Clinical Trial Results:
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
Summary
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EudraCT number |
2013-005199-17 |
Trial protocol |
ES |
Global end of trial date |
09 Jan 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Jul 2021
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First version publication date |
02 Jul 2021
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Other versions |
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Summary report(s) |
summary |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
IIBSP-TIM-2013-156
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02731287 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau - IIB Sant Pau
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Sponsor organisation address |
Sant Quintí 77-79, Barcelona, Spain, 08041
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Public contact |
Enrique Peña, Institut de Recerca HSCSP, 34 935537636, epenag@santpau.cat
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Scientific contact |
Enrique Peña, Institut de Recerca HSCSP, 34 935537636, epenag@santpau.cat
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
26 Nov 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
09 Jan 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Jan 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To determine the efficacy of timolol maleate 0.5% solution in the treatment of infantile hemangiomas surface during the early proliferative stage.
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Protection of trial subjects |
This study has been organized in accordance with the Declaration of Helsinki, the Good Clinical Practice guidelines and national regulations.
The study protocol has been reviewed by an Ethics Committee, whose task is to verify that the necessary requirements for the protection of the nursing baby and her rights have been met. The Ethics Committee issued a favorable opinion before the start of the study.
The study protocol has been sent to the health authorities and they have authorized it.
The doctor treating has been informed of the nursing baby's participation in this clinical trial. Likewise, they will be given a patient file with the contact details of the sponsor / researcher, the study drug and the indication.
The sponsor of the study has an insurance policy that complies with current legislation and compensation will be granted in the event of deterioration of health or injury that may occur in relation to the infant's participation in the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
06 Oct 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 70
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Worldwide total number of subjects |
70
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EEA total number of subjects |
70
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
70
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Seventy patients were included in this study. Thirty-three patients were randomly distributed in the treatment group (timolol) and 37 patients were distributed in the same way in the placebo group.In the timolol group, 22 patients completed the 36th week follow-up and in the placebo group just 25 patients. | |||||||||||||||||||||
Pre-assignment
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Screening details |
-Growth / ulceration of the lesion. Change to propranolol (n = 7) -Parents notice lack of effectiveness and want to do off-label treatment (n = 3) -Loss of follow-up / Refusal to finish the study (n = 12) -Fail screening (n=1) | |||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
70 | |||||||||||||||||||||
Number of subjects completed |
70 | |||||||||||||||||||||
Period 1
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Period 1 title |
Week 0
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Data analyst | |||||||||||||||||||||
Blinding implementation details |
The protocol has been designed as a double-blind, placebo-controlled study. The assignment of treatments will be done blindly. The package and label product's look similar. Researchers and parents or legal guardians doesn't know what product patients receive during the study.
Participants have been randomized with a 1: 1 ratio. Randomization has been managed by an independent randomization team carried out by the Department of Pharmacy (HSCSP)
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Timolol group | |||||||||||||||||||||
Arm description |
Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Timolol maleate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Ear/eye drops, solution
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Routes of administration |
Ophthalmic use
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Dosage and administration details |
Dosage: 2 drops / 12 hours
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Arm title
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Placebo group | |||||||||||||||||||||
Arm description |
Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Saline solution
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Ear/eye drops, solution
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Routes of administration |
Ophthalmic use
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Dosage and administration details |
Dosage: 2 drops / 12 hours
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Period 2
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Period 2 title |
Week 12
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Is this the baseline period? |
No | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Investigator, Monitor, Subject, Data analyst | |||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Timolol group | |||||||||||||||||||||
Arm description |
Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Timolol maleate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Ear/eye drops, solution
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Routes of administration |
Ophthalmic use
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Dosage and administration details |
Dosage: 2 drops / 12 hours
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Arm title
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Placebo group | |||||||||||||||||||||
Arm description |
Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Saline solution
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Ear/eye drops, solution
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Routes of administration |
Ophthalmic use
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Dosage and administration details |
Dosage: 2 drops / 12 hours
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Period 3
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Period 3 title |
Week 24
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Is this the baseline period? |
No | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst | |||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Timolol group | |||||||||||||||||||||
Arm description |
Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Timolol maleate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Ear/eye drops, solution
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Routes of administration |
Ophthalmic use
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Dosage and administration details |
Dosage: 2 drops / 12 hours
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Arm title
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Placebo group | |||||||||||||||||||||
Arm description |
Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Saline solution
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Ear/eye drops, solution
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Routes of administration |
Ophthalmic use
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Dosage and administration details |
Dosage: 2 drops / 12 hours
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Period 4
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Period 4 title |
Week 36
