinical trial 
Version date 
July 1, 2017 
Research Institutions 
Six separate investigation sties in China 
Principle Investigators 
Yi Ji, Siyuan Chen 
Purpose 
Comparing the efficacy and safety of propranolol versus 
atenolol 
in 
patients 
with 
problematic 
infantile 
hemangiomas. 
Design 
A prospective, multicenter, randomized, controlled, open-
label clinical trial. 
Subjects 
Patients with superficial or mixed infantile hemangiomas 
who require systemic therapy. 
Research Duration 
Four years 
Methods 
Participants are randomized to receive either propranolol or 
atenolol for at least 6 months. 
Participants complete a baseline survey and a survey at 96 
weeks of follow-up. 
The primary outcome measure is the clinical response at 
week 24. 
Secondary 
outcome 
measures 
include 
Hemangioma 
Activity Score, successful initial response, complete 
ulceration healing time, quality of life, rebound rate, and 
response at week 96. 
Frequency and severity of adverse events will be recorded. 
Expected results and 
meanings 
Evidence supporting the use of atenolol as a first-line 
treatment of choice in infantile hemangioma. 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
2 
 
Table of contents 
1 Title ……………………………………………………………………………
5 
2 Research institutions and addresses…..………………………………………. 
5 
2.1 Sponsors…..………………………..……………………………………...
5 
2.2 Information provided by (Responsible Parties) …..………………………
5 
3 Authors and affiliations………………………………………….……………. 
5 
4. Acknowledgement………………….………………………………………… 
8 
5. Study background and rationale……………………………………………….
9 
6. Overall study design…………………………………………………………...
11 
7 Approval and legal aspects….………………………………………………….
12 
7.1 GCP statement……………………………………………………………..
12 
7.2 Ethics Approvals…………………………………………………………..
12 
7.3 Study Registration…………………………………………………………
12 
7.4 Informed consent………………………………………………..................
11 
7.5 Confidentiality…………………………………………………………….
12 
8 Target disease and subjects…………………………………………………….
13 
9 Expected duration………………………………………………………………
14 
10 Eligibility/Inclusion criteria……………………………………......................
15 
11 Exclusion criteria…………………………………………………...................
16 
12 Sample size determination…………………………………………………....
17 
13 Enrollment/Randomization…………………………………………………...
18 
14 Trial schedules………………………………………………………………...
19 
15 Pretreatment evaluations..…………………………………………………….
20 
16 Study visits……………………………………………………………………
22 
17 Treatment ……………………………………………………………………..
23 
17.1 Standard case management ……………………………………………...
23 
17.2 Rebound management……………………………………………………
24 
17.3 Other co-interventions……………………………………………………
24 
18 Collection and assessment of series digital photographs……………………..
25 
19 Primary outcome measures…………………………………………………...
26 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
3 
 
20 Secondary outcome measures………………………………………………...
29 
20.1 Hemangioma Activity Score………………………………......................
29 
20.2 Successful initial response……………………………………………… 
30 
20.3 Quality of life…………..………………………………………………...
31 
20.3.1 Quality of life instrument for infantile hemangioma…………………..
31 
20.3.2 Pediatric Quality of Life Inventory 4.0 family impact module………...
31 
20.3.3 Procedures……………………………………………………………...
31 
20.4 Complete healing time of ulceration……………………………………..
32 
20.5 Rebound rate……………………………………………………………..
32 
20.6 Responses at Week 96……………………………………………………
33 
21 Safety assessments..…………………………………………………………..
34 
21.1 In-house monitoring……………………………………………………...
34 
21.2 Outpatient monitoring……………………………………………………
34 
21.3 Collection and management of adverse event…………………………... 
34 
21.4 Definition of adverse event………………………………………………
35 
21.5 Relationship of adverse event……………………………………………
35 
21.6 Grade of adverse event………………………………………………….. 
36 
21.7 Preventing and managing adverse event…………………………………
36 
21.8 Termination of the study…………………………………………………
37 
21.9 Outcome of the adverse event……………………………………………
38 
22 Tapering and discontinuation of treatment…………………………………...
39 
23 Data management and quality assurance……………………………………..
40 
24 Missing data…………………………………………………………………. 
41 
25 Statistical analyses……………………………………………………………
42 
25.1 Descriptive methods…………………………………………………….. 
42 
25.2 Baseline characteristics…………………………………………………..
42 
25.3 Primary outcome analysis………………………………………………..
42 
25.4 Secondary outcome analyses……………………………………………..
42 
25.5 Safety outcome analyses…………………………………………………
43 
25.6 Differences to trial protocol……………………………………………...
43 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
4 
 
25.7 Software………………………………………………………………….
43 
26 References…………………………………………………………………… 
44 
27 Study flow chart………………………………………………………………
47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
5 
 
1 Title 
Propranolol versus atenolol for problematic infantile hemangiomas: a randomized 
clinical trial 
 
2 Research institutions and addresses 
2.1 Sponsors 
Department of Pediatric Surgery, West China Hospital of Sichuan University 
Chengdu, 610041, China 
Department of Critical Care Medicine, West China Hospital of Sichuan University, 
Chengdu, 610041, China 
2.2 Information provided by (Responsible Parties) 
Department of Pediatric Surgery, West China Hospital of Sichuan University 
Chengdu, 610041, China 
Pediatric Intensive Care Unit, West China Hospital of Sichuan University Chengdu, 
610041, China 
Department of Pediatric Surgery, Fujian Provincial Hospital, Fuzhou, 350001, China 
Department of Dermatology, West China Hospital of Sichuan University, Chengdu, 
610041, China 
Department of Pediatrics, West China Second University Hospital, Sichuan 
University, Chengdu, 610041, China 
Department of Pediatric Surgery, Chengdu Shangjin Nanfu Hospital, Chengdu, 
611730, China 
Department of Pediatric Surgery, Sichuan Women and Children’s Hospital, Chengdu, 
610045, China 
Department of Pediatric Surgery, Chengdu Women and Children’s Central Hospital, 
Chengdu, 610031, China 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
6 
 
3 Authors and affiliations 
Author 
Affiliation 
Title 
Yi Ji 
Department of Pediatric Surgery, West 
China Hospital of Sichuan University 
MD, PhD 
Siyuan Chen 
Department of Critical Care Medicine, 
West China Hospital of Sichuan 
University 
MD, PhD 
Kaiying Yang 
Department of Pediatric Surgery, West 
China Hospital of Sichuan University 
MD 
Xuepeng Zhang 
Department of Critical Care Medicine, 
West China Hospital of Sichuan 
University 
MD 
Jiangyuan Zhou 
Department of Pediatric Surgery, West 
China Hospital of Sichuan University 
MD 
Lizhi Li 
Department of Pediatric Surgery, Fujian 
Provincial Hospital 
MD 
Bo Xiang 
Department of Pediatric Surgery, West 
China Hospital of Sichuan University 
MD, PhD 
Tong Qiu 
Department of Pediatric Surgery, West 
China Hospital of Sichuan University 
MD 
Shiyi Dai 
Department of Pediatric Surgery, West 
China Hospital of Sichuan University 
MD 
Xian Jiang 
Department of Dermatology, West China 
Hospital of Sichuan University 
MD, PhD 
Guoyan Lu 
Department of Pediatrics, West China 
Second University Hospital 
MD 
Liqing Qu 
Department of Pediatric Surgery, Chengdu 
Shangjin Nanfu Hospital 
MD 
Feiteng Kong 
Department of Pediatric Surgery, Sichuan 
Women and Children’s Hospital 
MD 
Yongbo Zhang 
Department of Pediatric Surgery, Chengdu 
Women and Children’s Central Hospital 
MD 
Hao Wu 
Vascular Biology Program and 
PhD 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
7 
 
