Efficacy and safety of Hemangiol solution in the treatment of high risk infantile hemangioma. A Multinational Single Arm Study

• Register: EUCTR
• Last refreshed on: 13 March 2017
• Main ID: EUCTR2014-005555-80-ES
• Date of registration: 14/04/2015
• Prospective Registration: Yes
• Primary sponsor: Pierre Fabre Dermatologie represented by IRPF
• Public title: Efficacy and safety of Hemangiol solution in the treatment of high risk infantile hemangioma. A Multinational Single Arm Study
• Scientific title: Efficacy and safety of Hemangiol solution in the treatment of high risk infantile hemangioma. A Multinational Single Arm Study
• Date of first enrolment: 21/05/2015
• Target sample size: 45
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-005555-80
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: Open: Single blind: Double blind: Parallel group: Cross over: Other: If controlled, specify comparator, Other Medicinial Product: Placebo: Other:
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Spain

Contacts

• Name: Clinical Trial Information Desk
• Affiliation: PIERRE FABRE MEDICAMENT

• Name: Clinical Trial Information Desk
• Affiliation: PIERRE FABRE MEDICAMENT

Key inclusion & exclusion criteria

Inclusion criteria:
1. Age 35-150 days old inclusive, also subject born prematurely but of his/her term equivalent age at inclusion (corrected age)
2. High risk IH in proliferative phase (target hemangioma):
- life-threatening IH
- peri-orbital, nasal, labial, laryngo-tracheal, limb joints IHs with functional impact or at risk of functional impact
- disfiguring IH (IH > 5cm, glabella location, nasal location, philtrum location, central chin location, central cheek location, labial IH with mouth deformities)
- ulcerated IH not responding to simple wound care measures, located anywhere on the body
3. If required by national regulations, registered with a social security or health insurance system and/or whose parent(s) or legal guardian(s) was (were) registered with a social security or health insurance system
4. Written informed consent(s) for study participation and the use of the subject?s images obtained according to national regulations from the subject?s parent(s) or guardian(s) prior to performing any study procedures
Are the trial subjects under 18? yes
Number of subjects for this age range: 45
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
5. Medically unstable health status that may interfere with his/her ability to complete the study, especially acute broncho-pulmonary abnormality
6. Presence of one or more of the following medical conditions:
- Congenital hemangioma
- Kasabach-Merritt syndrome
- PHACE syndrome
- Hepatic hemangioma
- Asthma
- History of bronchospasm
- At risk of hypoglycaemia according to the medical file of the subject
- Phaeochromocytoma
- Hypotension (SBP/DBP <65/45 mmHg for age 35-90 days, < 70/50 mmHg for age 91-150 days)
- Second or third degree heart block
- Cardiogenic shock
- Bradycardia (HR < 100 bpm for age 35-90 days, < 90 bpm for age 91-150 days)
- Severe peripheral arterial circulatory disturbances, Raynaud?s phenomenon
- Disease of the sinus node (including sinoatrial block)
- Uncontrolled heart failure
- Prinzmetal?s angina
- Hepatic and/or renal impairment
- Psoriasis
7. Kaliemia > 5.0 mmol/L (only measured for subjects presenting an IH with ulcerated area >= 3 cm)
8. Subject?s target hemangioma treated by LASER therapy within the past month,
9. The subject (and/or the mother if she is breastfeeding the subject) has received at least one of the following prohibited medications within 14 days before first study drug administration:
- Corticosteroids by systemic (oral, intra-venous or intra-muscular), intra-lesional or topical route
- Imiquimod
- Vincristine
- Alfa-interferon
- Propranolol or other beta-blockers
- Cardiovascular treatments:
. bradycardia-inducing calcium channel blockers (diltiazem, verapamil, bepridil),
. anti-arrhythmics (propafenone, quinidine, amiodarone, lidocaine),
. inotropic agents (digitalis glycosides),
. dihydropyridines (amlodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nitrendipine, etc?),
. antihypertensives (ACE Inhibitors, angiotensin II-receptors antagonists, diuretics, alpha-blockers whatever the indication, centrally-acting antihypertensives, reserpine, etc?)
- Drugs inducing orthostatic hypotension (nitrates derivatives, type 5-phosphodiesterase inhibitors, tricyclic antidepressants, antipsychotics, dopaminergic agonists, levodopa, amifostine, baclofen, etc?)
- Non-steroid anti-inflammatory drugs (NSAIDs) at anti-inflammatory dose
- Enzyme inducers (rifampicin, phenobarbital,?)
- Hypoglycaemic agents or drugs able to induce hypoglycaemia
- Lipid lowering agents (cholestyramine, colestipol)
- Halogenated anesthetic agents, lidocaine (exclusion period shortened to 48 hours if anaesthesia has been performed for diagnosis investigation, e.g. MRI?)
10. Hypersensitivity to any study drug ingredient
11. Hypersensitivity any beta-blocker
12. Medical history of anaphylactic reaction


