Clinical trial NCT02913612
Conditions: Infantile Hemangioma
Keywords: Hemangioma Infantile Hemangioma Pharmacokinetics
Sponsor: Kanecia Obie Zimmerman
Start date: 2017-05-05; Completion date: 2020-10-20
Enrollment: 105 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the safety and efficacy of Timolol 0.25% and 0.5% doses.

Detailed description:
Primary: Describe the efficacy of 0.25% and 0.5% topical timolol maleate Gel-forming solution (GFS) as assessed through Infantile Hemangioma (IH) changes in volume.

Secondary: Describe the safety of topical timolol maleate GFS for treatment of IH.

Arms: arm 1: Subjects assigned to this arm will be randomized to 0.25% timolol for 180 days. If during the 180 days the subject is considered a treatment failure, the subject will be unblinded. If the subject is on 0.25% timolol they will be changed to 0.5% timolol. arm 2: Subjects assigned to this arm will be randomized to 0.5% timolol for 180 days. If during the 180 days the subject is considered a treatment failure, the subject will be unblinded. If the subject is on 0.5% timolol the treating physician will decide to either continue 0.5% timolol or withdraw the subject and begin an alternative treatment. arm 3: Subjects assigned to this group will not receive treatment. The subject will only be photographed on the same schedule as the intervention group.
Interventions: intervention 1: 0.25% Timolol Maleate Gel Forming Solution intervention 2: 0.5% Timolol Maleate Gel Forming Solution
Intervention descriptions: intervention 1: 50:50 Randomized 0.25% Timolol Maleate Gel Forming Solution intervention 2: 50:50 Randomized 0.5% Timolol Maleate Gel Forming Solution

Protocol documents:
Prot_SAP_000.pdf: 
NICHD-2015-TIM01 
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i 
CLIENT CONFIDENTIAL 
 
 
Pediatric Trials Network 
 
Efficacy, Safety and Pharmacokinetics of Topical Timolol in 
Infants with Infantile Hemangioma (IH) 
 
NICHD-2015-TIM01 
 
Phase 2 Trial 
 
 
Funding Sponsor: 
The Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD) 
 
Funding Mechanism: Task Order 
Protocol Date: 
19 NOV 2021 
Protocol Version: 
8.0 
IND Number: 
129154 
Principal Investigator (IND Sponsor): 
Kanecia Zimmerman, MD, MPH 
Associate Professor of Pediatrics  
Duke University  
Duke Clinical Research Institute  
Durham, NC 27710 
Telephone: 919-668-8651 
Fax:  919-681-9457 
E-mail: kanecia.zimmerman@duke.edu 
 
 
NCT02913612


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STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, International Council for 
Harmonisation (ICH) E6(R2) guideline on Good Clinical Practice (GCP), and the applicable 
regulatory requirements from the United States Code of Federal Regulations (CFR), including 
45 CFR 46 (Human Subjects Protection), 21 CFR 312 (Investigational New Drug), 21 CFR part 
50 (Informed consent), and 21 CFR part 56 (Institutional Review Boards [IRB]) as well as 
international regulatory requirements if applicable. 
All individuals responsible for the design and/or conduct of this study have completed Human 
Subjects Protection Training and are qualified to be conducting this research. 
 


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SITE PRINCIPAL INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and the investigator brochure or product label, 
and I agree that it contains all necessary details for my staff and me to conduct this study as 
described. I will personally oversee the conduct of this study as outlined herein and will make a 
reasonable effort to complete the study within the time designated. I agree to make all reasonable 
efforts to adhere to the attached protocol. 
I will provide all study personnel under my supervision with copies of the protocol and access to 
all information provided by the sponsor or the sponsor’s representative. I will discuss this material 
with study personnel to ensure that they are fully informed about the effectiveness and safety 
parameters and the conduct of the study in general. I am aware that, before beginning this study, 
the institutional review board responsible for such matters must approve this protocol in the 
clinical facility where it will be conducted. 
I agree to provide all participants with informed consent forms, as required by government and 
International Council for Harmonisation regulations. I further agree to report to the sponsor or its 
representative any adverse events in accordance with the terms of this protocol and the U.S. 
Code of Federal Regulations, Title 21, part 312.64 as well as international regulatory requirements 
if applicable. 
 
 
 
 
 
 
 
Principal Investigator Name (Print) 
 
 
 
 
 
 
 
Signature 
 
Date 
 


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STUDY PRINCIPAL INVESTIGATOR / IND SPONSOR 
SIGNATURE 
The signature below documents the review and approval of this protocol and the attachments 
(e.g., package inserts), and provides the necessary assurances that this clinical study will be 
conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality and according to local legal and regulatory requirements and to the principles 
outlined in applicable U.S. federal regulations and ICH guidelines. 
 
 
 
 
Pediatric Trials Network  
Study Principal Investigator Name 
 
 
 
 
 
Signature 
 
Date 
 


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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ................................................................................... ii 
SITE PRINCIPAL INVESTIGATOR STATEMENT ........................................................ iii 
STUDY PRINCIPAL INVESTIGATOR / IND SPONSOR SIGNATURE ......................... iv 
TABLE OF CONTENTS .................................................................................................. v 
LIST OF ABBREVIATIONS ........................................................................................... ix 
PROTOCOL SYNOPSIS ................................................................................................ xi 
1 
KEY ROLES ..................................................................................................... 1 
2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .................. 3 
 
Background Information .............................................................................. 3 
 
Scientific Rationale ....................................................................................... 6 
 
Potential Risks and Benefits ........................................................................ 6 
 
Potential Risks ................................................................................................ 6 
 
Potential Benefits ............................................................................................ 7 
3 
OBJECTIVES ................................................................................................... 8 
 
Study Outcome Measures ............................................................................ 8 
 
Primary Efficacy Outcome ............................................................................... 8 
 
Secondary Outcome Measures ....................................................................... 8 
 
Exploratory Outcome Measures ...................................................................... 8 
4 
STUDY DESIGN ............................................................................................... 9 
 
Study Design ................................................................................................. 9 
4.1.1 
Study design for Control Cohort ...................................................................... 9 
 
Duration of Study Participation ..................................................................10 
5 
STUDY POPULATION ................................................................................... 12 
 
Selection of the Study Population ..............................................................12 
 
Inclusion/Exclusion Criteria ........................................................................12 
 
Inclusion Criteria ............................................................................................12 
 
Exclusion Criteria ...........................................................................................12 
 
Treatment Assignment Procedures ............................................................12 
 
Additional Participants ...................................................................................12 


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Randomization Procedures ............................................................................13 
 
Reasons for Participant Withdrawal ...............................................................13 
 
Withdrawal from Treatment Phase (study drug dosing) ..................................13 
 
Withdrawal of Consent for Study Participation ...............................................13 
 
Disease Progression Unmasking ...................................................................13 
 
Randomization of Participants in the Non-intervention Arm ............................14 
 
Termination of Study ......................................................................................14 
6 
STUDY PROCEDURES ................................................................................. 15 
 
Summary of Procedures .............................................................................15 
 
Screening/Rescreening ...............................................................................16 
 
Enrollment/Baseline ....................................................................................16 
 
Treatment Period .........................................................................................17 
 
Randomized Cohort .......................................................................................17 
 
Non-intervention Cohort .................................................................................17 
 
Follow-up Period ..........................................................................................18 
 
Efficacy Assessment Using Centralized VAS ............................................18 
 
Laboratory Evaluations ...............................................................................18 
 
PK Sampling ................................................................................................18 
 
Minimizing Blood Loss ...................................................................................19 
 
Specimen Preparation, Handling, and Shipping .............................................19 
7 
STUDY PRODUCT DESCRIPTION ............................................................... 20 
 
Dosage and Study Drug Information ..........................................................20 
 
Formulation, Packaging, and Labeling .......................................................20 
 
Product Storage and Stability .....................................................................20 
 
Other Medications/Treatments ...................................................................20 
8 
ASSESSMENT OF SAFETY .......................................................................... 21 
 
Methods and Timing for Assessing, Recording and Analyzing Safety 
  
Parameters .......................................................... ……………………………..21 
 
Adverse Event ...............................................................................................21 
 
Adverse Events of Special Interest ................................................................21 
 
Unexpected Adverse Event ...........................................................................22 
 
Identification of Events and Timeframe for Reporting .....................................22 
 
Follow-up of Adverse Events .........................................................................22 


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Guidelines for Assessing Grade of an Adverse Event ....................................22 
 
Guidelines for Determining Causality .............................................................23 
 
Discontinuation of a Participant Due to Adverse Events .................................23 
 
Reporting Procedures ....................................................................................23 
 
Serious Adverse Events ..............................................................................23 
 
Regulatory Reporting ..................................................................................23 
 
Safety Oversight ..........................................................................................23 
 
Halting Criteria: Safety Concerns ...............................................................24 
9 
CLINICAL MONITORING ............................................................................... 25 
10 
STATISTICAL CONSIDERATIONS ............................................................... 26 
 
Study Endpoints ..........................................................................................26 
 
Study Hypotheses Tested ...........................................................................28 
 
Sample Size Considerations .......................................................................28 
 
Analysis Plan ...............................................................................................29 
 Population for Analysis ..................................................................................29 
 Descriptive Statistics ......................................................................................29 
 Demographic and Baseline Characteristics ....................................................29 
 Efficacy Analysis ............................................................................................29 
 PK Analysis ...................................................................................................30 
 Safety Analysis ..............................................................................................30 
11 
PARTICIPANT CONFIDENTIALITY .............................................................. 31 
12 
INFORMED CONSENT PROCESS ................................................................ 32 
13 
FUTURE USE OF STUDY DATA AND STORED SPECIMENS .................... 33 
14 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
  
DATA/DOCUMENTS ...................................................................................... 34 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 35 
16 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS .................................. 36 
 
Ethical Standard ..........................................................................................36 
 
Institutional Review Board ..........................................................................36 
 
Study Discontinuation .................................................................................36 
17 
DATA HANDLING AND RECORD KEEPING ............................................... 37 


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Data Management Responsibilities ............................................................37 
 
Data Capture Methods .................................................................................37 
 
Timing/Reports ............................................................................................37 
 
Study Records Retention ............................................................................37 
 
Protocol Deviations .....................................................................................38 
 
Participant Privacy/Authorization ...............................................................38 
18 
PUBLICATION POLICY ................................................................................. 39 
19 
LITERATURE REFERENCES ....................................................................... 40 
APPENDIX I .................................................................................................................. 43 
APPENDIX II ................................................................................................................. 44 
 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse Event 
AUC0-24 
Area Under the Concentration Time Curve 0-24 hours 
AUCss 
Area Under the Concentration Time Curve at Steady State 
BP 
Blood Pressure 
BPD 
Bronchopulmonary Dysplasia 
BPCA 
Best Pharmaceuticals for Children Act 
BW 
Birth Weight 
CA 
Calcium 
CFR 
Code of Federal Regulations 
CL 
Clearance 
Cmax 
Maximum Concentration 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DCF 
Data Collection Form 
DCRI 
Duke Clinical Research Institute 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
FiO2 
Fraction of Inspired Oxygen 
FDA 
US Food and Drug Administration 
GA 
Gestational Age 
GAS 
Global Assessment Scale 
GCP 
Good Clinical Practice 
GFS 
Gel-forming solution 
HIG 
Hemangioma Investigator Group 
HIPAA 
Health Insurance Portability and Accountability Act 
HR  
Heart Rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDES 
Internet Data Entry System 
IEC 
Independent or Institutional Ethics Committee 
IH 
Infantile Hemangioma 


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Abbreviation 
Definition 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous 
K 
Potassium 
kg 
Kilogram 
L 
Liter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mcg 
Microgram 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
Na 
Sodium 
ng/mL 
Nanogram per milliliter 
NICHD 
Eunice Kennedy Shriver National Institute of Child Health and 
Human Development 
NIH 
National Institutes of Health 
NRN 
Neonatal Research Network 
PI 
Principal Investigator 
PICU 
Pediatric Intensive Care Unit 
PNA 
Postnatal age 
PMA 
Postmenstrual age (gestational age plus postnatal age) 
PK 
Pharmacokinetic 
PTN 
Pediatric Trials Network 
PTN POP01 
Pharmacokinetics of Understudied Drugs Administered to Children 
per Standard of Care 
QOL 
Quality of Life 
RAD 
Reactive airway disease 
SAE 
Serious Adverse Event 
TOF 
Tetralogy of Fallot 
TORO 
Transfer of Regulatory Obligations 
t1/2 
Half-life 
VAS 
Visual Analog Scale 
Vss 
Volume of distribution at steady state 
WHO 
World Health Organization 
 