Department of Surgery, Boston Children’s 
Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
8 
 
4 Acknowledgements 
(1) The authors are indebted to: 
-The participation of the investigational sties and site investigators. 
-All other investigators, participating practitioners, nurses and residents involved in 
the study. 
- All the patients and their parents and guardians who participated in this study. 
(2) The authors wish to acknowledge: 
-This work was supported by grants from the National Natural Science Foundation 
of China (Grants Nos. 81400862 and 81401606), the Key Project in the Science & 
Technology Program of Sichuan Province (Grant No. 2019YFS0322), the Science 
Foundation for The Excellent Youth Scholars of Sichuan University (Grant No. 
2015SU04A15), and the 1·3·5 project for disciplines of excellence-Clinical Research 
Incubation Project of West China Hospital of Sichuan University (2019HXFH056 and 
2020HXFH048). The funding bodies were not involved in the design of the study or 
the collection, analysis, and interpretation of data or the writing of the manuscript. 
-The authors declare that they have no competing interests, either financial or non-
financial, that could be perceived as prejudicing the impartiality of the research 
reported. 
-Written informed consent for publication in this study was obtained from the 
patients’ parents. Copies of the signed informed consent forms are available for 
review by the Journal Editors. 
-The datasets used and/or analyzed during the current study are available from the 
corresponding authors on reasonable request. 
-All the authors reviewed the manuscript drafts, trial protocol and supplemental 
data and approved the final version of the manuscript. 
-Yi Ji, Kaiying Yang and Siyuan Chen were involved in the integrity of the data and 
ensuring the completeness and fidelity of reporting the trial protocol. 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
9 
 
5 Study background and rationale 
IHs are the most common tumors of childhood and occur in approximately 4% to 
5% of infants. In the majority of cases, IHs are self-limited and resolve spontaneously 
without threat or complications. However, in approximately 10% of patients, the 
lesions can be disfiguring (e.g., facial involvement), destructive (e.g., ulceration), 
functionally significant (e.g., visual impairment), or even life-threatening (e.g., airway 
obstruction).1,2 
Currently, propranolol is the preferred treatment for problematic proliferating IHs.3-
5 Although propranolol is clearly efficacious, rare adverse effects, such as 
hypoglycemia and bronchial hyperreactivity, may be life-threatening.6-8 Nonselective 
β-adrenergic antagonists, such as propranolol, are competitive antagonists of 
catecholamines at the β1- and β2- adrenergic receptors (ARs). β2-AR blockade may 
result in hypoglycemia as a result of decreased glycogenolysis, gluconeogenesis, and 
lipolysis. Moreover, bronchial hyperreactivity is a direct effect of propranolol that 
results in bronchospasms due to pulmonic β2-AR blockade. In addition, the lipophilic 
nature of propranolol is also important. When given to infants, the long-term effects 
of propranolol may affect the developing central nervous system (CNS), specifically 
learning and memory.9 
A solution to minimize some of the side effects of propranolol may be the use of 
more selective β1-AR blockers, such as atenolol, which, at low dosages, have little β2 
activity. More importantly, atenolol is a large, hydrophilic compound and may exhibit 
fewer CNS-related adverse effects (e.g., sleep disturbance and agitation) in the 
treatment of IHs.10 Unfortunately, there is a paucity of clinical data comparing the 
efficacy and safety of propranolol and atenolol. 
Several retrospective studies and case reports and two small, prospective trials, 
including one randomized controlled trial, have demonstrated the efficacy of atenolol 
in the treatment of IHs.11-18 However, it is difficult to compare the efficacy and safety 
of atenolol treatment with those of propranolol treatment since the majority of the 
previously conducted studies were fragmented, non-large-scale clinical trials. 
Furthermore, because of the broad heterogeneity of IH (e.g., superficial, mixed or 
deep, localized or segmental, and proliferating or involuting), confounding by other 
pharmacologic exposures (e.g., corticosteroids or cardiovascular agents), and 
associated complications (e.g., ulceration and/or bleeding), observational and 
retrospective studies may be unable to definitively establish the clinical utility of β-


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
10 
 
blockers in IH. Therefore, questions regarding the efficacy and safety of propranolol 
and atenolol must be answered in large randomized clinical trials, which may 
represent the only way to overcome selection and ascertainment bias.19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
11 
 
6 Overall study design: 
This study is a prospective, multicenter, randomized, controlled, open-label clinical 
trial comparing propranolol and atenolol for the management of problematic IHs. 
Only patients who had never received IH-specific treatments and had normal heart, 
liver and renal functions were included. In both groups, patients were admitted and 
checked for side effects for 8 hours on day 0 and day 7. The patients were observed 
for therapeutic effects as outpatients during schedule visits. While comparing the 
efficacy of medication between propranolol and atenolol, the side effects of both 
drugs were also monitored. 
 
Study Type 
Interventional 
Study Design
Allocation: Randomized 
Endpoint Classification: Efficacy/Safety Study 
Intervention Model: Parallel Assignment 
Masking: Single Blind (Outcome Assessors) 
Primary Purpose: Treatment; Efficacy/Safety assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
12 
 
7 Approvals and legal aspects 
7.1 GCP statement 
This study was conducted in compliance with Good Clinical Practice of 
Pharmaceutical Products and the Declaration of Helsinki and in accordance with 
applicable legal and regulatory requirements. 
 
7.2 Ethics approvals 
Approval was obtained by the Ethics Committee (Institutional Review Board) of 
West China Hospital of Sichuan University, the study site of the principal investigator, 
and by the local institution review boards at each participating site. 
 
7.3 Study Registration 
The trial has been registered at www.clinicaltrial.gov (NCT02342275). 
 
7.4 Informed consent 
Informed written consent was obtained from the parents (or guardians) before 
enrolment and after the provision of detailed oral and written information concerning 
the context of the study and its potential benefit to the child and comprehensive safety 
aspects. The informed consent process was in accordance with Good Clinical Practice 
of Pharmaceutical Products, the International Council for Harmonization, the 
Declaration of Helsinki and local regulatory requirements. A patient information sheet 
containing background information and information about the safety of the study and 
its possible benefit was provided prior to obtaining consent for the study. 
 
7.5 Confidentiality 
The investigators will ensure that the subjects’ anonymity is maintained. The 
medical records will only be reviewed by investigators and will be kept confidential 
without any identifying information on any study materials. A unique study 
identification number will be assigned and used on all study materials. On the patient 
report forms or other documents, participants will be identified not by their names but 
instead by their assigned identification number. If participant names are included on 
copies of documents submitted to the principal investigator, the names will be 
obliterated, and the assigned subject numbers will be added to the documents. 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
13 
 
8 Target disease and subjects 
The target disease of this study is problematic IH. Patients who are diagnosed with 
problematic IH in the Department of Pediatric Surgery, Department of Dermatology, 
Department of Dermatology, and/or Department of Pediatrics in six separate 
investigation sites in China are subjects. Only patients who voluntarily consent to 
participate in the study after the study has been fully explained are subjects of the 
research. 
Volunteer recruitment posters will be released in the hospitals, and patients who 
volunteer to participate after fully understanding the study are targets. 
Before explaining the study and receiving consent, the investigators will explain to 
the parents or guardian that digital photographs will be used to measure the treatment 
response. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
14 
 
9 Expected duration 
Research duration: 4 years. 
Recruitment period: 2 years. 
After enrolment, each study subject was followed up for 96 weeks following the start 
of study treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
15 
 