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Is this the baseline period? |
No | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst | |||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Timolol group | |||||||||||||||||||||
Arm description |
Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Timolol maleate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Ear/eye drops, solution
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Routes of administration |
Ophthalmic use
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Dosage and administration details |
Dosage: 2 drops / 12 hours
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Arm title
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Placebo group | |||||||||||||||||||||
Arm description |
Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Saline solution
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Ear/eye drops, solution
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Routes of administration |
Ophthalmic use
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Dosage and administration details |
Dosage: 2 drops / 12 hours
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Baseline characteristics reporting groups
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Reporting group title |
Timolol group
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Reporting group description |
Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops | ||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo group
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Reporting group description |
Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops | ||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Timolol group
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Reporting group description |
Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops | ||
Reporting group title |
Placebo group
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Reporting group description |
Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops | ||
Reporting group title |
Timolol group
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Reporting group description |
Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops | ||
Reporting group title |
Placebo group
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Reporting group description |
Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops | ||
Reporting group title |
Timolol group
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Reporting group description |
Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops | ||
Reporting group title |
Placebo group
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Reporting group description |
Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops | ||
Reporting group title |
Timolol group
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Reporting group description |
Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops | ||
Reporting group title |
Placebo group
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Reporting group description |
Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops | ||
Subject analysis set title |
Eficacy evaluation
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Cualitative evaluation of Childish Hemangioma (CH):
-Color intensity
-Surface component
-Hemangioma resolution compared to baseline
-Evolution of the resolution of the hemangioma compared to the previous visit
-Evaluation of the hemangioma compared to the baseline
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End point title |
Resolution of Childish Hemangioma (CH) | ||||||||||||||||||||||||||||||
End point description |
The primary endpoint (complete /almost complete or not) will be evaluated comparing the cualitative characteristics of the CH pictures took between the 24 week and the basal visit. Success rates will be based on centralized independent qualitative assessments, that will be described in the complete set of analyzes by treatment group and time of evaluation (W12 and W24).
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End point type |
Primary
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End point timeframe |
the 24th week
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Statistical analysis title |
Resolution comparative | ||||||||||||||||||||||||||||||
Statistical analysis description |
This analysis will allow to know if there is a stadistic difference between Timolol and Placebo group.
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Comparison groups |
Placebo group v Timolol group
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Number of subjects included in analysis |
60
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Analysis specification |
Post-hoc
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Analysis type |
equivalence | ||||||||||||||||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||||||||||||||||
Method |
Fisher exact | ||||||||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||||||||||||
Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||
sides |
1-sided
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lower limit |
- | ||||||||||||||||||||||||||||||
upper limit |
- |
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End point title |
Size of CH | |||||||||||||||||||||||||||||||||||
End point description |
Evaluations will be made regarding the volume and thickness of HI in weeks 2, 4, 8, 12, 24 and 36. The data obtained will be expressed in percentages (%). The average of both measurements will be taken into account to determine the evolution of the HI with respect to the treatment and the evaluation time, using the Wilcoxon test. Any value of P <0.05 will be considered significant.
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End point type |
Secondary
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End point timeframe |
Weeks: 12,24
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Attachments |
Size of CH |
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Statistical analysis title |
Evolution of CH between treatment and time of eval | |||||||||||||||||||||||||||||||||||
Comparison groups |
Timolol group v Placebo group
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Number of subjects included in analysis |
47
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Analysis specification |
Post-hoc
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Analysis type |
equivalence | |||||||||||||||||||||||||||||||||||
P-value |
< 0.05 | |||||||||||||||||||||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | |||||||||||||||||||||||||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
After drug administration and durig the 36 weeks of follow-up.
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Adverse event reporting additional description |
treatment group, patient code, sex and age, term notified by the investigator, preferred term, starting day based on the date of the first administration of the study treatment, duration, measure taken in relation to the administration of the treatment of the study, use of a corrective treatment, outcome and relationship with the treatment
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
Timolol group
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Reporting group description |
Timolol maleate 0.5% solution (ophthalmic eye drops) Dosage: 2 drops / 12 hours Route of administration: topical Pharmaceutical form: ophthalmic eye drops | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo group
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Reporting group description |
Saline solution (ophthalmic eye drops) Dosage: 2 drops c / 12 hrs Route of administration: topical Pharmaceutical form: ophthalmic eye drops | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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17 Mar 2015 |
The amentment was done for including a new investigative site (Hospital Virgen de la Macarena- Virgen del Rocío en Sevilla) changing the protocol bversion ( V5.0) and the ICF (V3.0) |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |