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    Clinical Trial Results:
    Efficacy and safety of Hemangiol solution in the treatment of high risk infantile hemangioma

    Summary
    EudraCT number
    2014-005555-80
    Trial protocol
    ES  
    Global end of trial date
    21 Feb 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Sep 2017
    First version publication date
    03 Sep 2017
    Other versions
    Summary report(s)
    CSR Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    V00400 SB 3 02
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    PIERRE FABRE DERMATOLOGIE
    Sponsor organisation address
    45 Place Abel Gance, Boulogne-Billancourt, France, 92100
    Public contact
    Clinical Trial Information Desk, PIERRE FABRE DERMATOLOGIE, 34 931850200, contact_essais_cliniques@pierre-fabre.com
    Scientific contact
    Dr Athmane Bouroubi, INSTITUT DE RECHERCHE PIERRE FABRE, 33 534506345, athmane.bouroubi@pierre-fabre.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To document the efficacy of Hemangiol administered during at least 6 months and upto a maximum of 12 months of age in infants with high risk infantile haemangioma (IH)
    Protection of trial subjects
    The study was conducted in compliance with GCP (CPMP/ICH/135/95), ethical principles that have the origins in the amended version of the Declaration of Helsinki, and all SOPs interne to Pierre Fabre. Trial subjects were infants aged 35 to 142 days (corrected age) at inclusion. The informed consents were obtained from parents prior to screening. The information consent form, in the local language of the 2 participating countries (Spanish in Spain and Polish in Poland), detailled the procedures involved, the aims, methodology, constraints, potential risks to the study subject and the rights of the parents to withdraw consent at any stage or time of the study. The investigators exposed in detail to the parents, in a layman language the what, the why and the how of the study.
    Background therapy
    No other therapies, (other than the subject's usual treatments which do not fall in the non-inclusion criteria defined in the protocol), were administered in the framework of the study.
    Evidence for comparator
    This is a single arm, non comparative study carried out in real clinical situation.
    Actual start date of recruitment
    29 Jun 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 24
    Country: Number of subjects enrolled
    Spain: 21
    Worldwide total number of subjects
    45
    EEA total number of subjects
    45
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    45
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were recruited within the medical consultations of physicians who are familiar with the management of IH (4 centres in Poland, 6 in Spain): infants with severe IH in proliferative phase, in the age group 25 to 142days (corrected age). The included subjects had to be able to complete the initial treatment period (6 months) before age 1 year

    Pre-assignment
    Screening details
    46 subjects aged, 35 - 150 days (corrected age for premature infants), with high risk IH and, in accordance with Hemangiol SmPC were screened and 45 patients were included in the study. The one patient excluded did not meet the 35 - 150 days age criteria.

    Pre-assignment period milestones
    Number of subjects started
    46 [1]
    Number of subjects completed
    45

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Age criteria not met: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 46 patients were screened for enrolment and 45 patients were definitely enrolled in the study as an inclusion criterion was not met for one patient
    Period 1
    Period 1 title
    Initial Treatment Period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Hemangiol
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    HEMANGIOL
    Investigational medicinal product code
    V00400SB
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Dose titration: 1mg/kg/day from Day 1 - 7 2mg/kg/day from Day 8 - 14 3mg/kg/day up to the end of the initial treatment period. Orally, twice daily (morning and late afternoon) during or straight after a feed.

    Number of subjects in period 1
    Hemangiol
    Started
    45
    Basic 6 month treatment
    44
    Completed
    43
    Not completed
    2
         Lack of efficacy
    1
         Consent withdrawn by subject
    1
    Period 2
    Period 2 title
    Follow-up Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Hemangiol FU
    Arm description
    Patients in success at the end of the initial treatment period
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [2]
    Hemangiol FU
    Started
    34
    Completed
    34
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 43 patients completed the initial treatment period but only the patients in success at the end of this period (n=34) entered the follow-up period as per protcocol.
    Period 3
    Period 3 title
    Retreatment period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Retreatment
    Arm description
    Patients in success at the end of the initial treatment period and who had success regression during the follow-up period
    Arm type
    Experimental

    Investigational medicinal product name
    HEMANGIOL
    Investigational medicinal product code
    V00400SB
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Dose titration: 1mg/kg/day from Day 1 - 7 (re-treatment period) 2mg/kg/day from Day 8 - 14 (re-treatment period) 3mg/kg/day up to the end of the re-treatment period. Orally, twice daily (morning and late afternoon) during or straight after a feed.

    Number of subjects in period 3 [3]
    Retreatment
    Started
    8
    Completed
    8
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only 8 of the 34 patients who were in success at the end of the initial treatment period needed to be re-treated in the Investigator's opinion during the follow-up period (success regression) and entered the re-tretreatment period as per protocol.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Initial Treatment Period
    Reporting group description
    -

    Reporting group values
    Initial Treatment Period Total
    Number of subjects
    45 45
    Age categorical
    Units: Subjects
        Infants 35 - 150 days
    45 45
    Age continuous
    Units: days
        median (inter-quartile range (Q1-Q3))
    44 (44 to 50) -
    Gender categorical
    Units: Subjects
        Female
    33 33
        Male
    12 12
        Gender
    0 0

