Neoplasms

All Conditions

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Hemangioma

Hemangioma, Capillary

Port-Wine Stain

Neoplasms, Vascular Tissue

Neoplasms by Histologic Type

Congenital Abnormalities

Skin Abnormalities

Skin Diseases

Anti-Arrhythmia Agents

Antihypertensive Agents

Vasodilator Agents

All Drugs and Chemicals

Propranolol

Atenolol

Adrenergic beta-Antagonists

Adrenergic Agents

Adrenergic Antagonists

Neurotransmitter Agents

Sympatholytics

Adrenergic beta-1 Receptor Antagonists

Oral propranolol 1mg/kg/day as crushed tablets, in two divided doses, increased to 2mg/kg/day in two divided doses after 24 hours if tolerated well. Treatment will be stopped at complete clinical clearance of lesion (defined arbitrarily as \>90% reduction in the size of Infantile Hemangioma as assessed by Physician Global Assessment) or after 9 months of treatment (primary end point) whichever is earlier.

Oral atenolol 0.5mg/kg as a single dose, increased to 1mg/kg as a single dose after 24 hours if tolerated well. Treatment will be stopped at complete clinical clearance of lesion (defined arbitrarily as \>90% reduction in the size of Infantile Hemangioma as assessed by Physician Global Assessment) or after 9 months of treatment (primary end point) whichever is earlier.

oral propranolol 1-2mg/kg/day as crushed tablets in two divided doses

oral propranolol

oral atenolol 0.5-1mg/kg/day as crushed tablets in a single dose

oral atenolol

Raihan Ashraf, MBBS

RAHUL MAHAJAN, MBBS, MD, MNAMS

Rahul Mahajan, MBBS, MD, MNAMS

Through this study, the investigators shall compare the effectiveness of atenolol with propranolol in the treatment of IH. In addition, the investigators shall try to elucidate the mechanism of action of beta blockers by assessing their action on triggers such as hypoxia. The study design will be a parallel group comparative study wherein patients of IH will be randomized into two groups. One group will receive propranolol and the other atenolol for a maximum period of 9 months. The patients will then be followed up regularly for regression of the IH based on Physician global assessment, hemangioma activity score(HAS), serial photography and lesional ultrasonography. Any side effects encountered during the treatment period will also be noted. Also serial measurements of hypoxia inducible factor 1 alpha(HIF-1α) will be made to ascertain the mechanism of action of the drugs.

AIMS AND OBJECTIVES:

1. To compare the effectiveness and safety of oral atenolol versus oral propranolol in the treatment of infantile hemangiomas.
2. To elucidate the mechanism of action of atenolol and propranolol in the treatment of infantile hemangiomas.

STUDY DESIGN MATERIALS AND METHODS:

This investigator-initiated, prospective, observer blinded, parallel group comparative study on the effect of oral medication in infantile cutaneous hemangiomas is being conducted in the Department of Dermatology, Venereology and Leprology, and Pediatric Surgery, Post Graduate Institute of Medical Education and Research, after getting approval from the institutional Research and Ethics Committee.

Sample size: As this is a pilot study, an arbitrary sample size of 60 (30 in each group) was decided to be kept.

BASELINE CLINICAL ASSESSMENT:

Children satisfying the inclusion and exclusion criteria will be recruited into the study after obtaining an informed consent from the parents. Upon recruitment, each lesion will be evaluated clinically for size, colour, consistency and the phase of evolution- whether proliferative, plateau or regressing. Photographs will be taken along with Physician Global assessment scale and hemangioma activity score (HAS).26 Heart rate, BP, oxygen saturation, ECG , respiratory rate and random blood sugar will be recorded to rule out treatment contraindications. In patients with eyelid involvement, ophthalmologic examinations will be done. These observations will be noted in the case record form.

All patients will be admitted for 48 hours at initiation of treatment and escalation of dosage to record and monitor all parameters- heart rate, BP, blood sugar, oxygen saturation and respiratory rate.