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PROTOCOL SYNOPSIS 
Protocol Title: 
Efficacy, Safety and Pharmacokinetics of Topical Timolol in 
Infants with Infantile Hemangioma (IH) 
Phase: 
2 
Product: 
0.25% and 0.5% Timolol Maleate Gel Forming Solution (GFS) for topical 
application to IH 
Objectives: 
Primary: Describe the efficacy of 0.25% and 0.5% topical timolol maleate 
GFS as assessed through IH changes in volume 
Secondary: Describe the safety of topical timolol maleate GFS for 
treatment of IH 
Exploratory: Describe the pharmacokinetics (PK) of topical timolol 
maleate GFS for treatment of IH 
Study Design: 
Multi-center, double-masked randomized, efficacy, safety, and PK study 
Study Population: 
Inclusion Criteria 
1. Documented informed consent from legal guardian 
2. 0-84 days postnatal age at time of first study dose or when 
enrolled into the non-intervention cohort. 
3. Clinical diagnosis of superficial cutaneous or mucosal infantile 
hemangioma (must include all of the following): 
a. Superficial lesion in the dermis 
b. Thin <2 mm in thickness 
c. ≥0.5 cm at its longest dimension and ≤10 cm2 
d. Involves skin or keratinized mucosa 
 
Exclusion Criteria 
1. History of previous treatment with any pharmacologic or laser 
therapy for IH 
2. Ongoing therapy with an oral beta blocker or oral corticosteroid 
(e.g., cardiac arrhythmia, adrenal insufficiency, upper airway 
obstruction, tetralogy of fallot (TOF), hypertension, reactive 
airways disease) 
3. IH that requires systemic therapy (defined by dynamic 
complication scale >3) 
4. IH of the non-keratinized mucosa 
5. Infants with more than one hemangioma that requires therapy 
6. Hemodynamically significant cardiovascular disease, as 
determined by the investigator 
7. Known allergy to beta blockers or vehicle 
8. Heart rate <100 beats per minute at screening visit 
9. Known prenatal or postnatal diagnosis of 2nd/3rd degree 
atrioventricular block 
10. History of Reactive Airways Disease (RAD) 
11. Any condition which would make the participant, in the opinion of 
the investigator, unsuitable for the study 
Number of Participants: 
Approximately 110 
Number of Sites: 
Approximately 10 sites 
 


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Duration of 
Participation: 
Treatment arms: Up to 270 days (180 days of study drug plus 7 days of 
safety monitoring after last study dose for all adverse events and 90 days 
of safety monitoring after last study dose for adverse events of special 
interest). 
Non-Intervention cohort: Up to 180 days 
Estimated 
Duration of study 
Up to 2 years 
Dose Schedule: 
1:1 randomization to 0.25% versus 0.50% timolol GFS 
 
 


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KEY ROLES 
For questions regarding this protocol, contact: 
 
Protocol Chairs: 
Beth Drolet, MD 
Professor of Dermatology and Pediatrics 
Medical College of Wisconsin 
Milwaukee, WI 53022 
Telephone:  414-955-2818 
Fax:  414-456-6518 
E-mail:  bdrolet@mcw.edu 
Kristen Holland, MD 
Associate Professor of Dermatology 
Medical College of Wisconsin 
Milwaukee, WI 53022 
Telephone:  414-955-2818 
Fax:  414-456-6518 
E-mail:  kholland@mcw.edu 
 
Sub-Investigators:  
 
 
Sub-investigators are included in the signature log 
and consent form(s) at each clinical site. 
 
Medical Monitor: 
Jill Schwartz, MD 
Medical Director 
The Emmes  Company, LLC 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Telephone:  301-284-9275 
Fax:  800-383-9175 
Email:  bpcasafety@emmes.com 
 
BPCA DCC Principal Investigator: 
Ravinder Anand, PhD 
Vice President 
The Emmes Company, LLC 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Telephone:  301-315-6143 
Email:  timolol@emmes.com 
 
NICHD Contract Officer Representative: Perdita Taylor-Zapata, MD 
 
Contract Officer Representative 
National Institutes of Health 
6710B Rockledge Dr, MSC 7002  
Bethesda, MD 20892-7510 
Telephone:  301-496-9584 
Email:  taylorpe@mail.nih.gov 


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IND Sponsor:  
 
 
 
Kanecia Zimmerman, MD, MPH 
Associate Professor of Medicine  
Duke University, Duke Clinical Research Institute  
Durham, NC 27710 
Telephone:  919-668-8651 
Fax:  919-681-9457 
E-mail:  kanecia.zimmerman@duke.edu 
 


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BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
Background Information 
The Best Pharmaceuticals for Children Act (BPCA) mandates the National Institutes of Health 
(NIH) prioritize therapeutic areas in critical need for pediatric labeling, sponsor pediatric clinical 
trials, and submit these data to the United States Food and Drug Administration (FDA) for 
consideration for labeling changes. This study will be conducted in accordance with Section 409l 
of the Public Health Service Act; as such, the results from this research may be submitted to the 
FDA for review and use in negotiated labeling changes. This research study is contractually 
supported by the Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD). The NICHD awarded a contract to Duke University to establish the 
Pediatric Trials Network (PTN) through its Duke Clinical Research Institute (DCRI). The purpose 
of this contract is to facilitate trial design for studies supported by NIH. A separate contract was 
awarded to The Emmes Company to serve as the BPCA Data Coordinating Center (DCC). 
Infantile hemangiomas (IH) are the most common tumor of childhood. In the United States, 
approximately 80,000 children per year are diagnosed with the tumor, 12-20% of which are 
significantly complex and require referral to specialists for consideration of treatment. 
Complications of hemangiomas include permanent disfigurement, ulceration, bleeding, visual 
impairment, and airway obstruction. Hemangiomas occur exclusively in infants; therefore, 
efficacy, pharmacokinetic (PK), and toxicity data from older children and adults are not available. 
Furthermore, hemangiomas preferentially affect premature and low birth weight infants (<2500 g). 
According to a previous study, every 500 g reduction in birth weight below 2500 g results in a 
25% increased risk of developing a hemangioma.1 
Efficacy of systemic beta-blockers for the treatment of IH has been reported. Historically, 
agents with reported activity in treating IH include corticosteroids, interferon alpha, and vinca 
alkaloids. In 2008, the initial report of oral propranolol use for the treatment of IH was published.2 
This was followed by a number of case series describing its efficacy for IH.3-9 Given propranolol’s 
efficacy and immediate availability in a US suspension, it has rapidly been adopted as first-line 
therapy for IH.2,10 Furthermore, a multicenter, randomized, double-mask placebo-controlled, 
industry-sponsored trial of a new formulation of oral propranolol has been performed and this 
formulation was approved by the FDA for treatment of IH.10 In this study, 460 infants 1 to 5 months 
of age were randomized to either placebo or one of four dosing regimens. A rapid response to 
treatment was observed in 88% of infants receiving 3mg/kg/day by week 5.10 
Despite its adoption as first-line systemic therapy for IH, the mechanism of action of oral 
propranolol for IH remains poorly understood. Investigators have proposed multiple mechanisms, 
including 
pericyte-mediated 
vasoconstriction, 
inhibition 
of 
vasculogenesis 
and 
catecholamine-induced angiogenesis, the disruption of hemodynamic force-induced cell survival, 
and the inactivation of the renin-angiotensin system.11 
Pediatric dermatologists are using topical timolol despite limited efficacy, safety, or 
pharmacokinetic data. The success of oral propranolol for IH treatment has led many 
practitioners to use topical beta blockers off-label for the treatment of IH.12 There are currently no 
commercially available forms of propranolol designed for application to the skin; however, 
intraocular preparations of timolol are commercially available. Similar to the initial reports on oral 
beta blockers, publications on the use of 0.25% or 0.5% timolol maleate gel-forming intraocular 
solutions applied directly to hemangiomas on the skin or mucosa for off-label use in IH are rapidly 
emerging. 


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Efficacy of topical application of timolol for IH: Numerous case reports and small studies, 
including those of premature infants, have reported growth arrest and reduction in thickness and 
redness of IH within 2 weeks to 4 months topical application timolol maleate, particularly in 
superficial lesions.13-18 As a result, existing prospective studies of topical timolol for IH have 
focused on application to superficial IH rather than deeper lesions. In the largest available 
prospective study of 124 Chinese infants with IH, administration of timolol therapy directly to the 
IH for 4 months resulted in controlled growth of IH in 36/101 (36%) infants, and regression of IH 
in 56/101 (56%) infants. Only 3/23 (13%) infants in the control group had regression of IH.18 In a 
retrospective study, investigators treated 73 infants (median age 4.3 months, 25th, 75th percentiles: 
2.6, 7.2 months) for a mean of 3.4 months, and the mean visual analogue scale improvement at 
the last follow-up visit was 45%.19 Previous investigators also conducted a prospective, 
placebo-controlled analysis of topical timolol efficacy in 41 infants, ages 5 to 24 weeks. Among 
those who received treatment, a higher proportion of IH decreased in size as assessed by the 
visual analog scale by >5% at week 20 compared to those who did not receive treatment, 
p<0.02.20 In a study of 25 infants treated for 6 months, timolol was more effective when applied to 
thinner, plaque-type morphology than nodular superficial lesions.17 
Outcome scales used to assess efficacy of treatment for IH: 
Because most of the growth observed in IH 
is in tumor thickness not width, assessment 
of IH progression or regression has proven 
difficult 
with 
standard 
methods 
of 
measurement. Therefore, investigators have 
developed several scales to assess IH 
growth and efficacy of treatment for IH. All 
available scales are based on a shared 
concept of visual changes (progression or 
regression) at the determined endpoint 
compared to baseline or time zero, and aim 
to 
convert 
subjective improvement 
or 
worsening to quantitative measures. The 
visual analog scale (VAS) methodology is a widely accepted and frequently used measurement 
instrument for assessment of IH growth. When responding to a VAS item, raters specify the level 
of change from time zero to the endpoint (growth or regression) by indicating a position along a 
continuous line between two end-points. The best results are observed when lesional 
photographs are taken and a centralized assessment is made by unbiased, masked, and 
well-trained investigators. Although not formally validated, the VAS methodology has been used 
in several IH studies to evaluate response of IH to treatment with both topical and oral therapies. 
Most recently, a centralized VAS methodology was used in a study to gain FDA approval for an 
oral propranolol formulation for treatment of IH. Further, the VAS has demonstrated good 
agreement between masked observers, based on the intraclass correlation coefficient.19,21,22 
Studies have demonstrated the best interreader and intrareader reliability when primary efficacy 
is assessed by trained and validated raters using standardized digital photographs.23 
Safety of topical application of timolol for IH: In contrast to oral propranolol for which safety 
data from a completed industry-sponsored trial exists, publications reporting the efficacy of topical 
timolol have not been subjected to the usual stringency of Phase 1/2/3 clinical trials. In addition, 
these studies have been relatively small in size and short in duration, with no pharmacokinetic 
data and little to no prospective safety monitoring; therefore, rare adverse events (AEs) may have 
been missed. 
In a prospective study of 124 infants, parents reported no AEs related to study drug administration, 


