| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Proliferating Infantile Hemangioma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Proliferating Infantile Hemangioma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018814 |
| E.1.2 | Term | Haemangioma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To identify the appropriate dose and duration of propranolol treatment and demonstrate its superiority over placebo based on the complete/nearly complete resolution of target IH at W24. |
|
| E.2.2 | Secondary objectives of the trial |
Safety objective: To document the safety profile of the four regimens of propranolol in the treatment of IH in infants aged 1 to 5 months at inclusion.
Long term objective: To study the long-term efficacy and safety of the four regimens of propranolol in the treatment of IH. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A patient will be eligible if he/she meets all of the following criteria:
- Written informed consent(s) for study participation and the use of the patient’s images are obtained according to national regulations from the patient’s parent(s) or guardian(s) prior to performing any study procedures
- The patient is 35 to 150 days old, inclusive, at inclusion
- A proliferating IH (target hemangioma) requiring systemic therapy is present anywhere on the body except on the diaper area, with largest diameter of at least 1.5 cm.
- If required by national regulations, registered with a social security or health insurance system and/or whose parent(s) or legal guardian(s) is (are) registered with a social security or health insurance system. |
|
| E.4 | Principal exclusion criteria |
A patient will be ineligible if he/she meets any of the following criteria:
- The patient has a medically unstable health status that may interfere with his/her ability to complete the study
- The patient presents with one or more of the following medical conditions: Congenital hemangioma; Kasabach-Merritt syndrome; bronchial asthma; bronchospasm; hypoglycaemia (< 40 mg/dl or at risk); untreated phaeochromocytoma; hypotension (< 50/30 mmHg); second or third degree heart block; cardiogenic shock; metabolic acidosis; bradycardia (< 80 bpm); severe peripheral arterial circulatory disturbances; Raynaud’s phenomenon; sick sinus syndrome; uncontrolled heart failure or Prinzmetal’s angina; documented PHACES syndrome with central nervous system involvement
- The patient (and/or the mother if she is breastfeeding the patient) has received at least one of the following prohibited medications within 14 days of randomisation:
o Anaesthetic agents, lidocaïne (the exclusion period is shortened to 48 hours, if anaesthesia has been performed for diagnosis investigation e.g. MRI…)
o Cardiovascular treatments: anti-arrhythmics, calcium channel blockers, ACE inhibitors, inotropic agents, vasodilators (hydralazine hydrochloride…), clonidine…
o Hypoglycaemic agents or drugs able to induce hypoglycaemia
o Inducers of hepatic drug metabolism or substrates or inhibitors of CYP2D6, CYP1A2, CYP2C19
o Anti-ulcer drugs (cimetidine, ranitidine, proton pomp inhibitors other than omeprazole and lanzoprazole)
o Metoclopramide
o Non-steroid anti-inflammatory drugs (NSAIDs) at anti-inflammatory dose
o Sympathomimetic agents and parenteral adrenaline
o Benzodiazepines
o Neuroleptic drugs (chlorpromazine, sultopride hydrochloride…)
o Other drugs: triptans, ergotamine, theophylline, warfarin, thyroxine, floctafenine
- The patient has previously been administered at least one of the following prohibited medications: systemic (oral, intra-venous or intra-muscular), intra-lesional or topical corticosteroids, imiquimod, vincristine, alfa-interferon, propranolol or other beta-blockers
- The patient has previously been treated for IH, including any surgical and/or medical procedures (e.g. laser therapy)
- The patient’s mother has been breastfeeding the patient while she was also being treated with beta-blockers (including propranolol) or, she has been breastfeeding the patient within 14 days of randomisation while she was also being treated with systemic (oral, intra-venous or intra-muscular) corticosteroids, vincristine or alfa-interferon
- The patient is known to have a hypersensitivity to propranolol and/or any other beta-blockers
- The patient has previously experienced an anaphylactic reaction
- One or more of the following types of IH are present:
o Life-threatening IH
o Function-threatening IH (e.g. those causing impairment of vision, respiratory compromise caused by airway lesions, etc.)
o Ulcerated IH (whatever the localisation) with pain and lack of response to simple wound care measures
- Diagnosis of the soft tissue tumour as IH is not clinically certain, particularly in the case of sub-dermal lesions
- The patient was born prematurely and has not yet reached his/her term equivalent age (e.g. an infant born 2 months prematurely cannot be included before the age of 2 months)
- LVEF ≤ 40% and/or cardiomyopathy and/or hereditary arrhythmia disorder
- The patient is participating in another clinical study or the patient lives in the same household as an infant already participating in this study.