RANDOMISATION, ALLOCATION, CONCEALMENT AND TREATMENT PROTOCOL Upon inclusion, patients will be randomized into two groups; group A and group B, using a computer generated sequence (block randomization). Efforts will be made to reduce recruitment bias by the following allocation concealment. Patients will be screened by Dr Raihan Ashraf and recruited by Dr Sanjeev Handa, Dr Dipankar De and Dr Muneer Abas. Allocation to either group will be done by Mrs Asha based on block randomization. Thereafter, Dr Rahul Mahajan will prescribe the oral drug based on the group to which the patient is allotted such that the parents of the patient are not blinded to the drug administered. The child shall be admitted to Advanced Paediatric Centre for monitoring of parameters by Dr Raihan Ashraf. At follow up assessment will be done by Dr Raihan Ashraf blinded to the randomization and allocation.

Evaluation of improvement will be done by the following means

1. Physician Global Assessment: Score will be calculated by an independent dermatologist blinded to the management protocol with the help of photographs, at baseline and monthly thereafter. Serial Photography will be done at every 4 weeks.

   (The lesion will be photographed with and without flash with a standard 12 pixel digital camera at 30cm distance and approximately 180 dpi resolution)
2. HAS. Score will be calculated at baseline and monthly thereafter.
3. Ultrasonography : to objectively assess the size and depth of hemangioma will be done at baseline, 6 months and 9 months.

RECORDING OF ADVERSE EVENTS:

All the subjects will be reviewed at 1 month intervals. A full clinical examination will be performed during each visit, including growth chart measurements and cardiovascular status and any side effects like sleep disturbances, hypoglycemia, hypotension will be recorded in the case record form. Mild side effects will be recorded and managed. Serious side effects will be reported to the Safety committee and the patient withdrawn from the study.

LABORATORY EVALUATION Serum Hypoxia inducible factor 1α (HIF-1α) will be measured by ELISA at baseline and 9 months or completion of treatment.

PRIMARY OUTCOME MEASURES:

1. Mean difference in

   1. Number of patients achieving complete clinical clearance of lesion (PGA Score of 5) in the two groups
   2. Number of days required to achieve complete clinical clearance of lesion (PGA Score of 5) in the two groups
   3. Mean decrease in the volume of lesions in the two groups
   4. Mean decrease in HAS in the two groups
2. Frequency of adverse effects (minor and serious) in Group A versus Group B.

SECONDARY OUTCOME MEASURES:

1. Mean difference in HIF-1α levels before and after treatment in Group A and Group B.

STATISTICAL ANALYSIS The statistical analysis will be carried out using Statistical package for Social Sciences (SPSS Inc.,Chicago IL, version 15.0 Windows). The analysis will be done both for Per Protocol population( PP) as well as the Intention to Treat( ITT) population as primary population for analysis. All quantitative variables will be estimated using measures of central location (mean, median) and measures of dispersion (standard deviation and standard error). Normality of data will be checked by measures of skewness and Kolmogorov Smirnov tests of normality. For normally distributed data means will be compared using student's t test for groups. For skewed data Mann Whitney test will be applied for group. Qualitative or categorical variables will be described as frequencies and proportions. Proportions will be compared using Chi square or Fischer's exact test whichever is applicable. All statistical tests will be two sided and performed at a significance of α=0.05.

ETHICAL JUSTIFICATION Since the widespread use of propranolol for the use of infantile hemangiomas, there have come to light various side effects it may cause. Though usually mild and few, rare complications like asymptomatic hypoglycemia, hypotension and bronchial hyperreactivity can be life threatening. The proposed study aims to overcome these side effects with the use of cardio selective beta blocker atenolol which have safely been used in infants previously for cardiological indications like arrhythmias. In addition, it gives a reasonable treatment alternative for infants in whom propranolol is contraindicated. Furthermore, the exact magnitude of CNS effects resulting from propranolol use, especially in the early developmental stages is not currently known. Impairment in short- and long-term memory, psychomotor function, sleep quality and mood have been reported. These effects may not be readily recognizable and require specialized assessment of cognitive function not routinely performed. Furthermore, there may be a delay between exposure and cognitive defects. These side effects would theoretically be alleviated with the use of atenolol due to its impermeability through the blood brain barrier.