    End points

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    End points reporting groups
    Reporting group title
    Hemangiol
    Reporting group description
    -
    Reporting group title
    Hemangiol FU
    Reporting group description
    Patients in success at the end of the initial treatment period
    Reporting group title
    Retreatment
    Reporting group description
    Patients in success at the end of the initial treatment period and who had success regression during the follow-up period

    Subject analysis set title
    PP set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    FAS patients without major deviations or any bias for primary criterion assessment

    Primary: Primary Criterion - Success rate at the end of the initial treatment period (FAS)

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    End point title
    Primary Criterion - Success rate at the end of the initial treatment period (FAS) [1]
    End point description
    The primary outcome measure was treatment success at the end of the initial treatment period. Success was determined by the Investigator and was defined as the resolution of the target IH and the absence of functional impact linked to the target IH.
    End point type
    Primary
    End point timeframe
    11 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis was purely descriptive with no p value provided as the trial was non comparative for ethical reasons: the primary endpoint was the success rate at the end of the initial treatment period with Hemangiol(R) (after 6 months or until success before one year of age) and this rate was 34/45=75.6% 95% CI [61.7;86.3]. Of note the number of patients in success ("34") is specified in the field labelled "Count". The same has been done for the other efficacy endpoints.
    End point values
    Hemangiol
    Number of subjects analysed
    45
    Units: yes / no
    34
    No statistical analyses for this end point

    Secondary: Success rate at 6 months (FAS)

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    End point title
    Success rate at 6 months (FAS)
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Hemangiol
    Number of subjects analysed
    45
    Units: yes / no
    21
    No statistical analyses for this end point

    Secondary: Success rate after re-Initiation of treatment (retreated FAS subset)

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    End point title
    Success rate after re-Initiation of treatment (retreated FAS subset)
    End point description
    The number (%) of patients in success after re-initiation of treatment in the subset of patients who were in success at the end of the initial treatment period and had a success regression during the follow-up period.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Retreatment
    Number of subjects analysed
    8
    Units: yes / no
    7
    No statistical analyses for this end point

    Other pre-specified: Primary criterion (PP)

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    End point title
    Primary criterion (PP)
    End point description
    Number of PP patients in success at the end of the initial treatment period
    End point type
    Other pre-specified
    End point timeframe
    11 months
    End point values
    PP set
    Number of subjects analysed
    40
    Units: yes / no
    31
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Whole study period after first administration (initial treatment period + Follow-up + retreatment)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Full analysis set
    Reporting group description
    All patients treated

    Serious adverse events
    Full analysis set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 45 (17.78%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Thermal burn
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ulcerated haemangioma
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemangioma
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Choking
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis rotavirus
    Additional description: TESAE; Moderate; No causuality
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    Full analysis set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 45 (80.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Infantile haemangioma
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    4
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    8 / 45 (17.78%)
         occurrences all number
    14
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    8
    Rhinorrhoea
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    10 / 45 (22.22%)
         occurrences all number
    19
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Nightmare
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Sleep disorder
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Gastrointestinal disorders
    Teething
         subjects affected / exposed
    7 / 45 (15.56%)
         occurrences all number
    12
    Vomiting
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    13
    Abdominal pain
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    4
    Diarrhoea
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    10 / 45 (22.22%)
         occurrences all number
    13
    Conjunctivitis
         subjects affected / exposed
    9 / 45 (20.00%)
         occurrences all number
    9
    Nasopharyngitis
         subjects affected / exposed
    9 / 45 (20.00%)
         occurrences all number
    21
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 45 (17.78%)
         occurrences all number
    12
    Pharyngitis
         subjects affected / exposed
    6 / 45 (13.33%)
         occurrences all number
    6
    Bronchiolitis
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    6
    Ear infection
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Laryngitis
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Respiratory tract infection
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Tonsillitis
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2015
    Replacement of “relapse” by “success regression” throughout protocol. Success regression, based on the Investigator’s opinion could lead to 3 options: re-initiation, follow-up without re-initiation, withdrawal. Visits: renumbering of visits as D1, D8 and D15 (instead of D0, D7 and D14). Instructions to patients: clarification that syringes included in study treatment should be returned to the study centre. Note: as these above points were mentioned in the information leaflet, an additional information leaflet and corresponding ICF was prepared for signature by all patients’ parents at the time of amendment approval. Number of patients: clarification that the number of ulcerated IHs (as main severity reason) limited to 2 patients per centre. Recruitment per centre capped to 8 patients maximum to avoid excessive influence of any given centre. Note: these two criteria were met by the previous 41 patients enrolled under the initial protocol. Precisions to procedures in case of safety issues at titration and/or in case of lower respiratory tract infection (LRTI): In case of safety issue at dose increase, the dose could be postponed 2 times/dose (1 week between 2 attempts). If after the third attempt (i.e. 1 initial attempt + 2 additional) the safety issue remains, treatment was definitively stopped and patient withdrawn. In case of bronchitis or LRTI, treatment was stopped immediately until full recovery. Re-administration did not necessitate an up-titration (i.e. full maintenance dose can be given directly). BP and HR limits modified to take into account chronological age instead of corrected age. As chronological age may be greater than corrected age, BP and HR limits for age > 150 days were added to the exclusion criteria. Note: as recruitment was nearing completion at the time of the amendment, this change was implemented at statistical analysis. The BP and HR limit modification was with regard to 2 patients born prematurely (chronological age of 191 and 211

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None
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