- Parent(s) or guardian(s) who cannot be contacted by telephone in case of emergency. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy criterion is the evolution of target IH from baseline to W24. The binary primary endpoint (success/failure) will be evaluated based on the intra-patient blinded centralised independent qualitative assessments (Type 1) of W24 photographs of the target IH compared to baseline. A treatment success will be defined as a centralised assessment of complete/nearly complete resolution of the target IH at W24 compared to baseline, where nearly complete resolution is defined as a minimal degree of telangiectasis, erythema, skin thickening, soft tissue swelling and/or distortion of anatomical landmarks. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoint:
· Success/failure (binary endpoint) based on the investigator on-site qualitative assessment of complete resolution of the target IH at W48. In particular, in the case of complete resolution of the target IH at W48, investigators will then be asked to assess the level of sequelae (none, minimal, marked):
o Complete resolution with minimal sequelae is defined as minimal telangiectasis, macular discolouration and/or textural change
o Complete resolution with marked sequelae is defined as marked textural change with or without distortion of anatomical landmarks or skin contours. A treatment success will be defined as complete resolution of the target IH without sequelae or with minimal sequelae at W48.
Other secondary and exploratory efficacy endpoints include:
A. Centralised assessments of the target IH:
1. Endpoints based on the independent blinded Type 1 assessments of complete/nearly complete resolution:
o Success/failure (binary endpoints) at W12, W36 and W48 compared to baseline, where treatment success is defined as for the primary efficacy endpoint
o Time to first sustained complete/nearly complete resolution (W12, W24, W36 or W48 compared to baseline)
2. Endpoints based on the independent blinded Type 2 assessments of improvement, stabilisation or worsening:
o Categorical endpoints for target IH evolution (3-point scale: improvement, stabilisation, worsening) between paired patient-visits (W5, W8, W12, W16, W20 or W24 compared to baseline, W5, W8, W12, W16 or W20, respectively). A global improvement will also be computed on the W5-W24 period (Yes/No).
o Time to first sustained improvement (first improvement after which there is no worsening) of the target IH based on Type 2 centralised qualitative assessments of paired patient-visits (W5, W8, W12, W16, W20 or W24 compared to baseline, W5, W8, W12, W16 or W20, respectively)
3. Endpoints based on centralised quantitative assessments:
o Continuous and categorical endpoints (change in size and colour of target IH) at W12 and W24 compared to baseline.
B. Investigator on-site qualitative assessments at each scheduled postbaseline
visit compared to baseline:
o Categorical endpoints for complete/nearly complete resolution of target IH, where nearly complete resolution is defined as a minimal degree of telangiectasis, erythema, skin thickening, soft tissue swelling, distortion of anatomical landmarks and/or a minimal palpable component
o Categorical endpoints for complete resolution (3-point scale: no sequelae; minimal sequelae defined as minimal telangiectasis, macular discolouration and/or textural change; marked sequelae defined as marked textural change with or without distortion of anatomical landmarks or skin contours)
o Time to first sustained complete/nearly complete resolution
o Time to first sustained complete resolution without sequelae or with minimal sequelae
C. Investigator on-site qualitative assessments of paired consecutive patient-visits (each scheduled post-baseline visit compared to the previous scheduled visit):
o Categorical endpoints for target IH evolution (3-point scale: improvement, stabilisation, worsening)
o Time to first sustained improvement (first improvement after which there is no worsening)
D. Parent(s) or guardian(s) on-site qualitative assessments at each scheduled post-baseline visit compared to the previous scheduled visit:
o Categorical endpoints for target IH evolution (3-point scale: improvement, stabilisation, worsening)
o Time to first sustained improvement (first improvement after which there is no worsening)
E. Other investigator on-site qualitative assessments at each scheduled post-baseline visit:
o Categorical endpoints based on assessments of target IH complications: functional impairment/ulceration/haemorrhaging (patients presenting with any functional impairment, haemorrhaging or ulceration with pain and lack of response to simple wound care measures [Grade 3 or higher, see Appendix 17.3] at inclusion must not be included in the study)
o Categorical endpoints based on qualitative assessments of complete resolution of nontarget facial IH and non-facial IH at each scheduled post-baseline visit (3-point scale: no sequelae; minimal sequelae defined as minimal telangiectasis, macular discolouration and/or textural change; marked sequelae defined as marked textural change with or without distortion of anatomical landmarks or skin contours)
o Categorical endpoints based on whether or not invasive procedures were carried out during the study on the target/non-target facial/nonfacial IH. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Depending on the secondary endpoint considered. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Lithuania |
| Mexico |
| New Zealand |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last follow-up visit of the last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 36 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 36 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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