10 Eligibility/Inclusion criteria: 
Ages Eligible for Study: 
Between 5 and 20 weeks of age
Sexes Eligible for Study: 
Both 
Accepts Healthy Volunteers:  
No 
 
Presenting an infantile hemangioma with the following characteristics: 
(1) Superficial or mixed IHs. 
(2) Proliferating hemangioma lesions impairing function (including vision, eating 
and hearing), in cosmetically sensitive regions, or with ulceration and/or bleeding. 
(3) The minimum diameter of the lesion was 1.5 cm on the face and 3 cm outside 
the face (or 1.5 cm if it was ulcerated). 
(4) Consent of parents (or the person with parental authority in families): signed 
and dated written informed consent. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
16 
 
11 Exclusion Criteria: 
(1) Patients contraindicated for the administration of β-blockers, such as those with 
an allergy or hypersensitivity to propranolol; hypoglycemia (<40 mg/dL); 
hypotension (<50/30 mmHg); severe bradycardia (<80 bmp); second- to third-grade 
atrioventricular block; heart failure; bronchial asthma or bronchial obstruction. 
(2) Patients with any acute illness or gastrointestinal diseases, especially one 
interfering with normal oral intake. 
(4) Patients with inadequate liver function: 
Total bilirubin higher than or equal to 1.5 × the upper limit of the normal (ULN) for 
age and alanine aminotransferase and aspartate aminotransferase higher than or equal 
to 2.5 × the ULN for age. 
(5) Patients with inadequate renal function: 
Serum creatinine higher than or equal to 0.8 (mg/dL). 
(6) Patients diagnosed with deep IH, congenital hemangioma, Kaposiform 
hemangioendothelioma, tufted angioma, or other vascular anomalies. 
(7) Patients previously treated with any IH therapies, including corticosteroids, 
propranolol, atenolol, topical timolol, captopril, itraconazole, imiquimod, vincristine, 
interferon-α, laser therapy or other treatments. 
(8) Indication for treatment with corticosteroids, captopril, itraconazole, 
imiquimod, vincristine, interferon-α, sirolimus, or tacrolimus for an indication other 
than IH. 
(9) Indication for treatment with a beta-blocker for an indication other than IH. 
(10) Patients who received the following drugs within the 1 week before 
enrollment: β-AR agonists, such as epinephrine, norepinephrine and salbutamol, etc.; 
or other cardiovascular agents, including but not limited to calcium channel blockers, 
ACE inhibitors and inotropic agents, etc. 
(11) Patients with an inability to participate in or follow-up during the study 
treatment and assessment plan. 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
17 
 
12 Sample size determination 
In this trial, propranolol was used as the control group to evaluate the efficacy and 
safety of the atenolol group (experimental group). The treatment response after 6 
months of medication was used as the key therapeutic index. To calculate the sample 
size for this trial, we used the following assumptions: 
(1) A 2-sided 0.05 significance level; 
(2) Ratio of the propranolol group: atenolol group = 1:1; 
(3) A statistical power of 90%; 
(4) A 20% dropout rate due to ineligibility; 
(5) A follow-up of at least 96 weeks; 
(6) A 24-month recruitment period; and 
(7) In this trial, the atenolol group’s evaluation variables were compared with the 
propranolol group’s evaluation variables to test for noninferiority. The hypotheses are 
listed below: 
-H0: Twenty-four weeks after therapy initiation, compared to the treatment 
response of propranolol therapy, that of atenolol was inferior; and 
-H1: Twenty-four weeks after therapy initiation, compared to the treatment 
response of propranolol therapy, that of atenolol was non-inferior. 
(8) Very limited data are available in the literature that can be used to set 
hypotheses for atenolol treatment. Existing case studies are mainly based on small 
single-center experiences. According to previous studies, propranolol’s total treatment 
response is assumed to be 70-100%, and atenolol’s total treatment response is 
assumed to be 70-100%.4,5,13,20-22 In addition, assuming that the atenolol on 
propranolol response rate does not fall by greater than 15%, the noninferiority margin 
was selected to be -15%. 
(9) Assuming the ulceration rate in both groups to be 10%. 
(10) A sample size of 180 patients was determined to be required for each group (a 
total of 360 patients). 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
18 
 
13 Enrollment/Randomization: 
Before enrollment, the parents or guardians could decide if they wanted to be 
included the study. Each eligible subject whose parent or guardian provided informed 
consent for either drug was assigned a unique subject number. Randomization was 1:1 
according to computer-generated randomization sequences with blocks in random 
order. Statistical Analysis Software was used to produce random numbers, and there 
was no stratification factor in this study. 
The West China Hospital of Sichuan University is the central investigative site 
(CIS). The CIS generated a randomization list and implemented randomization using 
an interactive web-based system. The CIS was in charge of randomization data 
management and application. In addition, randomization information was 
independently managed, and access was limited for investigators who treated the 
patients. Two randomized sequences were used for each center so that enrollment 
could be stratified by exposure to either propranolol or atenolol. Subjects who were 
randomized to a treatment had their subject number linked to a corresponding drug 
kit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
19 
 
14 Trial schedules 
Contents 
Schedule (Study period: 192 weeks) 
24
48
72
96
120
144
168
192
Recruitment of participants 
 
Primary and secondary outcome 
measurement 
 
Adverse event measurement 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
20 
 
15 Pretreatment evaluations 
(1) At the initial visit, investigators collected demographic and clinical data. The 
patients’ parents who opted for oral β-blocker therapy provided a thorough medical 
history (e.g., existence of comorbidities) and family history (e.g., cardiovascular 
disease). 
Acquisition of general information: 
-Sex; 
-Gestational age; 
-Date of birth; 
-Age, 
-Body weight. 
Hemangioma histories were also taken from families, including: 
-Age when the hemangioma appeared; 
-Changes in the color of the hemangioma; and 
-The period during which the hemangioma showed the greatest growth before 
referral. 
(2) In all infants, the following inspections were performed before enrollment: 
-Heart rate; 
-Blood pressure; 
-Blood glucose; 
-Full blood count; 
-Liver function tests; 
-Renal function 
-Electrocardiogram (ECG); and 
-Echocardiogram. 
If cardiovascular abnormalities were detected, the patient were evaluated by 
pediatric cardiologists to ensure that it would be safe to initiate β-blocker treatment. 
Echocardiographic findings, such as a false tendon in the left ventricle, a patent ovale, 
left superior vena cava to the coronary sinus, and small systemic-to-pulmonary 
arterial collateral vessels, were considered normal variants and are not reported as 
anomalies. 
(3) When patients had more than one IH, detailed information was obtained for the 
most clinically important hemangioma (typically the largest or most ulcerated lesion). 
Hemangioma assessments included lesion size, lesion location, stage of growth, 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
21 
 
morphologic subtypes, depth of involvement, and treatment indication. 
(4) According to Chang et al., lesion size was recorded using ‘hemispheric’ 
measurement.23 A soft tape measure was draped over the hemangioma, and the 
longest diameter and a measurement perpendicular to it were noted to obtain a 
measurement in cm2. 
(5) Hemangioma lesions were classified by morphologic subtypes: 
-Localized: well-defined focal lesions; 
-Segmental: a hemangioma involving an anatomic region that was often plaque-like 
and often measured at >5 cm in diameter; or 
-Indeterminate: neither clearly localized nor segmental. 
(6) Hemangioma lesions were also be classified by soft-tissue depth: 
-Superficial, which was defined as red with little or no evidence of a subcutaneous 
component; 
-Deep, which was defined as blue and located below the skin surface (deep lesions 
were not considered target hemangiomas in this study); of 
-Mixed, which was defined as having both superficial and deep components. 
Investigators at all sites received standardized training on hemangioma 
assessments, including training in measurement techniques and the classification of 
hemangiomas. 
(7) Treatment indications included: 
-Disfigurement: Segmental IH; Head or facial IH ≥1.5 cm; Neck, truck or extremity 
IH ≥3.0 cm. 
-Causing functional disturbance: Periocular IH with threat to vision, nasal tip and 
lip (≥1.5 cm). If functional concerns were documented, indication for treatment was 
not classified as disfigurement (facial IH ≥1.5 cm). 
-Ulceration (IH ≥1.5 cm): ulcerated IH appearing anywhere on the body surface. 
-Bleeding (IH ≥1.5 cm): Bleeding IH appearing anywhere on the body surface. 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
22 
 