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although investigators did not formally monitor bradycardia or hypotension.18 In the retrospective 
analysis of 73 infants, parents reported sleep disturbance in one subject, but investigators 
reported no other AEs in the cohort.19 In the prospective trial of 41 young infants, only 19 of whom 
were treated, investigators monitored heart rate and blood pressure at specified intervals until the 
end of the study. 20 There were no significant differences in heart rate or blood pressure between 
the treatment and observation groups.20 
In contrast to the few documented AEs in the above studies, investigators documented episodic 
bradycardia in 4 of 22 infants who received Holter monitoring concomitant with timolol therapy for 
IH.24 Two of these infants with clinically significant bradycardia had weights <2500 g at the 
initiation of therapy, both were <40 weeks postmenstrual age (PMA) at drug initiation, and both 
were receiving a timolol dose higher than most of the cohort.24 In a case report of an infant treated 
with ophthalmic timolol and anti-glaucoma medications, the infant developed altered mental 
status, hypotonia, hypothermia, bradycardia, apnea, hypotension, and bronch- obstruction, and 
required intensive care.25 A second case report documented apneic spells in a 2-week-old 
premature infant who was receiving timolol therapy for glaucoma.26 Apneic spells ceased after 
discontinuation of timolol.26 In the randomized trial that supported use of intraocular timolol 
maleate gel-forming solution (GFS) in children with glaucoma, 3 of 72 subjects (4%) developed 
bradycardia or hypotension.27 
Pharmacokinetics of topical application of timolol for IH: Information regarding the PK of 
topical timolol in children is limited. Studies in adults with intraocular application have indicated 
systemic absorption of up to 80% of each drop of 0.5% timolol solution.28 In a limited PK study (5 
pediatric subjects) of intraocular application of 0.5% timolol solution, plasma timolol 
concentrations ranged from 3.5 ng/mL in a 5-year-old to 34 ng/mL in a 3-week-old.29 Although the 
GFS form of timolol is thought to have lower systemic absorption compared to the solution, the 
likelihood of transcutaneous absorption is potentially increased when timolol is applied to the 
highly vascularized or ulcerated tissue of IH, or in the presence of occlusion (e.g., diaper 
hemangiomas).12 Moreover, compromised barrier function of preterm infant skin and smaller 
volume of distribution relative to adults may lead to increased systemic absorption when 
compared to adults.12 Previous investigators measured plasma concentrations of timolol 30 
minutes after applying timolol solution to occluded skin over IH after treatment with fractionated 
CO2 laser.30 Timolol concentrations were below the limit of detection (20 pg/mL) in all 9 infants. 
An additional small study demonstrated absorption in all patients sampled (average of 
0.18 ng/dL), but the biologic significance of this is unknown.31 
Preliminary data on safety and outcomes of infants treated with topical timolol: The 
Hemangioma Investigator Group (HIG) conducted a retrospective, multicenter cohort study of 
topical timolol (applied directly to the hemangioma) solution for IH.32 This study included 
738 infants from 9 pediatric dermatology and vascular anomalies centers, thereby demonstrating 
the wide off-label use of topical timolol for IH. The majority of infants were prescribed timolol in 
the outpatient setting and none of these received prolonged monitoring. During the active growth 
phase (0-3 months of age) 51% of infants showed improvement after 3 months of therapy and 
82% after 6-9 months of therapy. AEs were rare, occurring in 3.4% of infants and there were no 
serious adverse events (SAEs).32 There were no serious cardiovascular adverse events. 
Univariate and multivariate mixed-effects models showed that only initial IH thickness significantly 
predicted early improvement in size (p = 0.0003) and color (p = 0.0001 with IH <1 mm responding 
more quickly than IH 1-3 mm or >3 mm. The difference in response lost significance with longer 
duration of treatment, which may reflect natural involution of thicker lesions. While rebound growth 
with discontinuation of propranolol is well-recognized, optimal treatment duration for topical 
therapy to prevent rebound upon discontinuation has not been determined 


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Preliminary data collection on pharmacokinetics of topical timolol: Through the PTN study 
entitled “Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care 
(NICHD-2011-POP01),” PK evaluation of topical timolol in premature infants with IH is ongoing. 
Preliminary serum levels in our PTN sponsored study range from 0.03-66.4 ng/ml with a median 
of 1 (standard deviation 13.0) ng/ml. None of the infants in this cohort had signs or symptoms of 
beta blockade or adverse events from timolol. 
Timolol clinical pharmacology and product label: Timolol maleate is a nonselective 
ᵝ-adrenergic receptor inhibitor formulated as a 0.25% and 0.5% solution, or GFS for ophthalmic 
administration. Timolol maleate was approved in 2007 for ophthalmic use for children <6 years of 
age with glaucoma. Safety and intraocular pressure-lowering effect of timolol maleate GFS 0.25% 
and 0.5% have been demonstrated in children in a 3-month, multicenter, double-masked, 
active-controlled trial. This trial included 107 subjects 1 week to <6 years of age who received 
1 intraocular drop of either timolol GFS 0.25% or 0.5% once daily.27 PK of timolol GFS was not 
assessed in this trial.27 
According to the product label, contraindications for intraocular inoculation of timolol include: 
bronchial asthma (or history of), severe chronic obstructive pulmonary disease, sinus bradycardia, 
second- or third degree atrioventricular block, overt cardiac failure, cardiogenic shock, and 
hypersensitivity to any component of the product.33 These contraindications mimic those of other 
oral beta blockers in children and adults. 
 
Scientific Rationale 
Given the perceived safety of topical application of beta blockers for IH, continued off-label use is 
expected. Specifically, we predict a precipitous and wide-spread adoption of topical timolol 
(applied directly to the IH) for treatment of IH by primary care providers over the next 2-5 years. 
This phenomenon will expose many more infants to this drug. For example, when comparing the 
incidence of IH (1-4/100) to that of infantile glaucoma for which timolol is FDA approved 
(1/50,000), 80 times more infants will receive timolol for IH compared to glaucoma, even if only 
10% of infants with IH receive beta blocker therapy. Given the likelihood for increased population 
exposure to topical timolol, and limited existing data about the efficacy, safety, and PK of different 
timolol formulations, the study of 0.25% and 0.5% topical timolol in a randomized, masked fashion 
represents an urgent public health need. 
 
Potential Risks and Benefits 
 Potential Risks 
 Risks of Blood Drawing 
There are small risks to blood sampling, usually some pain/discomfort with the blood stick and 
blood loss. Every effort will be made to avoid additional (to standard of care) sticks for this study 
and will time clinical blood draws to coincide with timed samples, using existing intravenous lines 
when possible.  
 Risks of topical timolol therapy 
Transcutaneous absorption of topical timolol solution has not been extensively studied in adults 
or children. Application of topical timolol to highly vascularized or ulcerated tissue of infantile 
hemangiomas or under occlusion (e.g. diaper hemangiomas) may increase transcutaneous 
absorption, and pose a greater risk of adverse events associated with systemic beta-blockers. 
Effects of systemic beta blockade include bronchial hyperreactivity, hypotension, bradycardia, 
hypoglycemia, sleep disturbance, hypothermia, and changes in extremity color or temperature 
e.g., coldness. Infants with known baseline risk factors for bradycardia, hypoglycemia, or 
bronchial hyperreactivity will be excluded from enrollment according to the protocol’s predefined 


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criteria. More specific to the topical application of timolol, irritation or dermatitis may occur. 
 Potential Benefits 
Initial studies suggest efficacy of topical application of timolol in the treatment of IH, improving 
both the color and the volumetric size of the lesion. Treatment may also prevent functional 
complications. Topical treatment of IH with beta blockers will likely have an improved safety profile 
when compared to oral therapy although transcutaneous absorption has not been fully 
characterized. Conclusions drawn from this study will benefit infants receiving timolol in the future 
through better understanding of the efficacy and the characterization of the safety and PK profile 
of two different formulation strengths of this drug. 


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3 
OBJECTIVES 
Primary: Describe the efficacy of 0.25% and 0.5% topical timolol maleate GFS as assessed 
through IH changes in volume. 
Secondary: Describe the safety of topical timolol maleate GFS for treatment of IH. 
Exploratory: Describe the PK of topical timolol maleate GFS for treatment of IH. 
 
Study Outcome Measures 
 Primary Efficacy Outcome 
Partial response of hemangioma volume from baseline to 180 days within each treatment arm 
and compared with untreated controls. 
 Secondary Outcome Measures 
1. Efficacy 
 
Partial response of hemangioma color from baseline to 
180 days within each treatment arm and compared with 
untreated controls 
 
Comparison of partial response of hemangioma volume 
from baseline to 180 days between the two treatment arms 
 
Comparison of partial response of hemangioma color 
from baseline to 180 days between the two treatment 
arms 
 
Improvement of hemangioma complication in 
infants within each treatment arm 
 
Assess time to partial response by comparing baseline to 
day 30, day 60, day 120 and day 180 in both treatment arms 
 
Hemangioma Quality of Life assessment for infants within 
each treatment arm 
2. Serious adverse events and adverse events of special interest in 
infants treated with topical timolol maleate (0.25% and 0.5%) GFS 
for the treatment of infantile hemangioma 
 Exploratory Outcome Measures 
 
Pharmacokinetics: Clearance (CL), Volume of 
distribution (V), Area under the curve (AUC), Maximum 
concentration (Cmax) 
 
Relationship between hemangioma characteristics and 
plasma concentrations 


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4 
STUDY DESIGN 
 
Study Design 
This is a prospective, multi-center, double-masked, randomized, efficacy, safety, and PK study. 
Infants who satisfy all eligibility criteria will be randomized (1:1) to 0.25% or 0.5% timolol GFS and 
will be treated for a period of 180 days (Figure 1). 
Randomization will be stratified using two age groups: <4 weeks postnatal age and ≥4 weeks 
postnatal age. Infantile hemangiomas are more common in preterm and low birth weight infants, 
therefore, it is expected that 10% of enrolled subjects will be preterm infants. Infants who are 
eligible for the study based on inclusion and exclusion criteria but whose parents decline 
treatment of the hemangioma will constitute the non-intervention arm of the study and will serve 
as a control group. 
Infants who have progressive disease and require additional therapy as determined by the 
treating physician will be unmasked: if on the 0.25% timolol maleate GFS they will receive open 
label 0.5% timolol GFS two times a day and continue to be followed per the schedule of study 
procedures (Table 6-1). If they are on 0.5% the investigator may choose to continue the 0.5% 
open label or withdraw the participants from the Treatment Phase and proceed into the safety 
follow-up period and receive alternate therapies.  
This study will be conducted in accordance with current U.S. Food and Drug Administration 
regulations and guidelines, (or, as applicable, international regulations and associated 
guidelines), the International Council for Harmonisation Guidelines on Good Clinical Practice 
(which incorporate the principles of the Declaration of Helsinki), as well as all other applicable 
national and local laws and regulations. 
 
4.1.1 
Study design for Control Cohort 
Previous experience with clinical trials designed for IH treatment and performed in the US have 
demonstrated 
that 
parents 
are 
unlikely 
to 
enroll 
in 
double-masked, 
randomized, 
placebo- controlled studies. Therefore, two different strategies will be implemented to obtain 
age- matched control data. One strategy will include sharing of data and clinical photographs from 
two other completed randomized, placebo controlled studies in infants with IH. The patients in 
these studies are of similar age to our study and present similar IH characteristics. For the purpose 
of this study, the control group and the placebo groups from the two similar studies will serve as 
the untreated control cohort in our study. 
The first study identified is a recently completed prospective, single-center, double-masked, 
randomized, placebo-controlled efficacy study in Barcelona, Spain (Efficacy and safety of topical 
administration of timolol maleate 0.5% solution in the treatment of Child Proliferative Hemangioma 
Early Stage Surface. Randomized Controlled Study). This study has enrolled a total of 70 patients, 
35 randomized to 0.5% timolol BID and 35 to placebo BID for 6 months. (EudraCT Number: 
2013-005199-17). In addition, photographs from a second previously published double-masked, 
randomized, placebo-controlled trial (Australian and New Zealand Clinical Trials Registry 
Number: ACTRN12610001069044) are anticipated to be provided for analysis.20 These studies 
are anticipated to provide paired clinical photographs of approximately 35 placebo-treated 
patients through up to 180 days following baseline. 
As a secondary strategy, approximately 10 infants who are eligible for this study based on 
inclusion and exclusion criteria, but whose parents decide not to treat the IH, will be enrolled and 
also serve as a part of the untreated control cohort. 


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Duration of Study Participation 
Duration of infant participation in the study is up to 270 days for infants in the treatment arms 
(180 days of study drug, 7 days of safety monitoring after last study dose for all adverse events 
and 90 days of safety monitoring after last study dose for adverse events of special interest) or 
180 days for infants in the non-intervention arm. 
 