The investigations planned are necessary for the optimum management of participants. All blood samples will be taken with a 26 gauge needle so that there is minimal pain and discomfort to the patient and the amount of blood drawn for investigations will not cause any haemodynamic instability.

According to the guidelines set up by ICMR (1994) and Helsinki declaration (modified 2000), the following will be adhered in all patients enrolled in the study:

* The patients involved in the research project will be informed participants.
* Each patient will be adequately informed of the aims, methods, the anticipated benefits and potential risks of the study and the discomfort it may entail to him/her and the remedies thereof.
* Every precaution will be taken to respect the privacy of the patient, the confidentiality of the patient's information and to minimize the impact of the study on his/her physical and mental integrity and his/her personality.
* The patient will be given the right to abstain from participation in the study or to withdraw consent to participate at any time of the study without reprisal.
* Due care and caution will be taken at all stages of the research to ensure that the patient is put to the minimum risk, suffer from no irreversible adverse effects and, generally, benefit from and by the research or experiment.
* Written informed consent will be obtained from all the patients included in the study.

Comparative Study to Evaluate the Effectiveness of Atenolol and Propranolol in the Treatment of Infantile Hemangiomas

Physician Global Assessment

Responses to therapy (change of thickness, color, and area) will be recorded on each follow up.The therapeutic responses will be evaluated on a score of 1-5 as follows by an independent dermatologist who will not know the therapies:

Score 5: \>90% improvement or complete clinical involution Score 4: excellent improvement(75-90% decrease) Score 3: good improvement(50-74% decrease) Score 2: minimal improvement( 25-49% decrease) Score 1: poor improvement(1-24% decrease) Score 0: failure (no difference or regrowth)

Hemangioma Activity score

Patient name:

Age:

Location of infantile hemangioma:

("Bright red edge" should only be scored when the HOI is not totally "bright red" Skin colored after activity". Do not score in deep HOI (deep swelling) unless the HOI has changed into it after activity)

Date

Deep swelling:

tense HOI(6) 'neutral' HOI at t=0 or less than 50% reduction at follow up(4) \>=50% reduction at follow up (2) No more swelling at follow up (0)

Bright red/ shining red HOI(5) OR bright red edge(4) Matt red/reddish purple HOI/ matt red edge(3) Blue HOI or Blue shining through in deep HOI(2) Grey HOI(1) Skin colored after activity(0)

Total score:

Number of items scored Preliminary HAS= total score/number of items scored

Ulcer=\<1cm2 (+0.5) Ulcer 1-25cm2(+1) Ulcer \>=25cm2(+2) HAS= preliminary HAS + ulcer score

Post Graduate Institute of Medical Education and Research, Chandigarh

Junior Resident, Department of Dermatology

Pharmaceutical Solutions

Anti-Infective Agents

Ophthalmic Solutions

Captopril

Timolol

Maleic acid

Enzyme Inhibitors

Angiotensin-Converting Enzyme Inhibitors

HIV Protease Inhibitors

Protease Inhibitors

oral propranolol therapy at a dose of 1 mg/kg/d (Inderal 20 mg/5 mL) in three divided doses. If the child will tolerate the treatment with no side effects, therapy will continue in an outpatient clinic. Blood glucose level will be also measured in a periodic manner during therapy. The dose will be increased gradually to 2 mg/kg/d in three divided doses if there will be no adverse effects from the initial therapy.

A test dose of 0.1 mg kg) will be administered orally with pulse rate and blood pressure monitored at 0.5, 1 and 2 h and at each follow up. If the test dose is tolerated, captopril administration will start at 0.15 mg kg) per dose 8-hourly. Pulse rate and blood pressure will be monitored 4-hourly and doses will be withheld if hypotension is documented. After 24 h, the dose will be increased to 0.3 mg kg) per dose 8-hourly .