16 Study visits 
Study visits were scheduled at enrolment; at 1, 4, 12, and 24 weeks after treatment; 
and then every 12 weeks until the end of the study or if there was any specific need 
after enrolment. Body weight, height, heart rate, blood pressure, blood glucose, full 
blood count, liver function tests, renal function and ECG were obtained during 
protocol visits and in-between periods if needed. All adverse events, which were 
identified by the investigators as at least possibly treatment-related during the 24-
week treatment phase, were collected by the investigator. At each visit, the drug will 
be handed over to the parent/guardian in an amount sufficient to last the interim 
duration. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
23 
 
17 Treatment 
17.1 Standard case management 
Arms 
Assigned Interventions 
Active 
Comparator:  
Propranolol 
Drug: Propranolol 
Initiated at a dosage of 1 mg/kg per day divided 3 times daily for 
1 week and then increased to 2 mg/kg per day divided 3 times 
daily from week 2. 
2 mg/kg per day in 3 doses from week 2 after a gradual increase 
in the dose in the first week. 
Other Name: None 
Active 
Comparator: 
Atenolol  
Drug: Atenolol 
Initiated at a dosage of 0.5 mg/kg per day in a single dose for 1 
week and then increased to 1 mg/kg per day in a single dose 
from week 2. 
1 mg/kg per day in a single dose from week 2 after a gradual 
increase in the dose in the first week 
Other Name: None 
 
In the propranolol group, propranolol was initiated at a dosage of 1.0 mg/kg per 
day divided 3 times daily for 1 week and then increased to 2 mg/kg per day divided 3 
times daily from week 2. The treatment schedule was at least 6 months. 
In the atenolol group, atenolol was initiated at a dosage of 0.5 mg/kg per day in a 
single dose for 1 week and then increased to 1 mg/kg per day in a single dose from 
week 2. The treatment schedule was at least 6 months. 
Patients were administered the first dose of β-blocker at 8:00 am. During β-blocker 
treatments, the dose was adjusted for weight gain. At the end of treatment, the drug 
dose was adjusted according to the tapering schedule, which was determined by 
investigators and was supposed to be 4 weeks. 
 
Tapering schedules of drug discontinuance 
Week 
Propranolol 
Atenolol 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
24 
 
1 
1.5 mg/kg per day divided 3 times daily 
0.75 mg/kg per day in a single dose 
2 
1.0 mg/kg per day divided 3 times daily 
0.5 mg/kg per day in a single dose 
3 
0.5 mg/kg per day divided 3 times daily 
0.25 mg/kg per day in a single dose 
4 
2.5 mg/kg per day divided 3 times daily 
0.125 mg/kg per day in a single dose
5 
Discontinued 
Discontinued 
 
17.2 Rebound management 
Significant rebound after stopping the medication was treated by reinstitution of 
daily therapy with either propranolol (2 mg/kg per day) or atenolol (1 mg/kg per day) 
until hemangioma remission. 
 
17.3 Other co-interventions 
In both arms, oral antibiotics (cefaclor suspension), topical ointment antibiotics 
(mupirocin) and/or wound dressings were permitted to treat ulcerated IH and were 
recorded. The requirement for any additional IH-specific intervention was considered 
treatment failure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
25 
 
18 Collection and assessment of series of digital photographs 
Digital photographs of each target hemangioma were acquired by the site 
investigators at baseline and at 1, 4, 12, 24 and 96 weeks after treatment. The detailed 
procedures are listed below: 
(1) The investigators used a unified camera model. The acquisition procedures 
ensured consistency in lighting, exposure and distance from the camera. All digital 
photographs were obtained using digital single-lens reflex cameras (Nikon D7000 or 
Nikon D7100, Nikon Inc., Melville, NY). 
(2) For each participant site, the series images were taken in the same room. The 
room was a naturally well-lit room. The acquisition of digital photographs was 
performed carefully to avoid glare and direct light deep into the room. 
(3) The background behind the patient when the images are acquired was either the 
parent’s (or guardian’s) chest or shoulder or an examination couch. The parents and 
patients wore light-color, nonreflective clothes. Similarly, the examination couch was 
covered with a light blue, non-reflective bed sheet. 
(4) For each patient, at least one photograph (a front-on view with or without side-
on view) was taken at each visit. If the patient had a mixed hemangioma, front-on 
view and side-on view photographs were taken (not mandatory). 
(5) The quality of all the photographs was verified by site investigators before they 
were transferred to the CIS. If the photographs were not compliant with the 
acquisition protocol, repeated acquisition of the images was immediately performed. 
(6) Each photograph was uploaded with the following information: patient ID 
number and date of photograph acquisition. The central investigators assessed the 
quality of the digital photograph once more. 
(7) Digital photographs were independently assessed by three investigators 
(research assistants) working in the CIS who were unknown to the study group 
assignment and blinded to the clinical information. None of these investigators was 
involved in the clinical management of patients with IH. They were trained 
specifically to assess hemangioma evolution (response or nonresponse), hemangioma 
size and hemangioma color using a series of digital photographs. 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
26 
 
19 Primary outcome measures 
The primary outcome measure was the clinical response at 6 months in the 
intention-to-treat population. The intention-to-treat population was defined as all 
patients who had undergone randomization. If after assignment, a patient did not 
receive a drug administration or if an evaluation was never made after drug 
administration, the patient was excluded from the intention-to-treat population. 
Digital photographs of IHs were independently obtained by three investigators who 
were unknown to the study group assignment. In the case of multiple IHs, only the 
most clinically important IH (typically the largest or most ulcerated IH) was 
documented. 
Changes in IH size and color were classified as a complete response, nearly 
complete response, partial response or no response. The primary outcome measure 
was any response or nonresponse at 6 months in the intention-to-treat population of 
all patients who underwent randomization. The any response included compete, 
nearly complete and good responses; the nonresponse included stable or deteriorated: 
-A complete response was defined as no redundant tissue or telangiectasia was 
identified. 
-A nearly complete response was defined as a minimal degree of telangiectasis, 
erythema and skin thickening.5 
-A partial response was defined as a size reduction or change in color that did not 
meet the nearly complete resolution criteria. 
-Stable was defined as no changes in size or color between baseline and month 6. 
-Deterioration was defined as further growth of the target hemangioma. 
Treatment failure was defined as patients withdrawing from trial treatment due to 
nonresponse and/or severe adverse events. 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
27 
 
 
Examples of baseline and primary endpoint photographs (any response): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
28 
 
 
Examples of baseline and primary endpoint photographs (nonresponse): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
29 
 