 


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Figure 1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Infants that cross from randomized, masked timolol maleate GFS to open label 0.5% timolol 
maleate GFS will continue to be followed per the schedule of study procedures (Table 6-1). 
Participation 
thru day 180 
50 Participants 
0.25% Timolol Therapy 
50 Participants 
0.50% Timolol Therapy 
Treatment thru day 180 
7 Days AE Monitoring 
110 Participants 
End of Study 
Randomization
Double-Masked 
90 Days AEs of special interest monitoring 
Progressive 
Disease
10 Participants 
Non-Intervention
Unmasked1 
Treatment thru day 180 


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5 
STUDY POPULATION 
 
Selection of the Study Population 
Young infants with superficial small hemangiomas in the proliferative phase and who have been 
identified by their treating physician as needing topical treatment with timolol maleate GFS will be 
considered for the study. For infants with more than one lesion, a target lesion (a lesion that will 
require treatment with study drug) will be identified. The infants will be administered study drug 
only on that lesion. Infants who are eligible for the study based on inclusion and exclusion criteria 
but whose parents decline treatment with timolol will be included in the non-intervention (control 
group) in the study. 
The majority of recruitment is anticipated to be from outpatient pediatric dermatology clinics, but 
additional recruitment may occur from inpatient units including the newborn nursery and neonatal 
intensive care units. 
 
Inclusion/Exclusion Criteria 
 Inclusion Criteria 
1. Documented informed consent from legal guardian 
2. 0-84 days postnatal age at time of first study dose or when enrolled into the 
non-intervention cohort. 
3. Clinical diagnosis of superficial cutaneous or mucosal infantile hemangioma: 
(must include all of the following): 
a. superficial lesion in the dermis of the skin 
b. thin (<2 mm in thickness) 
c. ≥0.5cm at its longest dimension and ≤10 cm2 
d. Involves skin or keratinized mucosa 
 Exclusion Criteria 
1. History of previous treatment with any pharmacologic or laser therapy for IH 
2. Ongoing therapy with an oral beta blocker or oral corticosteroid 
(e.g., cardiac arrhythmia, adrenal insufficiency, upper airway obstruction, tetralogy of 
fallot, hypertension, reactive airways disease) 
3. IH that requires systemic therapy (defined by dynamic complication scale >3) 
4. Infants with more than one hemangioma that requires therapy 
5. IH of the non-keratinized mucosa 
6. Hemodynamically significant cardiovascular disease, as determined by the investigator 
7. Known allergy to beta blockers or vehicle 
8. Heart rate <100 beats per minute at screening visit 
9. Known prenatal or postnatal diagnosis of 2nd/3rd degree atrioventricular block 
10. History of reactive airway disease (RAD) 
11. Any condition which would make the participant, in the opinion of the 
investigator, unsuitable for the study 
 
Treatment Assignment Procedures 
 Additional Participants 
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infants are withdrawn at any time in the study for reasons other than lack of efficacy after 
randomization, additional infants may be enrolled. All infants receiving ≥1 dose of study drug will 
have safety follow up for at least 7 days after the last dose. 
 Randomization Procedures 
Patients meeting eligibility criteria whose parents agree to treatment with timolol will be 
randomized in a 1:1 ratio to 0.25% or 0.50% timolol GFS. Randomization will be stratified by study 
site and age group: <4 weeks postnatal age vs ≥4 weeks postnatal age at time of randomization. 
The infant’s randomized treatment assignment will be obtained through the Advantage eClinicalSM 
enrollment module. In the event that Advantage eClinicalSM is not available at the time of 
randomization, a back-up system specified in the MOP will be used. 
 Reasons for Participant Withdrawal 
 Withdrawal from Treatment Phase (study drug dosing) 
The clinician or family may choose to suspend study drug dosing for any reason during the study 
period, and the infant will remain in the study. 
If at any time during the study, the treating physician determines that the target hemangioma 
failed therapy and the IH requires more aggressive surgical or alternate pharmacologic therapy 
(e.g., oral beta blockers, or oral or topical corticosteroids), the infant may be withdrawn from the 
Treatment Phase and move into the 7 day safety follow-up period. If the participant continues to 
participate in the study, they will be followed for safety for 7 days after last study dose, and should 
continue to return for planned study visit activities including photography of the IH. 
If a treating physician chooses to withdraw the participant from the Treatment Phase 
(i.e. discontinue timolol maleate GFS dosing), the treating physician must immediately report this 
to the DCRI study PI and Protocol Chairs. 
The investigator will withdraw a participant from receiving further study drug if: 
1. Any clinically significant adverse event (AE) is deemed by the principal 
investigator to require discontinuation of study drug. 
2. The treating physician determines that the target hemangioma 
failed therapy and requires alternate pharmacologic, laser or 
surgical intervention. 
3. Participant develops ulceration of the target hemangioma after therapy is initiated. 
4. Participant receives oral or intravenous corticosteroids or additional oral, 
intraocular, or topical beta blockers for treatment of any other conditions. 
5. Requested by the NIH, FDA, DMC, or PTN. 
 Withdrawal of Consent for Study Participation 
The infant’s parents or legal guardians may withdraw consent voluntarily from participation in the 
study at any time. The infant’s parent or legal guardian is not obligated to state the reason for 
withdrawal. The reasons for withdrawal, or failure to provide a reason, must be documented by 
the investigator on the completion/withdrawal section of the electronic case report form (eCRF). 
Following withdrawal of consent, no study procedures or collection of data may occur. 
 Disease Progression Unmasking 
Infants enrolled in the treated arms who are determined by the treating physician to have 
progressive disease will be unmasked and: 
 


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 
If on 0.25% timolol maleate GFS they will receive open label 0.5% timolol 
GFS two times a day. 
 
If on 0.5% timolol maleate GFS the investigator may choose to continue 
study treatment with 0.5% open label, or withdraw the infant from the 
Treatment Phase and proceed directly into the 7 day safety follow-up 
period. Participants may receive alternate therapies during the safety 
follow-up period. 
Infants that are unmasked and receive open label 0.5% timolol maleate GFS will continue to be 
photographed and followed per the schedule of study procedures (Table 6-1). 
 Randomization of Participants in the Non-intervention Arm 
If at any time during the study the parents of an infant in the non-intervention arm change their 
mind and want timolol maleate GFS therapy, the infant will be randomized for participation in the 
study if there is a need for additional enrolled subjects and the infant meets the inclusion criteria 
and none of the exclusion criteria at the time of first dose. 
 Termination of Study 
This study may be terminated at any time by FDA, NIH, the Investigational New Drug (IND) 
application sponsor, or upon recommendation by the Data Monitoring Committee (DMC). 


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6 
STUDY PROCEDURES 
 
Summary of Procedures 
Table 6-1: Schedule of Study Procedures 
 
Screen/ 
Baseline
Treatment phase 
 
Time (Day)* 
01 
Visit #00/ 
Visit #018
30 
(±5 
days)
Visit 
#02 
60 
(±- 5 
days) 
Visit 
#03 
90 
(± 5 
days) 
Phone 
contact
Visit 
#04 
120 
(± 5 
days) 
Visit #05
150 
(± 5 
days) 
Phone 
contact 
Visit #06
180 
(± 5 
days) 
Visit 
#07 
Day 7 
(+ 5 days)
Phone 
contact 
post 180 
day study 
period or 
early 
withdrawal
Visit #08
Day 270
(± 5 days)
Phone 
contact 
Confirm 
ongoing 
therapy 
Visit #09
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Vitals: HR, BP10 
X8 
X 
X 
 
X 
 
X 
 
 
X
Physical Exam of lesion2 
X 
X 
X 
 
X 
 
X 
 
 
X
Photograph of lesion 
X 
X 
X 
 
X 
 
X 
 
 
X
Medical History 
X 
 
 
 
 
 
 
 
 
Physical Exam (systems 
assessment)9 
X 
X 
X 
 
X 
 
X 
 
 
X
Actual Weight 
X 
X 
X 
 
X 
 
X 
 
 
X
Study Drug Dispensation 
X 
X 
X 
 
X 
 
 
 
 
X
Review of Participant Diary 
(Treatment Administration 
Info) 
X 
X 
X 
 
X 
 
X 
 
 
X
SOC Timolol Dosing Info (from 
Phone Script/Follow-up Diary) 
 
 
 
 
 
 
 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
X
Adverse Events 
X4,8 
X 
X 
X 
X 
X 
X 
X 
X3 
X
Blood sampling5 
X 
X 
X 
 
X 
 
X 
 
 
Parent reported QOL Survey7 
X 
 
X 
 
 
 
X 
 
 
X
Hemangioma Dynamic 
Complication Scale6 
X 
X 
X 
 
X 
 
X 
 
 
X
Assessment for treatment 
failure 
 
X 
X 
 
X 
 
X 
 
 
X
1 Refers to time point prior to start of study drug and may be the same calendar date as day 1. 
2This includes treating physician’s assessment by Visual Analog Scale (VAS) and measure of width and 


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thickness. Note: VAS should only be performed at visits 02, 03, 05, 07 and unmasking. 
3AEs of special interest will include bradycardia, hypotension, new alteration in mental status, new local 
skin irritation, new sleep disturbance, apnea, bronchospasm, hypoglycemia, and diarrhea. 
4AEs will be collected following initial study-specific procedure (e.g., screening, blood draws, dosing) 
5For infants who are enrolled into the PK portion of the study; up to 3 samples will be obtained throughout the 
study period and at least one sample should be collected within 2 hours of dosing. Clinic visits for infants in the 
PK portion of the study will be scheduled to fall within the appropriate time period. Blood pressure and heart rate 
must be collected within 15 minutes before or after sample collection. 
6The Hemangioma Dynamic Complication Scale must be collected for all participants. 
7The parent-reported QOL survey is not required for non-English speaking parents. 
8OUTPATIENT: When possible the participant should remain in clinic for 2 hours after the first application of 
timolol in order to monitor for heart rate and BP at 1 hour (+/-15 mins) and 2 hours (+/- 15 mins) after first 
application. The site PI must also monitor for signs of bradycardia, bronchospasm and hypoglycemia. 
INPATIENT: All inpatients will be monitored for the first 24 hours for any signs of bradycardia or any other SAEs of special 
interest. Hospital staff must also 
monitor BP and HR 1 and 2 hours after the first administration of timolol. 
9If performed per local standard of care (SOC) 
10 Blood Pressure Measurement should include systolic and diastolic measurements  
*All visits (except for Day 7 post 180 days study period or early withdrawal) can occur within a 5 day window (±5 
days). Day 7 post 180 day study period or early withdrawal must occur within a +5 day window (+5 days). 
 
 
Screening/Rescreening 
Infants 0-84 days postnatal age with IH will be screened for eligibility. 
A participant may be rescreened if there is a transient disease status (e.g., parent/guardian 
reports a “cold or fever” and met a temporary delaying enrollment criterion of acute illness or 
fever). No participant may be screened more than twice due to a screening failure result. 
 
Enrollment/Baseline 
Research staff will obtain informed consent from the parent/guardian for all participants who 
satisfy eligibility criteria. 
Once the informed consent has been obtained the following information will be recorded in the 
CRF: 
1. Infant demographics, including birth weight and gestational age at birth 
and postnatal age. 
2. Medical history (birth history and cardiac or pulmonary diagnoses) 
3. Physical examination, including weight, height/length, baseline blood 
pressure, heart rate. Note, at the Baseline Visit, blood pressure* and 
heart rate must be at 1 hour and 2 hours after the first application of 
timolol. 
4. Photographs and measurements of the IH. Collection of data on the 
clinical characteristics and measurement of width and thickness of 
the target hemangioma. 
5. Adverse events following initial study-specific procedure (see Table 6-1) 
6. Hemangioma Dynamic Complication Scale 
7. Parental Hemangioma Quality of Life (QoL) screen 
8. Concomitant Medications 
* The preferred method of blood pressure collection is auscultation (i.e. manual), however, blood 
pressure may be collected via machine. Whichever method is used at visit #01 (baseline) should 
be used at all subsequent visits. Blood pressure measurements should include systolic and 
diastolic pressure measurements.  