Oral Captopril

intralesional propranolol injection 1 mg/mL

intralesional propranolol injection

To be Applied on the surface of the lesions three times daily

topical Timolol maleate 0.5% eye drops

Atta

Ayman El-Baghdadi, MD

Ayman El-Boghdadi, MD

Rana Atta, BSc

Is to compare and evaluate the efficacy of oral captopril with oral propranolol, intralesional propranolol injection, and topical Timolol in the treatment of infantile hemangioma and their effect on vascular endothelial growth factor and CD 133.

Infantile hemangiomas are the most common benign tumor of infancy, affecting up to 10% of the pediatric population with a higher incidence in female (3:1), preterm infants, and Caucasian population. The molecular mechanisms underlying pathogenesis remain incompletely understood, but the clinical course follows a stereotyped pattern: a phase of early vascular proliferation over the first year of life followed by a gradual phase (1 to7 years in duration) of spontaneous involution and replacement of vascular channels by fibro-fatty tissue. Despite their benign nature,in certain cases IHs can cause severe morbidities and therefore sometimes require medical intervention.

Vascular endothelial growth factor A is the predominant growth factor associated with endothelial proliferation, migration, and survival. Vascular endothelial growth factor, being a potent inducer of vascular permeability, is known to cause edema and lead to formation of hemangiomas in high concentrations along with CD133 is a transmembrane glycoprotein which represents a cell surface marker for hemangioma-derived stem cells (HemSCs). CD133-positive HemSCs can still be diﬀerentiated into hemangiomas, suggesting that CD133-positive HemSCs have continuous ability to form hemangiomas. Targeted elimination of CD133-positive HemSCs could fundamentally inhibit the proliferation of hemangioma.

Aim of the study is to compare and evaluate the efficacy of oral captopril with oral propranolol, intralesional propranolol injection, and topical Timolol in the treatment of infantile hemangioma and their effect on vascular endothelial growth factor and CD 133.

Methodology : Open label Randomized Controlled trail will be carried out at Vascular malformation clinic of Pediatric Surgery department of Ain Shams University ,Patients of the study will be randomly allocated equally into 4 groups (A, B, C, D), 25 patients each.

* Group A: Subjected to oral propranolol therapy at a dose of 2 mg/kg/d in three divided doses.
* Group B: Oral Captopril will be administered as a test dose of 0.1 mg kg orally with pulse rate and blood pressure monitored at 0.5, 1 and 2 h and at each follow up. If the test dose is tolerated, captopril administration will start at 0.15 mg/ kg) per dose 8-hourly. Pulse rate and blood pressure will be monitored 4-hourly and doses will be withheld if hypotension is documented. After 24 h, the dose will be increased to 0.3 mg/ kg) per dose 8-hourly.
* Group C: Subjected to intralesional propranolol injection 1 mg/mL. The volume of injected drug depends on the size of the lesion (0.2 mL will be injected per cm of lesion diameter), with a maximum volume of 1 mL for a lesion of 5 cm diameter
* Group D: Subjected to topical Timolol maleate 0.5% eye drops on the surface of the lesions three times daily and gentamycin ointment will be applied around the lesions to prevent the timolol from leaking.

Following up: Venous blood samples will be withdrawn from all study participants at study entry and after 6 months of treatment for assessment of serum levels of VEGF and CD 133 by ELISA technique along with the size of the lesion.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Comparative Study to Evaluate the Effectiveness of Atenolol and Propranolol in the Treatment of Infantile Hemangiomas	NCT03237637	Infantile Heman...	oral propranolo... oral atenolol	- 12 Months	PGIMER
Evaluation of the Efficacy of Captopril Versus Propranolol and Timolol as a Treatment of Infantile Capillary Hemangioma	NCT04288700	Infantile Heman...	oral propranolo... Oral Captopril intralesional p... topical Timolol...	2 Months - 12 Years	Ain Shams University
Comparative Study to Evaluate the Effectiveness of Atenolol and Propranolol in the Treatment of Infantile Hemangiomas	NCT03237637	Infantile Heman...	oral propranolo... oral atenolol	- 12 Months	PGIMER

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