20 Secondary outcome measures 
20.1 Hemangioma Activity Score 
The key secondary outcome measure was the Hemangioma Activity Score (HAS), 
which was measured at baseline and at 1, 4, 12 and 24 weeks using digital 
photographs. The photographs of the target hemangioma acquired at each visit were 
sent to the CIS. The consecutive digital photographs were assessed by centralized 
evaluation at West China Hospital of Sichuan University. Three trained investigators 
who were unknown to the study group assignments independently evaluated the 
digital photographs taken at baseline and the follow-up visits. According to previous 
reports, changes in an individual HAS could be used to evaluate the effect of 
treatment. Baseline scores were subtracted from posttreatment scores to obtain the 
change in HAS or the decrease in hemangioma proliferative activity after 
treatment.24,25 
The HAS system has three scoring forms, including the degree of deep swelling, 
the color of the hemangioma, and the ulceration assessment: 
(1) Assessment of the degree of swelling (or protrusion or elevation). A 
proliferating superficial or mixed IH can present as a protrusion with an overlying red 
tint. If there is visible swelling (or protrusion or elevation), it was scored as follows: 
-Six points if the swelling (or protrusion or elevation) was tense; 
-Four points if the swelling (or protrusion or elevation) was ‘neutral’ (i.e., not tense 
or less tense) at baseline or had <50% reduction at follow-up; 
-Two points when the swelling (or protrusion or elevation) was reduced by 50% or 
more at follow-up; or 
-Zero points when there was no more visible swelling (or protrusion or elevation) at 
a follow-up. 
If the patient had superficial IH and showed no visible evidence of swelling (or 
protrusion or elevation) at baseline, this step was omitted or we set the point as 0. 
However, the score for no swelling (which was zero) affected the final score. 
(2) Assessment of the color of the IH. The hemangioma color was assessed by 
blinded central investigators. A bright-red (or shining-red) color suggested that the 
hemangioma was very actively proliferating. A diminishing red color on the surface 
was seen during the phases of involution. It is therefore possible that different scores 
might have been applied to different phases of the same hemangioma. A bright-red 
hemangioma received the highest score. 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
30 
 
The intensities of hemangioma color were rated from 5 through 0: 
-Five points if the hemangioma lesion was bright red all over; 
-Four points if only the edge of the hemangioma lesion was bright-red; 
-Three points if the hemangioma lesion was matte red or reddish-purple (totally or 
partially) or if the hemangioma lesion was matte red only at the edge; 
-Two points if the hemangioma lesion was totally or partially blue or showed blue 
shining through in deep lesions; 
-One point if the hemangioma lesion was totally or partially gray; 
-Zero points if the hemangioma lesion was totally or partially skin-colored after 
involution. At this stage, the hemangioma color was imperceptible. 
If the hemangioma lesion was bright red, whereas the edge was not scored, then a 
bright-red edge was only be scored when the rest of the hemangioma lesion was not 
bright red. The total number was divided by the number of items scored to give to the 
mean score. Even the score for a normal skin color (which will be zero) would have 
an effect on the final score and thus was scored only if the hemangioma lesion had 
previously been another color. 
(2) Assessment of the ulceration. If ulcerations were visible, additional points were 
given. The scoring system for an ulcerated hemangioma was as follows: 
-0.5 point for an ulcer ≤1.0 cm2; 
-One point for an ulcer >1.0 cm2 but <25 cm2; 
-Two points for an ulcer ≥25 cm2. 
Overall, for an individual hemangioma lesion, the HAS scale ranges from 0 to 8. 
Several examples of HAS system scoring are shown in eFigures 8 and 9. The HAS 
system scoring for these digital photographs is illustrated in eTable 3. 
 
20.2 Successful initial response 
A successful initial response was assessed by using HAS in the intention-to-treat 
population. A successful initial response was defined as an HAS decrease at 1 week 
after treatment. Previous studies demonstrated that HAS decreases over time after β-
blocker treatment, with a dramatic drop occurring in the first week, indicating an 
immediate therapeutic response.24,25 HAS can reflect the rapid effect of β-blocker 
(either propranolol or atenolol) therapy shortly after initiation. 
 
20.3 Quality of life 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
31 
 
Quality of life (QOL) was measured at baseline and week 48. 
20.3.1 Quality of life instrument for IH 
The Quality of life instrument for IH (IH-QOL), which was developed by Sarah L 
Chamlin et al,26 was designed to measure the impact of treatment on IH patients and 
their parents. This module consists of 4 domains and 29 items. The domains include 
physical symptoms of the patient (4 items), social functioning of the patient (5 items), 
social and psychological functioning of the caregiver (10 items), and emotional 
functioning of the caregiver (10 items). IH-QOL is self-administered by the patients’ 
parents and takes approximately 5 minutes to complete. The Chinese Mandarin 
Version of IH-QOL has previously been translated according to standardized 
procedures, which consist of 4 steps: forward translation (Chinese), backward 
translation (English), preliminary test and field test. The Chinese version of the IH-
QOL has been demonstrated to have good internal consistency in patients with IH.27 
20.3.2 Pediatric Quality of Life Inventory 4.0 family impact module 
The Pediatric Quality of Life Inventory 4.0 family impact module (PedsQLTM 4.0 
FIM), which was developed by Varni et al.,28 is used to measure the impact of 
pediatric chronic disease on family functioning. The PedsQLTM FIM can stand alone 
or be integrated into the other measurement model, allowing an overall assessment of 
QOL in children and their parents. Chen et al. translated it cross-culturally into a 
Chinese version.29 The Chinese version of the PedsQLTM FIM demonstrates good 
internal consistency and discriminant and construct validity. The FIM is a parent-
reported instrument that measures the impact of chronic health conditions on 
children’s health-related QOL (HRQOL) and their family functioning. This 
instrument is composed of 9 dimensions and 37 items. The dimensions include 
physical functioning (6 items), emotional functioning (5 items), social functioning (4 
items), cognitive functioning (5 items), communication (3 items), worry (5 items), 
daily activities (3 items), family relationships (5 items) and financial issues (1 item). 
The first six dimensions measure parent self-reported HRQOL, while the latter three 
dimensions measure parent-reported family functions. 
20.3.3 Procedures 
The site investigators are trained by the project managers to guarantee the quality 
of the investigation. Before completing the questionnaires, the site investigators 
provided a good explanation of the purpose and significance of the questionnaires. 
Under the supervision of site investigators, when necessary, the site investigators 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
32 
 
explained the study to the parents individually. If the parents had questions related to 
semantic or conceptual understanding, the site investigators assisted the parents in 
completing the questionnaires. In addition, the site investigators were responsible for 
ensuring that there were no missing data in the questionnaires. 
In two questionnaires, standardized response choices consisted of five categories 
scored from 0 to 4. Likert-type scale responses were provided for each item: 0 = never 
a problem; 1 = almost never a problem; 2 = sometimes a problem; 3 = often a 
problem; and 4 = almost always a problem. The items were then linearly transformed 
to a 0-100 scale (0 = 100, 1 = 75, 2 =50, 3 = 25, 4 = 0), with higher scores indicating 
better HRQOL. The dimension scores are computed as the sum of the items divided 
by the number of items answered within a particular dimension. 
 
20.4 Complete healing time of ulceration 
Additional information was collected by site investigators for patients with 
ulceration. Ulceration is defined as a break in the integrity of the hemangioma surface 
epithelium (or skin) with or without infection. The information included the extent of 
ulceration, complications of ulceration, prior duration of ulceration (before treatment), 
concurrent treatments, and complete healing time. Prior duration of ulceration was 
defined as the time from the first sign of ulceration until before β-blocker treatment. 
The complete healing time of the ulceration was defined as the time from the first 
dosage of propranolol or atenolol until complete healing of the hemangioma 
ulceration. Concurrent treatments, including oral pain medication, oral antibiotics, 
topical ointment antibiotics and/or wound dressings, were permitted to treat ulcerated 
IH and were recorded. 
 