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Treatment Period 
 Randomized Cohort 
For those randomized to one of the two treatment arms the study drug Treatment period will 
include days 1 to 180 days for all infants. 
Hospitalized infants who are enrolled in the study will be monitored for the first 24 hours for any 
signs of bradycardia or any other AEs or AEs of special interest. Hospital staff must also monitor 
heart rate and blood pressure at 1 and 2 hours (+/- 15 minutes) after the first application of timolol. 
Data from a minimum of 25 outpatient infants remaining in clinic after initial application must be 
collected. Parents of all outpatient infants enrolled in one of the treatment arms will be requested 
to remain in or close to the  clinic for a period of 2 hours after the initial application of timolol.  Vital 
signs (heart rate and blood pressure) will be collected at 1(+/-15 mins) and 2 hours (+/-15 mins) 
after the first application of timolol. The infant will  be monitored for signs and symptoms of an AE 
or AE of special interest during this period, particularly bronchospasm, arrhythmias, and 
hypoglycemia .  
Thereafter, all infants enrolled in one of the treatment arms will have follow-up office visits at day 
30±5 days, 60±5 days, 120±5 days, and 180±5 days and follow-up phone calls at day 
90±5 days,150±5 days. Participants will be monitored by their parent/caregiver as instructed in 
the patient diary. For parents who have agreed to the PK portion of the study, at least one visit 
should be scheduled to occur within 2 hours of study drug administration when possible. 
Parents will be instructed to administer the study medication immediately after or soon after 
feeding to avoid hypoglycemia. For each participant, the first application of topical timolol will be 
applied by the site study team (Site PI or designee).  
During the office visits, the following procedures will be performed as specified in Table 6-1: 
1. Physical examination, including weight, blood pressure, heart rate. 
2. Photographs and measurements of the IH. Collection of data on the 
clinical characteristics, measurement of width and thickness of the 
target hemangioma, and color and volumetric size VAS assessments. 
3. Hemangioma Dynamic Complication Scale 
4. Adverse events/ solicitation of AEs of special interest 
5. Parent Hemangioma QoL screen 
6. PK sampling (see 6.8) for infants whose parents have consented to this 
portion of the study (optional). PK sampling will not be collected during 
the unmasking visit. 
7. Concomitant medications 
8. Timolol dosing log (to record dose, timing) 
9. Weighing of the timolol bottle to verify compliance 
During the phone calls, solicitation of concomitant medications and assessment of adverse events 
will be conducted and documented. 
 Non-intervention Cohort 
Infants whose parents decline treatment with timolol will have follow-up office visits at day 
30±5 days, 60±5 days, 120±5 days, and 180±5 days.  
During the office visits, the following procedures will be performed as specified in Table 6-1: 
1. Physical examination, including weight, blood pressure, heart rate. 
2. Photographs and measurements of the IH. The treating physician will collect data 


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on the clinical characteristics and measure width and thickness of the target 
hemangioma and perform color and volumetric size VAS assessments. 
3. Hemangioma dynamic complication scale for IH that are ulcerated or threaten 
function 
4. Adverse events/ solicitation of AEs of special interest 
5. Parent Hemangioma QoL screen 
6. Concomitant medications 
 
Follow-up Period 
For treated participants, a follow-up period through day 7 (+5 days) after completing study drug 
or last study procedure, as applicable, will include solicitation of concomitant medications and 
assessment of adverse events/AEs of special interest. 
For all treated participants that complete 180 days of treatment on study drug, the follow-up period 
through day 90 (±5 days) after study drug has been completed, will include solicitation of timolol 
dosing information and adverse events of special interest. 
If a participant’s last day of treatment phase ends after day 180 (+5 days) (e.g., out-of-window 
visit), site staff should continue the follow-up period for the full 90 days post last dose.  
Infants who participate in the non-intervention cohort, will have no further follow up beyond 
180 days. 
 
Efficacy Assessment Using Centralized VAS 
Efficacy will be determined at the end of the study by centralized evaluation of five standardized 
digital photographs (taken by investigators at each visit). All collected images from both arms of 
the study and the untreated control group will be evaluated in a masked fashion by expert pediatric 
dermatology Raters. Each study site will be given photographic equipment and a minimum of two 
individuals at each site will be trained to capture standardized photographs. Detailed information 
will be in the MOP and the photography vendor’s User’s Manual on how to take the pictures of 
the infant’s hemangioma in order to obtain a systematic and consistent approach. All study and 
control photographs will undergo a centralized/standardized color calibration by the photography 
vendor before they are sent for assessment by the Raters. Two expert Raters and one Adjudicator 
will be trained on the Visual Analog Scale (VAS), how to recognize change in volume and color, 
and in the comparison of the hemangioma from baseline to study endpoint. However, assessment 
will initially be completed by 2 of the Raters. Adjudication by the Adjudicator will occur in a case 
of disagreement between the two Raters (see Rater’s User’s Manual). For the purpose of this 
study, a disagreement will be defined as a difference in both Raters’ assessment concerning the 
treatment response categories on the VAS scale. Raters will use the VAS (see Section 10.1) to 
rate changes in volume and changes in color separately. Raters will be masked to both treatment 
assignment and timing of the digital photograph. Interreader and intrareader reliability of the 
Raters will be assessed prior to evaluation of study infants. The scores of the centralized Raters 
will be used to determine the success or failure of timolol therapy to obtain partial or complete 
regression of hemangioma in each study infant. 
 
Laboratory Evaluations 
When clinically indicated, investigators will evaluate infants for the presence of hypoglycemia 
(serum glucose < 60 mg/dL). 
 
PK Sampling 
Parents/guardians of infants in the treated groups will have the option to consent for PK blood 
draws, heel sticks, or finger sticks. Refusal to provide consent for the PK portion of the study 


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does not preclude involvement in the main study. Infants who have parental/guardian consent 
for the PK portion of the study will have up to 3 blood samples obtained during the study period 
and at least one sample should be collected within 2 hours of any dosing. Table 6-2 below outlines 
optimal sampling periods. Efforts should be made to obtain samples according to the sampling 
schedule; however, samples obtained outside of the sampling windows will not be considered 
protocol deviations. Blood pressure and heart rate must be collected within 15 minutes before or 
after sample collection. 
 
Table 6-2: Optional sampling collection windows (relative to drug application) 
Sample option*
Sampling Window
1
Within 2 hours
2
2-4 hours
3
5-7 hours
4
8-10 hours
5
11-12 hours (prior to repeat dose)
* At least one sample should be collected within 2 hours of dosing. 
 Minimizing Blood Loss 
Blood samples will be collected in 250 µL aliquots. To minimize the amount of blood sampling, no 
more than 3 PK samples (750 µL in total) will be obtained from each infant for analysis. 
 Specimen Preparation, Handling, and Shipping 
Detailed information will be in the MOP. 


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7 
STUDY PRODUCT DESCRIPTION 
 
Dosage and Study Drug Information 
Dosing scheme 
Parents/guardians or hospital providers will topically apply 1 drop [approx. 0.05 ml of timolol 
maleate 0.5% GFS, which is 0.25 mg, or approximately 0.05 ml of timolol maleate 0.25% GFS, 
which is 0.125 mg] twice daily soon after feeding, to the surface of the hemangioma. The site will 
remain uncovered unless ulcerated or under the diaper, in which case a bandage will be applied 
when possible. Parents will record daily dosing in a log. Written instructions on how to apply study 
drug on the hemangioma will be provided to the parents at time of randomization and/or first study 
drug dispensing; the study site team (PI or designee) will show the parents how to apply the 
correct dose (i.e.,  drop) by applying the first treatment. Detailed instructions will be provided in 
the MOP. At each visit study drug bottles will be weighed to verify compliance. A discrepancy of 
>0.75g (+/-) between the expected bottle weight and the actual bottle weight at Visits 02 and 03 
will be recorded as a protocol deviation. A bottle weight discrepancy of >1.5g (+/-) at Visits 05 and 
07 will be recorded as a protocol deviation.  Participants will not be early terminated because of 
a bottle weight discrepancy or participant non-compliance. 
A deviation for participant non-compliance will be recorded if:  
A participant has 12 or more missed doses per visit (previous 30 days of the treatment period)  
A participant has 72 or more missed doses over the 6-month treatment period  
A participant has 4 consecutive missed doses. 
 
Formulation, Packaging, and Labeling 
Any requisite clinical trial materials will be provided with labeling in accordance with all applicable 
regulatory requirements. Detailed information will be part of the MOP. 
 
Product Storage and Stability 
All investigational products must be stored in a secure area with access limited to the investigator 
and authorized site staff and under physical conditions that are consistent with investigational 
product-specific requirements provided by the Sponsor. Detailed information will be part of the 
MOP. 
 
Other Medications/Treatments 
The following concomitant medications are not permitted during the study: 
1. 
Topical corticosteroids applied to the IH (topical corticosteroids used on 
areas unaffected by IH are permitted) 
2. 
Oral or intravenous beta blockers 
3. 
Oral or intravenous corticosteroids 
All other drugs are permitted while on study. 


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8 
ASSESSMENT OF SAFETY 
 
Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters 
Safety will be assessed in all infants following initial study-specific procedure through 7 days 
(+5 days) post last study dose or last study procedure, as applicable, and will be assessed by 
frequency and incidence of AEs and SAEs. Those outpatient infants whose parents are willing 
and able to remain in clinic for a period of 2 hours after the initial application of timolol will also 
have vital signs (heart rate and blood pressure) collected at 1 hour and 2 hours (+/- 15 mins). The 
infant will be monitored for signs and symptoms of an AE or AE of special interest during this 
period, particularly bronchospasm, arrhythmias, and hypoglycemia. 
Inpatient infants will be monitored by hospital staff. Hospital staff will collect vital signs (heart rate 
and blood pressure) 1 and 2 hours after the initial application of timolol and monitor for signs of 
an AE or AE of special interest during this period.  
For all treated participants that complete 180 days of treatment on study drug, the follow-up period 
through day 90 (±5 days) after study-specific drug has been completed will include solicitation of 
adverse events of special interest only. Infants whose parents decline treatment with timolol will 
have no further follow up beyond 180 days. Refer to Figure 1 and Table 6-1. A safety monitoring 
committee (DMC) will be convened by NIH to review data and safety information from study 
infants throughout the study. 
 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in humans, whether or not 
considered drug-related, which occurs during the conduct of a clinical trial. (Any change in clinical 
status, routine labs, x-rays, physical examinations, etc.), that is considered clinically significant by 
the study investigator is considered an AE. 
Suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. A reasonable possibility implies that there is evidence that 
the drug caused the event. 
Adverse reaction is any adverse event caused by the drug. 
Serious adverse event or serious suspected adverse reaction or serious adverse reaction 
as determined by the investigator or the sponsor is any event that results in any of the following 
outcomes: 
1. Death 
2. Life-threatening AE (“life-threatening” means that the study participant was, in the 
opinion of the investigator or sponsor, at immediate risk of death from the reaction 
as it occurred and required immediate intervention) 
3. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
4. Inpatient hospitalization or prolongation of existing hospitalization 
5. Important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study participant or require medical or surgical 
intervention to prevent one of the outcomes listed in the above definition of serious 
event 
 Adverse Events of Special Interest 
In addition, we will specifically evaluate infants for the following adverse events of special interest: 


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1. Bradycardia (need for pharmacologic intervention, or a persistent heart rate below 
100 while awake and alert after drug administration) (per study clinician or per 
parent report if informed by another clinician) 
2. Hypotension (need for pharmacologic intervention, or blood pressure < 80% 
standard values for age) (per study clinician or per parent report if informed by 
another clinician) 
3. New alteration in mental status (e.g., drowsiness, lethargy) (per study clinician or 
parent report) 
4. New local skin irritation (per study clinician or parent report) 
5. New sleep disturbance (per study clinician or parent report) 
6. Apnea (per study clinician or parent report) 
7. Bronchospasm (evaluated by study clinician when clinically indicated or per parent 
report if informed by another clinician) 
8. Hypoglycemia (serum glucose < 60 mg/dL) (evaluated by study clinician when 
clinically indicated or per parent report if informed by another clinician) 
9. Diarrhea (per parent report) 
10. Arrhythmias  
 Unexpected Adverse Event 
This is defined as any adverse event, the specificity or severity of which is not consistent with the 
package insert or investigational plan. 
 Identification of Events and Timeframe for Reporting 
Pre-existing conditions will not be considered as adverse events. New events that occur or 
pre- existing conditions that worsen in terms of frequency or intensity will be reported as adverse 
events. 
All reportable events as defined above, determined to be an AE based on physical examination, 
laboratory findings, or other means, will be reported in the electronic case report form (e-CRF). 
The investigator will provide the date of onset and resolution, intensity, action(s) taken, changes 
in study drug dosing, relationship to study drug, and outcome. 
Any event excluding adverse events of special interest beginning more than 7 days after the last 
dose of study drug or last study procedure will not be reported. For participants in the treatment 
arm adverse events of special interest only will be reviewed and reported at 90 days after the last 
dose of study drug. 
 Follow-up of Adverse Events 
All events (study-related or not) must be followed to adequately evaluate the infant’s safety or 
until the event stabilizes/resolves. Any safety event that is identified at the last assessment (or an 
early termination) must be recorded on the appropriate eCRF with the status of the safety event 
noted. All serious suspected adverse reactions and serious adverse reactions will be followed 
until resolution or until the infant is medically stable. All other events that cannot be resolved by 
37 days after the last study dose or last study procedure, as applicable, will have the status of the 
ongoing event entered in the electronic data capture (EDC) system at that time. 
 