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

High risk infantile haemangioma
MedDRA version: 17.1 Level: PT Classification code 10018814 Term: Haemangioma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]

Intervention(s)

Trade Name: HEMANGIOL
Pharmaceutical Form: Oral solution
INN or Proposed INN: PROPRANOLOL HYDROCHLORIDE
CAS Number: 318-98-9
Current Sponsor code: V0400SB
Other descriptive name: (2RS)-1-[(1-methylethyl)amino]-3-(naphthalen-1-yloxy)propan-2-ol hydrochloride
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 4.28-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: End of the initial treatment period: 6 months minimum to 11 months maximum

Secondary Objective: To document
- the safety of Hemangiol.
- the persistence of IH response up to 3 months after treatment interruption.
- the efficacy of Hemangiol re-administered during up to 6 months in case of hemangioma relapse based on investigator?s judgment.
- the impact of Hemangiol on family burden and quality of life linked to the IH.

Primary end point(s): Success, defined by investigator, at the end of initial treatment period.
A subject
- who is prematurely withdrawn for inefficacy or safety reason with a related AE leading to definitive study drug discontinuation (before the end of initial treatment period),
- and/or
- receiving (before the end of initial treatment period), prohibited treatments used to treat target IH (systemic [oral, intra-venous or intra-muscular], intra-lesional or topical corticosteroids, imiquimod, vincristine, alfa-interferon, beta-blockers other than the study treatment), in usual conditions for treating IH with appropriate formulation, dose and treatment duration,
will be considered for statistical analysis as treatment failure, whatever the evaluation of investigator.

Analyses of primary outcome measure:
- Primary analysis: number, percentage and 95% CI of success on the FAS.
- Supportive analysis: same analysis on the PP set.

Main Objective: To document the efficacy of Hemangiol administered during at least 6 months and up to a maximum of 12 months of age in infants with high risk IH.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Depending of the secondary endpoint as defined above:
- at each visit
or
- at end of first study treatment
or
- at time to first sustained success

Secondary end point(s): All analyses on the secondary outcome measures will be performed on the FAS.
- Success at each visit (defined in the same way than the primary outcome measure):
. On the initial treatment period, number (% and 95% CI) of success at each visit
. Persistence of effect: on the Follow-Up period, number (% and 95% CI) of success on the subset of FAS who are in success at the end of initial treatment period.
. On the period of re-initiation of treatment, number (% and 95% CI) of success on the subset of FAS who needed to be re-treated.
- Time to first sustained success from D0 up to the end of study
Kaplan-Meier cumulative incidence estimates were provided at each time-point where the success assessment was scheduled for two subsets of FAS:
. Subset of patient in FAS with only the initial treatment period.
. Subset of patient in FAS with the initial treatment and re-initiation period.
- Three-point evolution (improvement/stabilization/worsening) of the target IH compared to baseline evaluation:
. On the initial treatment period, qualitative description at each visit
. On the Follow-Up period, qualitative description on the subset of FAS who are in improvement at the end of initial treatment period.
. On the period of re-initiation of treatment, qualitative description on the subset of FAS who needed to be re-treated.
- Time to first sustained improvement (compared to the previous visit) from D0 up to the end of study:
.same analyses performed on the time to first sustained success.
- Time to first sustained improvement (compared to the baseline) from D0 up to the end of study
. same analyses performed on the time to first sustained success.
- Re-initiation of treatment:
. number (%) of patients needed to be re-treated on the subset of FAS who are in success at the end of initial treatment period.
- Investigator?s qualitative assessment of IH characteristics:
. description by visit.
- Functional impact of target IH:
. graphics plotting evolution by functional impact and by patient.

Safety analysis:
The safety analysis will be performed on the FAS.
- Adverse events (AE):
. Descriptive statistics according to the status of AE (Emergent or Non-emergent)
- Height, Weight:
. Descriptive statistics by visit
- Vital Signs (Blood pressure and heart rate):
. Descriptive statistics by visit
. Descriptive analysis relative to normal ranges

Quality of life
The quality of life will be performed on the FAS.
- Haemangioma Family Burden (HFB) questionnaire:
For the 5 dimension scores (Family life, Relationship and Work, Emotions/Feelings, Psychological and Disease management) and the HFB total score: Descriptive statistics by visit.
- SF-36 questionnaire:
For the 8 dimension scores (physical functioning, role limitations because of physical problems, bodily pain, general health perceptions, energy/vitality, social functioning, role limitations due to emotional problems, mental health) and for the two summary measures of physical and mental health: Descriptive statistics by visit.

Secondary ID(s)

V00400SB302

Source(s) of Monetary Support

Pierre Fabre Dermatologie