20.5 Rebound rate 
Regrowth of more than 20% in hemangioma appearance (including changes in 
color and/or volume) after stopping the medication was considered significant 
rebound. The inclusion criteria for rebound analysis were as follows: (1) patients who 
completed 6 months of treatment and (2) patients who discontinued therapy or were 
tapering treatment after achieving an any response. The exclusion criteria were as 
follows: (1) patients who were noncompliant with treatment and (2) patients who did 
not respond to treatment. Whether a patient had hemangioma rebound was based on 
the site investigators’ assessments after the week 24 treatment. In patients with 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
33 
 
significant rebound, reinitiation of systemic therapy (either propranolol or atenolol) 
was recommended. Minor rebound, which was defined as those patients in whose 
rebound was noted but no reinitiation of systemic therapy or further treatment was 
necessary, was not included in the analysis. 
 
20.6 Responses at Week 96 
A complete/nearly complete response at week 96 was considered median-term 
efficacy. The digital photographs of the target hemangioma were assessed by 
centralized evaluation at West China Hospital of Sichuan University. Three trained 
investigators who were unknown of the study-group assignments independently 
evaluated the digital photographs taken at baseline and week 96 after the initial 
treatment. For more details regarding the procedures for median-term efficacy, refer 
to the Collection and Assessment of Series Digital Photographs section. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
34 
 
21 Safety assessments 
21.1 In-house monitoring 
All patients were monitored as in-house patients for 8 hours with hourly 
measurements of cardiovascular examination at day 0 (week 0) and day 7 (week 1). 
Continuous bedside monitoring was performed on all infants during hospitalization by 
using a noninvasive multiparameter monitor. Blood pressure and heart rate were 
obtained before (baseline) and at 1, 2, 3, 4 and 6 hours following the first dose of β-
blocker therapy. The blood glucose level was measured by fingerstick using an 
automated glucometer and obtained before (baseline) and at 4 hours after the first 
dose of propranolol or atenolol during hospitalization. These values were also 
recorded before and following the first dose of β-blocker on day 7 (week 1) after dose 
escalation. Blood pressure and heart rate values were compared with age-related 
reference ranges. 
 
21.2 Outpatient monitoring 
The patients’ parents or guardians were asked to inform the investigators about 
adverse events at any time to ensure that potential adverse events could be handled 
promptly and appropriately. Parents or guardians were also provided with a patient 
booklet to record any possible adverse events during treatment. Data on adverse 
events was obtained at scheduled or unscheduled study visits based on information 
spontaneously provided by the subject and/or through questioning of the participant. 
Each scheduled visit included an evaluation of efficacy and routine examination. 
Routine examinations included physical examination, electrocardiography, routine 
blood tests, and blood glucose measurement. 
 
21.3 Collection and management of adverse events 
The frequency of adverse events (e.g., sleep disturbance, cool or mottled 
extremities, diarrhea, etc.) were collected by the investigator and reported by parents. 
The investigators collected any untoward medical occurrence in the form of signs, 
symptoms, abnormal laboratory findings, or diseases that emerged or worsened 
relative to baseline assessment. All adverse events that were identified by the 
investigators as at least possibly treatment-related (treatment-emergent adverse events 
or adverse events that have worsened since baseline) were included in the analysis. 
For each adverse event, the percentage of subjects who experienced at least 1 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
35 
 
occurrence of the given event was summarized by treatment group. Adverse events 
during the initial 24-week treatment phase were compared between the two groups. 
 
21.4 Definition of adverse events 
Identified adverse events were coded using the latest version of the Medical 
Dictionary for Regulatory Activities. Adverse events included suspected adverse drug 
reactions, other medical experiences, regardless of their relationship with the 
investigative drugs, such as infections, injury, surgery, accidents, extensions of 
symptoms or apparently unrelated illness, and significant abnormalities in clinical 
laboratory values or physical examination findings. These medical conditions relate to 
the disease under study whose changes during the study are consistent with natural 
disease progression. Therefore, they are not considered adverse events, but they shall 
be recorded by the investigators. Medical conditions that were present at baseline 
shall not be considered adverse events unless worsening occurred. 
Blood pressure and heart rate values were compared with age-related reference 
ranges: hypotension was defined as an SBP less than 50 mmHg and/or a DBP less 
than 30 mmHg; bradycardia was defined as an HR less than 80 beats per minute 
(bpm) while awake or less than 60 bpm while asleep. 
Intolerable CNS-related adverse effects (e.g., sleep disturbance and agitation) were 
defined as adverse events that did not disappear or were not relieved after treatment 
administration was altered (e.g., earlier evening dose or a decrease in daily dose). 
Sleep disturbance was characterized by difficulty in falling sleep and/or remaining 
sleep, or development of increased waking or night terrors. Agitation was 
characterized by a state of restlessness associated with unpleasant feeling of 
irritability and tension. 
Bronchial irritation was classified as hyperreactivity, bronchospasm, bronchiolitis, 
and cold-induced wheezing. 
 
21.5 Relationship of adverse events 
All adverse events were collected and graded according to Common Terminology 
Criteria for Adverse Events, version 4.0 (CTCAE v4.0). The investigators evaluated 
each adverse event that occurred after administration of β-blockers regarding the 
relationship with the administration of β-blockers. The causality of the adverse event 
was determined by the investigators and classified as definitively not related, 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
36 
 
probably not related, possibly related, probably related, or definitively related. Only 
patients with events that were at least possibly treatment-related were taken into 
consideration: 
(1) Definitively not related: only a remote connection exists between the 
administration of β-blocker and the reported adverse event. Other conditions, 
including concurrent illness, progression or expression of the disease state or reaction 
of the concomitant medication, appear to explain the reported adverse event. 
(2) Most likely, not related: an adverse event that does not follow a reasonable 
temporal sequence related to the administration of β-blocker and is likely to have been 
produced by the patient’s clinical state, other modes of treatment or other known 
etiology. 
(3) Possible related: an adverse event that has a reasonable possibility that the event 
may have been caused by the administration of β-blocker. The adverse event has a 
timely relationship to the administration of β-blockers. However, the pattern of 
response is atypical, and an alternative cause seemed more likely, or there is 
significant uncertainly about the cause of the event. 
(4) Probable related: an adverse event that has a reasonable possibility that the 
event is likely to have been caused by the administration of β-blocker. The adverse 
event has a timely relationship and follows a known pattern of response, but a 
potential alternative cause may be presented. 
(5) Definitely related: there is a reasonable possibility that the event might have 
been caused by the administration of β-blocker. A certain event has a strong temporal 
relationship, and an alternative cause is unlikely. 
 