 
Guidelines for Assessing Grade of an Adverse Event 
The investigator should use the following definitions when assessing intensity of an adverse 
event: 
1. MILD: Participant is aware of symptoms or has minor findings but tolerates them 
well, and no or minimal intervention required. 
2. MODERATE: Participant experiences enough symptoms or findings to require 


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intervention. 
3. SEVERE: Participant experiences symptoms or findings that require significant 
intervention. 
 Guidelines for Determining Causality 
The investigator will use the following question when assessing causality of an adverse event to 
study drug, where an affirmative answer designates the event as a suspected adverse reaction: 
Is there a reasonable possibility that the drug caused the event? ‘‘Reasonable possibility’’ means 
that there is evidence to suggest a causal relationship between the drug and the adverse event. 
 Discontinuation of a Participant Due to Adverse Events 
Infants may be withdrawn from the study at any time. Infants withdrawn from the study due to an 
AE, whether serious or non-serious, must be followed by the investigator until the clinical outcome 
from the AE is determined. Any infant who experiences an AE may be withdrawn at any time from 
the study at the discretion of the investigator. The AE(s) should be noted on the appropriate CRFs, 
and the infant’s progress should be followed until the AE is resolved or considered stable. The 
Medical Monitor and the Protocol Chair/PI must be notified. 
 Reporting Procedures 
Information about AEs will be solicited by investigators and study coordinators. 
All adverse events will be entered into the safety data system within 7 days of study staff 
identification. Serious events will be entered into the data system within 24 hours of study staff 
identification. If there are any technical difficulties, the SAE will be reported by direct 
communication with the Medical Monitor. 
 
Serious Adverse Events 
Any serious adverse event entered in the safety database will generate an automatic email 
notification to the DCC, IND sponsor and funding sponsor. The DCC medical monitor will review 
all SAEs at the time that they are reported but no later than one business day. Investigators must 
also submit safety reports locally as required by their IRB. 
 
Regulatory Reporting 
Any event that requires expedited reporting based on federal regulations will be forwarded to the 
IND sponsor. The IND sponsor will submit expedited safety reports (e.g. IND safety reports) to 
the regulatory agencies as necessary, and will inform the investigators of such regulatory reports. 
Site investigators must submit safety reports as required by their IRB. Documentation of the 
submission and receipt by the IRB must be retained for each expedited safety report. 
All serious events irrespective of their designation as “related” or “not related” to study product(s) 
will be reported to the FDA at least annually in a summary format. 
 
Safety Oversight 
The DMC will review serious adverse events at regularly scheduled meetings. In addition, a 
qualified and experienced clinician not otherwise associated with this protocol will serve as the 
medical monitor. The medical monitor will review all SAEs at the time they are reported. If safety 
concerns are identified, the medical monitor may request a meeting of the DMC to review safety 
data. At a minimum, the medical monitor will comment on the outcomes of the SAE and causal 
relationship of the SAE to the study product. The medical monitor will also indicate whether he/she 
concurs with the details of the report provided by the study investigator. If no SAEs prompt review 
at an earlier time point, the DMC will review AEs and SAEs at the regularly scheduled meeting. 
The DMC will convene and make recommendations on termination of the study based on review 


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of safety reports and halting rules. The safety data will be compiled by DCC. Based on the 
recommendations of the DMC, NIH and IND sponsor will make a decision to terminate or continue 
the study. 
 
Halting Criteria: Safety Concerns 
The trial will be halted (paused) for a safety review by the DMC if there are 2 or more Serious 
Adverse Reactions. 


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9 
CLINICAL MONITORING 
Site monitoring will be conducted to ensure that human subject protection, study procedures, 
laboratory procedures, study intervention administration, and data collection processes are of 
high quality and meet sponsor, GCP/ICH, and regulatory guidelines, and that the study is 
conducted in accordance with the protocol and DCRI sponsor standard operating procedures. 
The IND sponsor, or as detailed in the Transfer of Regulatory Obligations (TORO), NIH, FDA, or 
its designee will conduct site-monitoring visits as detailed in the monitoring plan or in the manual 
of procedures. 
Site visits will be made at standard intervals as defined by the site monitoring plans and may be 
made more frequently as directed by the IND sponsor. Monitoring visits will include, but are not 
limited to, review of regulatory files, accountability records, CRFs, informed consent forms, 
medical and laboratory reports, and protocol compliance. Study monitors will meet with 
investigators to discuss any problems and actions to be taken and document visit findings and 
discussions. 


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10 STATISTICAL CONSIDERATIONS 
 Study Endpoints 
Efficacy Categories for IH volume: 
 Progressive disease: >20% increase in hemangioma volumetric size
 Partial response: >20% and up to 80% reduction in volumetric size of hemangioma
 Complete/near complete response: >80-100% reduction in 
volumetric size of hemangioma
 Stable disease: none of the above or between 20% increase in 
hemangioma volumetric size and 20% reduction in volumetric 
size
Efficacy Categories for IH Color: 
 Progressive disease: >30% increase in hemangioma color
 Partial response: >30% and up to 80% reduction in color of hemangioma
 Complete/near complete response: >80-100% reduction in color of hemangioma
 Stable disease: none of the above or between 30% increase in hemangioma color 
and 30% reduction in color
 
Complete/ 
Near Complete 
Response 
Partial Response 
Stable Disease 
Progressive Disease 
+100 
0 
-100
 
Visual Analog Scale (VAS)21: 100 mm scale used to independently grade volume and color 
-100 indicates hemangioma has doubled in volumetric size/color: twice as intense  
0 indicates no change 
+100 indicates complete shrinkage or complete resolution of volumetric size/color 
 
The partial response or greater of hemangioma will be based 
on centralized VAS-volume and VAS-color scores from 
baseline to Day 180 in both treatment arms assessed by three 
independent, expert and masked pediatric dermatologists 
(Section 6.6). 
 
Primary Efficacy Endpoints: 
Estimation of the proportion of infants with partial response in hemangioma volume (partial 
response or greater as assessed by VAS-volume) from baseline to day 180 within each 
randomized treatment arm and compared with the untreated controls. 
 
 
 
 
 
 
Example of partial response in 
VAS- volume after 32 days of 
timolol treatment.


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Secondary Endpoints: 
Secondary efficacy endpoints will include the following: 
1. Estimation of the proportion of infants with partial response in hemangioma color 
(partial response or greater as assessed by VAS-color) from baseline to day 
180 within each randomized treatment arm and compared with the untreated 
controls. 
2. Comparison of partial response of hemangioma volume (partial response or greater 
as assessed by VAS-volume) between the two treatment arms. 
3. Comparison of partial response of hemangioma color (partial response or greater as 
assessed by VAS-color) between the two treatment arms. 
4. Absolute change in hemangioma dynamic complication scale from Day 0 to end of 
study within each treatment arm. 
5. Assess time to partial response by comparing baseline to day 30, day 60, day 120 
and day 180 in both treatment arms. 
6. Absolute change in IH-QoL score scale from Day 0 to end of study within each 
treatment arm. 
Secondary safety endpoints are the rate of serious adverse events and adverse events of special 
interest (Section 8.1.2) from randomization to Day 180 in infants treated with topical timolol 
maleate (0.25% and 0.5%) GFS for the treatment of infantile hemangioma. 
Exploratory Endpoints: 
Exploratory PK endpoints include estimation of PK parameters such as clearance (CL), volume 
of distribution (V), area under the curve (AUC), and maximum concentration (Cmax), as possible. 
The relationship between different hemangioma characteristics and plasma concentrations may 
also be described as an exploratory endpoint. 
Treatment Failure for Partial Response in Hemangioma Color or Volume 
The infant will be considered a treatment failure for the primary endpoint of partial response of 
VAS-volume or the secondary endpoint of partial response of VAS-color from baseline to Day 180 
if any of the following conditions are met: 
1. Partial response not achieved at the Day 180 visit in infants who complete the 
180-day treatment period. 
2. Infant withdrawn from masked treatment due to progressive disease. This will 
include participants randomized to the 0.25% treatment arm and switched to the 
0.5% treatment arm. 
3. Ulceration of the target hemangioma after initiation of masked treatment. 
4. Infant withdrawn from study treatment due to safety concerns. 
5. Study drop-out or loss to follow-up after the 30-day visit and before the 180-day visit 
for reasons other than progressive disease, ulceration, or safety concerns without 
having achieved partial response at the last study visit before drop-out. 
Partial response will not be evaluated in participants who drop-out from the study for reasons 
other than progressive disease, ulceration, or safety concerns or are lost to follow-up before the 
30-day visit. Sensitivity analyses will be performed to assess the impact of assumptions made to 
account for drop-out on the primary analysis. This will include summaries of partial response that 
exclude participants who withdrew for reasons other than lack of efficacy. Other methods, such 
as multiple imputation, may be considered based on drop-out rates and cause of missingness. 


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In addition to the assessments of partial response through the 180-day visit, the proportion of 
participants who achieve partial response through each study visit will be summarized. The 
number of participants with partial response before but not at the 180-day visit will be summarized. 
 Study Hypotheses Tested 
For the primary analyses of treatment efficacy, let pRC be the proportion with partial or greater 
response in hemangioma volume for the control cohort, pR25 the proportion with partial or greater 
response in hemangioma volume for the 0.25% arm, and pR50 the proportion with partial or greater 
response in hemangioma volume for the 0.5% arm. The following set of hypotheses will be 
assessed: 
Hypothesis 1 (H1): The partial response proportion in the 0.5% arm is greater than the partial 
response proportion in the control cohort. 
Null hypothesis H10: pR50 ≤ pRC  
Alternative hypothesis H1A: pR50 > pRC 
Hypothesis 2 (H2): The partial response proportion in the 0.25% arm is greater than the partial 
response proportion in the control cohort. 
Null hypothesis H20: pR25 ≤ pRC  
Alternative hypothesis H2A: pR25 > pRC 
A secondary efficacy hypothesis comparing treatment arms will also be tested: 
Secondary efficacy hypothesis (H3): The partial response proportion in the 0.25% arm is not equal 
to the partial response proportion in the 0.5% arm. 
Null hypothesis H30: pR25 = pR50 
Alternative hypothesis H3A: pR25 ≠ pR50 
The =0.05 level will be used for hypothesis testing. Hypotheses will be tested with chi-square or 
Fisher’s exact tests. A Bonferroni multiplicity correction will be applied to the  level for the primary 
hypotheses. Response proportions will be further compared between groups using the odds ratio 
or estimated differences in proportions and corresponding confidence interval estimates. 
 Sample Size Considerations 
Sample size calculations for primary efficacy hypotheses assume that 35 participants will have 
evaluable data in the untreated control cohort. The following success rates are assumed: 
0.15 response proportion in the control cohort, 0.45 response proportion in the 0.25% arm, and 
0.50 response proportion in the 0.5% arm. With 45 participants in each treatment arm and  = 
0.05 as in Section 10.2, this gives the efficacy hypothesis comparing the 0.5% and control arms 
a power of 93% and the efficacy hypothesis comparing the 0.25% and control arms a power of 
85% after applying the Bonferroni multiplicity correction to the alpha level. The study sample size 
of 100 randomized participants was determined by assuming that up to 10% of randomized infants 
will drop out with unevaluable partial response. 
Sample size calculations for the secondary safety analyses assume that approximately 20% of 
participants will experience an AE of special interest and 5% will experience an SAE of special 
interest.24,32 With 100 participants across the two treatment groups, 95% Wilson score confidence 
intervals are (0.02,0.11) (confidence interval width=0.09) for SAEs and (0.13,0.29) (confidence 
interval width=0.16) for AEs. These intervals are thought to be sufficiently precise for the 
estimation of key event rates. The probability is 0.63 and 0.99 that at least one event will be seen 
in the study population for rare events with probabilities 0.01 and 0.05, respectively, of occurring. 


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 Analysis Plan 
 Population for Analysis 
All randomized infants who received study dose and non-randomized participants enrolled in the 
untreated control cohort will be included in the intent-to-treat population. The primary analysis will 
use the intent-to-treat population with treatment group determined by randomization assignment. 
All infants enrolled and receiving at least one dose of timolol therapy will be included in the safety 
population and the safety analysis. All infants who had at least one interpretable PK sample will 
be included in the PK analysis. 
 Descriptive Statistics 
Descriptive statistics such as number of observations, mean, median, standard deviation, 
standard error, minimum and maximum will be presented by groups for continuous variables 
(such as age, weight, etc.). Other descriptive statistics such as counts, proportions, and/or 
percentages will be presented by group to summarize discrete variables (such as race, sex, etc.). 
Participant disposition will be summarized, including the number of infants completed and early 
terminated from the study and the reasons for termination. 
 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will also be summarized. Variables include race, 
postnatal age, gestational age, sex, and selected clinical variables recorded prior to initiation of 
study drug. Study drug administration will be summarized in terms of number of days of dosing 
and reasons for final discontinuation of study drug. 
 Efficacy Analysis 
Key efficacy endpoints are summarized in Section 10.1. Chi-square or Fisher’s exact tests will be 
used to test response proportion hypotheses at study end. Response proportions will be further 
compared via odds ratio, difference in proportion, and confidence interval estimates. 
Further adjusted analyses taking into account postnatal age, gestational age, and other baseline 
or demographic covariates of interest via logistic regression will be performed. Differences 
between studies used for the control data will be assessed. 
As discussed in Section 10.1, randomized participants who switch to unmasked treatment with 
timolol maleate 0.5% GFS due to disease progression will be classified as treatment failures in 
the primary analysis. VAS scores following the switch to unmasked treatment will be analyzed as 
a secondary analysis. Both the VAS assessment of change from study baseline and change in 
VAS score from the time of treatment switching will be summarized in this secondary analysis. 
The duration of unmasked treatment will be summarized. Partial response of color or volume from 
the start of randomized treatment will be evaluated in participants who switch treatment using 
data collected after the treatment switch. 
Additional secondary efficacy variables for analysis between randomized treatment arms include 
severity of the hemangioma, time to partial response, and quality of life measurement variables. 
Absolute change in overall severity will be measured via hemangioma dynamic complication scale 
from baseline to Day 180 within each treatment arm. Absolute change in quality of life will be 
measured via IH-QoL score scale from baseline to Day 180 within each treatment arm. Linear 
mixed effects modeling techniques will be used to analyze changes in the quantitative VAS 
scores, severity scale, or quality over time, and adjustments for demographic covariates of 
interest will be considered. 


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 PK Analysis 
If possible, PK parameters will be estimated by the population PK approach using non-linear 
mixed effects modeling in NONMEM. The relationship between hemangioma characteristics (e.g.  
hemangioma thickness, timolol formulation, sex, application site, hemangioma surface area, 
ulceration, or occlusion) and study drug concentration will be estimated.  Timolol data from the 
Pharmacokinetics of Understudied Drugs Administered to Children per Standard of Care study 
(PTN POP01) will be combined with the data obtained from this study for the exploratory PK 
analysis.  
 Safety Analysis 
The number and percent of AEs and SAEs will be summarized overall and by each Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. Prior and 
concomitant medications will be summarized by World Health Organization (WHO) drug class. 
Summary statistics for proportion of infants with AEs of special interest will be presented. The 
equality of AE and SAE event rates will be tested between treatment arms as an exploratory 
analysis. 


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11 PARTICIPANT CONFIDENTIALITY 
Participant confidentiality is held strictly in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples, in addition to the clinical information relating to participating participants. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
The study monitor or other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the investigator. This documentation includes, but is 
not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants 
in this study. Clinical study sites will permit access to such records. 
The principal investigator will ensure that the use and disclosure of personal health information 
obtained during this research study complies with the Federal Privacy Regulation. In the U.S., the 
Health Insurance and Portability and Accountability (HIPAA) Privacy Rule applies. The rule 
provides U.S. federal protection for the privacy of protected health information sent to or collected 
in the U.S. for the purposes of this research by implementing standards to protect and guard 
against the misuse of individually identifiable health information of participants participating in 
clinical trials. “Authorization” is required from each research participant (i.e., specific permission 
granted by an individual to a covered entity for the use or disclosure of an individual’s protected 
health information). A valid authorization must meet the implementation specifications under the 
applicable Federal Privacy Regulations. The relevant privacy authorization will be combined in 
the informed consent document (approved by the IRB). 
This study is covered by a Certificate of Confidentiality (CoC) from the National Institutes of 
Health. The CoC limits the ability of courts and other agencies from forcing the study team to 
share participant information or body fluids during a legal or legislative action without the 
participant’s permission. The CoC does not restrict the parents from sharing information 
voluntarily. 


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12 INFORMED CONSENT PROCESS 
Informed consent is a process that is initiated prior to the infant’s parent or legal guardian agreeing 
to participate in the study and continuing throughout the infant’s study participation. Extensive 
discussion of risks and possible benefits of participation in this study will be provided with the 
infant’s parent(s) and/or legal guardian (if applicable). Consent forms describing in detail the study 
procedures and risks will be given to the infant’s parent(s)/legal guardian, and documentation of 
informed consent is required prior to enrolling in the study. Consent forms will be IRB-approved, 
and local IRBs will determine whether one or two parent signatures are required based on the 
risk level of study or local regulatory requirements. The infant’s parent(s)/legal guardian will be 
asked to read and review the document. Upon reviewing the document, the investigator will 
explain the research study to the infant’s parent(s)/legal guardian and answer any questions that 
may arise. The infant’s parent(s)/legal guardian will provide informed consent prior to the conduct 
of any study procedures. The infant’s parent(s)/legal guardian should have the opportunity to think 
about the study prior to allowing the infant to participate. The infant’s parent(s)/legal guardian may 
withdraw consent at any time throughout the course of the study. A copy of the executed informed 
consent document will be given to the infant’s parent(s)/legal guardian for their records. The rights 
and welfare of the infants will be protected by emphasizing to their parent(s)/legal guardian that 
the quality of their medical care will not be adversely affected if they decline to allow their infant 
to participate in this study. For non-English speakers, a fully translated consent or an oral 
presentation accompanied by a short form may be used to obtain informed consent. The fully 
translated consent and the short form must be approved by the IRB and executed according to 
local requirements. 
The IND sponsor or designee will provide the investigator, in writing, any new information that 
bears significantly on the infants’ risk to receive the investigational product. This new information 
will be communicated by the investigator to infants’ parent(s)/legal guardian who have consented 
for their infant to participate in the trial in accordance with IRB requirements. The informed consent 
document will be updated, and infants’ legal guardians will be re-consented, if necessary. 
Site staff may employ IRB-approved recruitment efforts prior to informed consent; however, 
before any protocol-specific procedures are performed to determine protocol eligibility, informed 
consent must be obtained and properly executed. The investigator will choose infants in 
accordance with the eligibility criteria detailed previously. To prevent bias, the investigator will not 
exercise selectivity. 
By providing consent, the infant’s parent/legal guardian agrees that the infant will complete all 
evaluations required by the trial, unless the infant’s parent/legal guardian withdraws the infant 
voluntarily or the infant is withdrawn from the trial for any reason. 


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13 FUTURE USE OF STUDY DATA AND STORED 
SPECIMENS 
After study-specific testing is complete, information about the study, including study data, will be 
de-identified and submitted to the NIH data repository (https://dash.nichd.nih.gov; referred to 
below as “DASH”) in compliance with NIH policies on data sharing. Other researchers may submit 
requests to DASH to use these data for future, unspecified research. The NICHD DASH Data 
Access Committee reviews all requests to determine whether the proposed use of the data is 
scientifically and ethically appropriate. 
The de-identified photographs that were sent to the external raters and adjudicator will be 
destroyed after all study analyses and the FDA review of the study results are complete. 
PK samples will be labeled at the site with a study-provided barcode label. The barcode will only 
contain a unique code number without protected health information (PHI) or any other information 
that could identify the study participant. These samples will be stored at the site and then shipped 
to a central lab for study-specific PK testing. After analysis, these PK samples will be stored until 
the FDA completes review of the final research study report and proposed drug label changes. 
Once FDA review of the study results is complete, the samples will be destroyed. No other 
biospecimens will be collected or stored in this study. 
 


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14 SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
An electronic case report form (eCRF) will be used to record participation data. The eCRF will be 
used for the recording of all historical participant information and study data as specified by this 
protocol. The eCRF must be completed by designated and trained study personnel. 
According to ICH E6(R2), source data are defined as all information in original records and 
certified copies of original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents (original records or certified copies). Source documents are defined as original 
documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, 
memoranda, infant diaries or evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions certified after verification as being accurate 
and complete, microfiches, photographic negatives, microfilm or magnetic media, x- rays, 
participant files, and records kept at the pharmacy, at the laboratories, and at medico- technical 
departments involved in the clinical trial). 
It will be the responsibility of the investigator(s) to ensure that the regulatory binder at the site is 
maintained. The study file will contain, but will not be limited to: 
 
Current package inserts, and all previous versions 
 
Final study protocol 
 
Protocol amendments (if applicable) 
 
Manual of Procedures 
 
Informed consent form (blank) 
 
Signed informed consent form 
 
Revised informed consent forms and/or all addenda (blank) 
 
IRB registration or other documentation of IRB compliance with FDA regulations 
 
Documentation of IRB approval of protocol, consent form, any protocol 
amendments, and any consent form revisions 
 
Annual IRB updates and approvals 
 
All correspondence between the investigator and IRB 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6(R2), Section 4.9, and regulatory and institutional requirements for the 
protection of confidentiality of participants. Each site will permit authorized representatives of the 
sponsor, its designees, and appropriate regulatory agencies to examine (and, when required by 
applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, and 
evaluation of the study safety and progress. These representatives will be permitted access to all 
source data, which include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and participant files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments involved 
in the clinical trial. Case report forms will be derived from the eCRFs and provided by the Data 
Coordinating Center (DCC). 


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15 QUALITY CONTROL AND QUALITY ASSURANCE 
The principal investigator will provide direct access to all trial-related sites, source 
data/documents, case report forms, and reports for the purpose of monitoring and auditing by the 
sponsor, and inspection by local and regulatory authorities. The principal investigator will ensure 
that all study personnel are appropriately trained and applicable documentations are maintained 
on site. 
Clinical monitors will verify that the clinical trial is conducted and data are generated, documented 
(recorded), and reported in compliance with the protocol, Good Clinical Practice, and the 
applicable regulatory requirements. Clinical monitoring reports will be submitted to the PI, and 
NIH. 
The DCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for prompt clarification and resolution. 