21.6 Grade of adverse events 
Grade referred to the severity of the adverse event. CTCAE v4.0 displays grades 1 
through 5 with unique clinical descriptions of severity for each adverse event based 
on the general guidelines. A serious adverse event is defined as any of the following 
toxicities identified during the 6 months of treatment: 
-Grade ≥3 of any adverse events; 
-Persistent hypotension; 
-Persistent bradycardia; and 
-Intolerable CNS-related adverse effects. 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
37 
 
21.7 Preventing and managing adverse events 
(1) Before treatment, all of the parents were advised by investigators of the 
potential risk of side effects and educated on relative evocative signs, which included 
but were not limited to weakness, unusual tiredness, losing consciousness, trouble 
awakening, difficulty feeding, respiratory difficulty, and severe diarrhea. 
(2) To avoid the risk of hypoglycemia, we requested that β-blockers should be 
administered within 30 min after the patients were fed. The patients’ parents were 
instructed to ensure that their children were free to eat as often they desired. If there 
were any possible hypoglycemia alteration, the parents were instructed to administer 
oral liquids containing sugar and seek medical support in the case of persistence of 
these signs. 
(3) In patients in whom severe complication symptoms were observed, medical 
support from site investigators or pediatricians was sought immediately. 
(4) In cases of mild hypoglycemia, bronchitis with dyspnea, bronchial 
hyperreactivity or mild to moderate bronchospasms, treatment was suggested to be 
temporarily discontinued based on the patients’ symptoms. 
(5) Mild CNS-related adverse effects (e.g., sleep disturbance and agitation) might 
have subsided without any interventions, or they often resolved when the treatment 
administration was altered (e.g., earlier evening dose or a decrease in daily dose). In 
patients associated with intolerable CNS-related adverse effects, discontinuation of β-
blocker administration was recommended. 
(6) Any dose reductions, interruptions, or cessations enacted at the discretion of the 
investigators were recorded. 
 
21.8 Termination of the study 
All participants were informed that they had the right to withdraw from the study at 
any time without prejudice to their medical care and that they were not obliged to 
state their reasons. Follow-up was considered complete when the participant 
completed all study procedures and assessments up to the 96-week visit. Termination 
of the study was mandatory in the following situations: 
-Any grade ≥4 adverse event; 
-Recurrent or persistent cases of hypoglycemia, bronchitis with dyspnea, bronchial 
hyperreactivity or bronchospasms. 
-Persistent hypotension; or 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
38 
 
-Persistent bradycardia. 
 
21.9 Outcome of the adverse event 
The outcome of an adverse event at the time of the last observation/assessment was 
classified as: 
(1) Recovered/resolved: All signs and/or symptoms of an adverse event 
disappeared without any sequelae at the time of the last observation/assessment. 
(2) Recovering/resolving: The intensity of signs and symptoms was diminishing 
and/or their clinical pattern was changing up to the time of the last 
observation/assessment in a way typical for its resolution. 
(3) Not recovered/not resolved: signs and symptoms of an adverse event had 
mostly unchanged or worsened at the time of the last observation/assessment. 
(4) Recovered/resolved with sequelae: actual signs and symptoms of an adverse 
event disappeared, but there were sequelae related to the adverse event at the time of 
the last observation/assessment. 
(5) Fatal: resulting in death. If there was more than one adverse event, only the 
adverse event leading to death was characterized as ‘fatal’. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
39 
 
22 Tapering and discontinuation of treatment 
Propranolol or atenolol were tapered and stopped at an appropriate time, which was 
primarily based on the response and lesion regression after treatment. In this trial, the 
treatment was tapered and discontinued on complete or nearly complete resolution of 
IH or if no further improvement of IH (for 12 weeks of observation) was observed 
after month 6. At the end of the treatment period, the drug dose was gradually reduced 
over 4 weeks and then cease. For more detail regarding the procedures for tapering 
and discontinuation of treatment, refer to the Treatment section. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
40 
 
23 Data management and quality assurance 
The site investigators were responsible for recording all study data in the patient 
report form. All of the clinical and laboratory data were entered in electronic format. 
The patient report form was completed as soon as possible after the clinical and 
laboratory data were collected, preferably on the day of the scheduled visit. Double 
data entry was performed, and the documents were compared. At the visit interval, the 
data entries were checked for completeness, and the documents were reviewed for 
errors. For more details regarding the procedures for digital photograph management 
and quality assurance, refer to the Collection and Assessment of Series Digital 
Photographs section. For more details regarding the procedures for adverse event 
collection, refer to the Collection and Management of Adverse Event section. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
41 
 
24 Missing data 
If a patient dropped out of the study, the site investigators at the participant site 
attempted to ascertain the reason or reasons for the patient not continuing. If a patient 
missed one of the scheduled visits, the site investigators communicated with the 
parents or guardians to determine if the patient would come back for the next 
scheduled visit. As the trial progressed, missing data were monitored to ensure that 
there was not one data point that, for some reason, was routinely not being captured. 
If data were missing, the analyses were performed in several ways. The investigators 
first analyzed the data assumed to be missing completely at random. However, when 
the missingness depended on the outcome, the parameter estimation was most likely 
biased. The investigators would then assess the missing data mechanism according to 
the types of observed outcomes. When the missingness depended on the set of 
observed outcomes, a correctly specified covariance structure accommodated the 
situation. However, if the missingness was due to a primary outcome value that 
should have been obtained at week 24, the investigators performed a sensitivity 
analysis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
42 
 
25 Statistical analyses 
Statistical analyses were used to assess the recruitment, quality of data, and 
homogeneity of treatment groups and to evaluate the efficacy and safety of the 
treatments. 
25.1 Descriptive methods 
Continuous variables are described using the number of nonmissing values, mean 
(SD), mean (range), and median (interquartile range), as appropriate. For binary or 
categorical variables, absolute and relative frequencies (number and percentage) are 
provided. For comparisons between the groups, descriptive P-values are provided to 
show comparability of the groups in baseline characteristics and to provide a further 
descriptive measure. 
 
25.2 Baseline characteristics 
Both the propranolol and atenolol groups were characterized using descriptive 
methods based on the intention-to-treat principle. Table 1 gives an overview of what 
to describe at baseline in the intention-to-treat population. 
 
25.3 Primary outcome analysis 
Based on the intention-to-treat principle, the primary outcome analysis was 
performed in the intention-to-treat population. All patients treated with at least one 
dose of study medication (propranolol or atenolol) were included and analyzed in the 
group to which they were randomized. 
Primary outcomes were analyzed by sensitivity analysis. Best-case (response) and 
worse-case (nonresponse) scenarios were evaluated based on the intention-to-treat 
principle (in the best-case scenario, missing data in the propranolol group were 
considered failures, and missing data in the atenolol group were considered 
successes). In addition, missing data in the propranolol group were considered 
successes, and missing data in the atenolol group were considered failures. 
In addition, a per protocol analysis was performed. This means that only patients 
without major protocol violations are included. These patients fulfilled all inclusion 
and exclusion criteria and carried out all medical procedures/visits according to the 
protocol. 
 
25.4 Secondary outcome analyses 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
43 
 
Quantitative variables were compared with Student’s unpaired t-test, paired t-test, 
Wilcoxon rank sum test (Mann-Whitney U test), or generalized linear mixed models 
(GLMM). GLMMs were employed to compare the difference between the two groups 
in HAS changes from baseline to 6 months. Categorical variables were analyzed with 
Fisher’s exact test or a chi-square test, and 95% confidence intervals were calculated. 
Kaplan-Meier curves were used to visualize the time to treatment discontinuation. 
All secondary outcomes were analyzed based on the intention-to-treat principle 
without imputation of missing values. 
 
25.5 Safety outcome analyses 
All safety outcomes were analyzed based on the safety population, which 
comprises all patients who were treated with at least one dose of trial treatment and 
included in a treatment group. 
All premature study discontinuations are listed along with treatment group, time in 
study and reason for discontinuation. 
Unless specified otherwise, no data imputation was applied for missing safety 
evaluations. For analysis and reporting purposes, partial dates for adverse events and 
concomitant therapies were imputed. 
 
25.6 Differences from the trial protocol 
Despite the amendment to the protocol, there were no differences from the trial 
protocol. 
 
25.7 Software 
All analyses were performed using SPSS 23.0 for Windows (SPSS Inc., Chicago, 
IL, USA). 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
44 
 
26 References 
1. 
Leaute-Labreze C, Harper JI, Hoeger PH. Infantile haemangioma. Lancet. 
2017;390(10089):85-94. 
2. 
Darrow DH, Greene AK, Mancini AJ, et al. Diagnosis and Management of 
Infantile Hemangioma. Pediatrics. 2015;136(4):e1060-1104. 
3. 
Krowchuk DP, Frieden IJ, Mancini AJ, et al. Clinical Practice Guideline for 
the Management of Infantile Hemangiomas. Pediatrics. 2019;143(1). 
4. 
Kim KH, Choi TH, Choi Y, et al. Comparison of Efficacy and Safety Between 
Propranolol and Steroid for Infantile Hemangioma: A Randomized Clinical 
Trial. JAMA Dermatol. 2017;153(6):529-536. 
5. 
Leaute-Labreze C, Hoeger P, Mazereeuw-Hautier J, et al. A randomized, 
controlled trial of oral propranolol in infantile hemangioma. N Engl J Med. 
2015;372(8):735-746. 
6. 
Droitcourt C, Kerbrat S, Rault C, et al. Safety of Oral Propranolol for Infantile 
Hemangioma. Pediatrics. 2018;141(6). 
7. 
Leaute-Labreze C, Boccara O, Degrugillier-Chopinet C, et al. Safety of Oral 
Propranolol for the Treatment of Infantile Hemangioma: A Systematic Review. 
Pediatrics. 2016;138(4). 
8. 
Xiao Q, Li Q, Zhang B, Yu W. Propranolol therapy of infantile hemangiomas: 
efficacy, adverse effects, and recurrence. Pediatr Surg Int. 2013;29(6):575-
581. 
9. 
Langley A, Pope E. Propranolol and central nervous system function: potential 
implications for paediatric patients with infantile haemangiomas. Br J 
Dermatol. 2015;172(1):13-23. 
10. 
Ji Y, Chen S, Wang Q, et al. Intolerable side effects during propranolol therapy 
for infantile hemangioma: frequency, risk factors and management. Sci Rep. 
2018;8(1):4264. 
11. 
Alexopoulos A, Thanopoulou I, Dakoutrou M, Georgiadou E, Chrousos GP, 
Kakourou T. Atenolol treatment for severe Infantile Hemangiomas: a single-
centre prospective study. J Eur Acad Dermatol Venereol. 2018;32(3):e117-
e119. 
12. 
Bayart CB, Tamburro JE, Vidimos AT, Wang L, Golden AB. Atenolol Versus 
Propranolol for Treatment of Infantile Hemangiomas During the Proliferative 
Phase: 
A 
Retrospective 
Noninferiority 
Study. 
Pediatr 
Dermatol. 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
45 
 
2017;34(4):413-421. 
13. 
Abarzua-Araya A, Navarrete-Dechent CP, Heusser F, Retamal J, Zegpi-Trueba 
MS. Atenolol versus propranolol for the treatment of infantile hemangiomas: a 
randomized controlled study. J Am Acad Dermatol. 2014;70(6):1045-1049. 
14. 
Raphael MF, de Graaf M, Breugem CC, Pasmans S, Breur J. Atenolol: a 
promising alternative to propranolol for the treatment of hemangiomas. J Am 
Acad Dermatol. 2011;65(2):420-421. 
15. 
Ji Y, Wang Q, Chen S, et al. Oral atenolol therapy for proliferating infantile 
hemangioma: A prospective study. Medicine (Baltimore). 2016;95(24):e3908. 
16. 
Dakoutrou M, Alexopoulos A, Miligkos M, Georgiadou E, Kanaka-
Gantenbein C, Kakourou T. Atenolol treatment for severe infantile 
hemangiomas: comparison with a propranolol group of our centre. J Eur Acad 
Dermatol Venereol. 2019;33(5):e199-e200. 
17. 
Tasani M, Glover M, Martinez AE, Shaw L. Atenolol treatment for infantile 
haemangioma. Br J Dermatol. 2017;176(5):1400-1402. 
18. 
Ruitenberg G, Young-Afat DA, de Graaf M, Pasmans SG, Breugem CC. 
Ulcerated infantile haemangiomas: the effect of the selective beta-blocker 
atenolol on wound healing. Br J Dermatol. 2016;175(6):1357-1360. 
19. 
Ji Y, Chen S, Xu C, Li L, Xiang B. The use of propranolol in the treatment of 
infantile haemangiomas: an update on potential mechanisms of action. Br J 
Dermatol. 2015;172(1):24-32. 
20. 
Hogeling M, Adams S, Wargon O. A randomized controlled trial of 
propranolol for infantile hemangiomas. Pediatrics. 2011;128(2):e259-266. 
21. 
Bauman NM, McCarter RJ, Guzzetta PC, et al. Propranolol vs prednisolone 
for symptomatic proliferating infantile hemangiomas: a randomized clinical 
trial. JAMA Otolaryngol Head Neck Surg. 2014;140(4):323-330. 
22. 
Wedgeworth E, Glover M, Irvine AD, et al. Propranolol in the treatment of 
infantile haemangiomas: lessons from the European Propranolol In the 
Treatment of Complicated Haemangiomas (PITCH) Taskforce survey. Br J 
Dermatol. 2016;174(3):594-601. 
23. 
Chang LC, Haggstrom AN, Drolet BA, et al. Growth characteristics of 
infantile 
hemangiomas: 
implications 
for 
management. 
Pediatrics. 
2008;122(2):360-367. 
24. 
Janmohamed SR, van Oosterhout M, de Laat PC, van Rosmalen J, Madern 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
46 
 
GC, Oranje AP. Scoring the therapeutic effects of oral propranolol for infantile 
hemangioma: A prospective study comparing the Hemangioma Activity Score 
(HAS) with the Hemangioma Severity Scale (HSS). J Am Acad Dermatol. 
2015;73(2):258-263. 
25. 
Janmohamed SR, de Waard-van der Spek FB, Madern GC, de Laat PC, Hop 
WC, Oranje AP. Scoring the proliferative activity of haemangioma of infancy: 
the Haemangioma Activity Score (HAS). Clin Exp Dermatol. 2011;36(7):715-
723. 
26. 
Chamlin SL, Mancini AJ, Lai JS, et al. Development and Validation of a 
Quality-of-Life Instrument for Infantile Hemangiomas. J Invest Dermatol. 
2015;135(6):1533-1539. 
27. 
Wang C, Li Y, Xiang B, et al. Quality of life in children with infantile 
hemangioma: a case control study. Health Qual Life Outcomes. 
2017;15(1):221. 
28. 
Varni JW, Sherman SA, Burwinkle TM, Dickinson PE, Dixon P. The PedsQL 
Family Impact Module: preliminary reliability and validity. Health Qual Life 
Outcomes. 2004;2:55. 
29. 
Chen R, Hao Y, Feng L, Zhang Y, Huang Z. The Chinese version of the 
Pediatric Quality of Life Inventory (PedsQL) Family Impact Module: cross-
cultural adaptation and psychometric evaluation. Health Qual Life Outcomes. 
2011;9:16. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinicaltrial.gov Identifier: NCT02342275 
Version 1.3/Final version 
47 
 
27 Study flow chart 
Patients with problematic IH 
Screening 
Fulfilled the inclusion criteria 
Absent the exclusion criteria 
Informed consent of parents or guardians 
Screening failure 
Randomization 
Allocated to propranolol arm 
Allocated to atenolol arm 
Follow-up for 24 weeks 
Follow-up to 96 weeks