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16  ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
 Ethical Standard 
The investigator will ensure that the study will be conducted in accordance with the protocol, the 
ethical principles of Good Clinical Practice [ICH E6(R2)] that have their origin in the Declaration 
of Helsinki, and all applicable national and local regulations. The investigator will ensure that the 
study is conducted in accordance with the provisions as stated and will comply with the prevailing 
local laws and customs. 
 Institutional Review Board 
Prior to enrollment of infants into this trial, the protocol, the informed consent form, and any 
materials or advertisements presented to infants’ parent/legal guardian will be reviewed and 
approved by the appropriate IRB. 
The responsible official for the IRB will sign the IRB letter of approval of the protocol prior to the 
start of this trial, and a copy will be provided to the DCC. Notification of the IRB's composition and 
the institution’s federal-wide assurance number (if applicable) will be provided to the DCC. 
If amendments to the protocol are required, the amendments will be written by the sponsor and 
provided to the investigator for submission and approval to the IRB. 
 Study Discontinuation 
If the study is discontinued, enrolled infants will continue to be followed for safety assessments 
for 7(+5) days. All adverse events must be followed through resolution. 


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17 DATA HANDLING AND RECORD KEEPING 
The investigator is obligated to conduct this study in accordance with U.S. Federal Regulation 21 
CFR 312.60-69 as specified on the signed form FDA 1572, applicable local laws, and the 
International Council for Harmonisation: Good Clinical Practice: Consolidation Guideline. The 
investigator is responsible for informing the IRB of any safety issues related to the study and the 
study drug, including reports of serious adverse events, if required, and all expedited safety 
reports. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported. 
Case report forms will be derived from the eCRFs and provided by the DCC to the sites to record 
and maintain data for each participant enrolled in the study. All source documents should be 
completed in a neat, legible manner to ensure accurate interpretation of data. Permanent ink is 
required to ensure clarity of reproduced copies. When making a change or correction, the original 
entry should be crossed out with a single line, and the change should be initialed and dated. Do 
not erase, overwrite, or use correction fluid or tape on the original. 
Data reported in the eCRF should be consistent with the case report form/source documents, or 
the discrepancies should be documented. The sponsor and/or its designee will provide guidance 
to investigators on making corrections to the case report forms and eCRFs. 
 Data Management Responsibilities 
All case report forms and laboratory reports must be reviewed by the clinical team and data entry 
staff, who will ensure that they are accurate and complete. Adverse events must be graded, 
assessed for severity and causality, and reviewed by the site principal investigator or designee. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site principal investigator. During the study, the investigator must maintain complete and accurate 
documentation for the study. 
The DCC for this study will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
 Data Capture Methods 
Clinical data (including AEs and concomitant medications) will be entered into a 21 CFR Part 
11-compliant internet data entry system provided by the DCC. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify data 
that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
case report forms/source documents/take home logs. 
Timolol data from the PTN POP01 study will be combined with the data obtained from this study 
for the exploratory PK analysis.  
 Timing/Reports 
The DMC will convene and make recommendations on study continuation based on the safety 
data collected periodically. 
 Study Records Retention 
Records and source documents pertaining to the conduct of this study must be retained by the 
Investigator for a period of 2 years following the date the application is approved for the drug for 
the indication for which it is being investigated; or, if no application is to be filed or if the application 
is not approved for such indication, until 2 years after the investigation is discontinued and FDA 


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is notified. No records will be destroyed without the written consent of the Sponsor. 
 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or manual of 
procedures requirements. The noncompliance may be on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly. 
These practices are consistent with Good Clinical Practice: 
4.5. Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1. Quality Assurance and Quality Control, section 5.1.1 
5.2. Noncompliance, sections 5.20.1, and 5.20.2 
It is the responsibility of the site to use continuous vigilance to identify and report deviations within 
5 working days of identification of the protocol deviation or within 5 working days of the scheduled 
protocol-required activity. All deviations must be promptly reported to the sponsor, via the DCC’s 
Internet Data Entry System (IDES). 
All deviations from the protocol must be addressed in study case report forms. A completed copy 
of the protocol deviation form must be maintained in the regulatory file. Protocol deviations must 
be submitted to the local IRB/IEC per their guidelines. The site PI/study staff is responsible for 
knowing and adhering to their IRB requirements. 
 Participant Privacy/Authorization 
The principal investigator will ensure that the use and disclosure of protected health information 
obtained during a research study complies with the HIPAA Privacy Rule. The rule provides U.S. 
federal protection for the privacy of protected health information by implementing standards to 
protect and guard against the misuse of individually identifiable health information of participants 
participating in clinical trials. Authorization is required from each research participant (i.e., specific 
permission granted by an individual to a covered entity for the use or disclosure of an individual’s 
protected health information). A valid authorization must meet the implementation specifications 
under the HIPAA Privacy Rule. Authorization will be combined in the informed consent document 
(approved by the IRB). 


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18  PUBLICATION POLICY 
Following completion of the study, the investigator may publish the results of this research in a 
scientific journal under the oversight of the Publication Committee of the Protocol. The Publication 
Committee comprises representatives of the network cores, thought-leaders, DCC, and is 
responsible for generation and coordination of the publications that report scientific findings of the 
network. All public presentations (abstracts, manuscripts, slides and text of oral or other 
presentations, and text of any transmission through any electronic media) by participating 
investigators, participating institutions, DCC, and those that use data and are intended to 
represent the sponsor or the PTN will be reviewed by the Publication Committee per the 
Publication Committee charter. 
The Publication Committee guarantees that the study results are presented by experts in the field 
that have working knowledge of the study design, implementation, data synthesis/analysis, and 
interpretation. The committee goals are to ensure that any confidential or proprietary information 
is protected, and that all appropriate statistical analyses have been included. 
The Publication Committee will adhere to the trials registration policy adopted by the International 
Committee of Medical Journal Editors (ICMJE) member journal. This policy requires that all 
clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored 
by the National Library of Medicine. Other biomedical journals are considering adopting similar 
policies. It is the responsibility of the IND holder to register this trial in an acceptable registry. 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
participants to intervention or comparison groups to study the cause-and-effect relationship 
between a medical intervention and a health outcome. Studies designed for other purposes, such 
as to study pharmacokinetics or major toxicity (e.g., phase I trials), would be exempt from this 
policy. 
All investigators funded by the NIH must submit or have submitted for them to the National Library 
of Medicine’s PubMed Central an electronic version of their final, peer-reviewed manuscripts upon 
acceptance for publication, to be made publicly available no later than 12 months after the official 
date of publication. The NIH Public Access Policy ensures the public has access to the published 
results of NIH-funded research. It requires investigators to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. Further, the policy stipulates that these papers must be accessible to the public on 
PubMed Central no later than 12 months after publication. Refer to: http://publicaccess.nih.gov/ 
and http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08- 033.html 


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19 LITERATURE REFERENCES 
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hemangiomas: an emerging health issue linked to an increased rate of low birth weight 
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Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile 
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Chu DH, Castelo-Soccio L, Wan J, et al. Retrospective analysis of beta-blocker instituted 
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Manunza F, Syed S, Laguda B, et al. Propranolol for complicated infantile 
haemangiomas: a case series of 30 infants. The British journal of dermatology. 
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Solman L, Murabit A, Gnarra M, Harper JI, Syed SB, Glover M. Propranolol for infantile 
haemangiomas: single centre experience of 250 cases and proposed therapeutic 
protocol. Arch Dis Child. 2014;99(12):1132-1136. 
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Luo Y, Zeng Y, Zhou B, Tang J. A retrospective study of propranolol therapy in   
635 infants with infantile hemangioma. Pediatr Dermatol. 2015;32(1):151-152. 
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Leaute-Labreze C, Dumas de la Roque E, Nacka F, et al. Double-blind randomized pilot 
trial evaluating the efficacy of oral propranolol on infantile haemangiomas in infants  
< 4 months of age. The British journal of dermatology. 2013;169(1):181-183. 
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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. The British journal of 
dermatology. 2015;172(1):24-32. 
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McMahon P, Oza V, Frieden IJ. Topical timolol for infantile hemangiomas: putting a note 
of caution in "cautiously optimistic". Pediatr Dermatol. 2012;29(1):127-130. 
13. 
Chambers CB, Katowitz WR, Katowitz JA, Binenbaum G. A controlled study of topical 
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hemangiomas. Ophthal Plast Reconstr Surg. 2012;28(2):103-106. 
14. 
Moehrle M, Leaute-Labreze C, Schmidt V, Rocken M, Poets CF, Goelz R. Topical 
timolol for small hemangiomas of infancy. Pediatr Dermatol. 2013;30(2):245-249. 
15. 
Oranje AP, Janmohamed SR, Madern GC, de Laat PC. Treatment of small superficial 
haemangioma with timolol 0.5% ophthalmic solution: a series of 20 cases. Dermatology. 
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Semkova K, Kazandjieva J. Rapid complete regression of an early infantile hemangioma 


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with topical timolol gel. Int J Dermatol. 2014;53(2):241-242. 
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Semkova K, Kazandjieva J. Topical timolol maleate for treatment of infantile 
haemangiomas: preliminary results of a prospective study. Clin Exp Dermatol. 
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Evaluation of short-term efficacy and safety in infants. Exp Ther Med. 
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Chakkittakandiyil A, Phillips R, Frieden IJ, et al. Timolol maleate 0.5% or 0.1% 
gel- forming solution for infantile hemangiomas: a retrospective, multicenter, cohort 
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Chan H, McKay C, Adams S, Wargon O. RCT of timolol maleate gel for superficial 
infantile hemangiomas in 5- to 24-week-olds. Pediatrics. 2013;131(6):e1739-1747. 
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Pope E, Chakkittakandiyil A. Topical timolol gel for infantile hemangiomas: a pilot study. 
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Pope E, Krafchik BR, Macarthur C, et al. Oral versus high-dose pulse corticosteroids for 
problematic infantile hemangiomas: a randomized, controlled trial. Pediatrics. 
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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. 
24. 
Frommelt P JA, Siegel D, Holland K, Seefeldt M, Yu J, Uhing M, Wade M, Drolet B 
Adverse Events in Young and Preterm Infants Receiving Topical Timolol for Infantile 
Hemangioma. Medical College of Wisconsin; 2014. 
25. 
Kiryazov K, Stefova M, Iotova V. Can Ophthalmic Drops Cause Central Nervous System 
Depression and Cardiogenic Shock in Infants? Pediatric Emergency Care. 
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in a neonate. Am J Ophthalmol. 1979;88(1):120-122. 
27. 
Plager DA, Whitson JT, Netland PA, et al. Betaxolol hydrochloride ophthalmic 
suspension 0.25% and timolol gel-forming solution 0.25% and 0.5% in pediatric 
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Korte JM, Kaila T, Saari KM. Systemic bioavailability and cardiopulmonary effects of 
0.5% timolol eyedrops. Graefes Arch Clin Exp Ophthalmol. 2002;240(6):430-435. 
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Passo MS, Palmer EA, Van Buskirk EM. Plasma timolol in glaucoma patients. 
Ophthalmology. 1984;91(11):1361-1363. 
30. 
Ma G, Wu P, Lin X, et al. Fractional carbon dioxide laser-assisted drug delivery of topical 
timolol solution for the treatment of deep infantile hemangioma: a pilot study. Pediatr 
Dermatol. 2014;31(3):286-291. 
31. 
Weibel L SH, Barysch M, Kongis I, Subotic U, Muller D, Schiestl C, Rentsch K. Topical 
Betablockers for infantile hemangiomas are effective but systemically absorbed. 
European Journal of Pediatric Dermatolgy. 2012;22(1):10-11. 


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32. 
Püttgen KA, Denise; Pope, Elena; McCuaig, Catherine; Feigenbaum, Dana; Savva, 
Yulia; Baselga, Eulalia; Holland, Kristen; Morel, Kimberly; Garzon, Maria; Nopper, Amy; 
Horii, Kim; Newell, Brandon; Frieden, Ilona. Timolol in the Treatment of Infantile 
Hemangiomas: Results of a Multicenter Cohort Study. Paper presented at: 73rd 
American Academy of Dermatology Annual Meeting2015. 
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http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72b0d0ec- 832a-4c25-b845-25
37ab506354. Accessed 05/01, 2015. 


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APPENDIX I 
Hemangioma Quality of Life Assessment (prototype) 
 
 


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APPENDIX II 
Hemangioma Dynamic Complication Scale