Infantile Hemangioma
Conditions
Keywords
Infantile Hemangioma, Propranolol
Brief summary
There is an unsatisfied medical need for a first-line treatment of proliferating IHs with a good benefit/risk profile. Based on the recent findings of encouraging results obtained with propranolol in a series of infants with severe Infantile Hemangioma (IH), propranolol is expected to be of significant benefit in the management of the condition. The present study has been designed to confirm efficacy of propranolol in severe IH by demonstrating superiority over placebo and to document the safety profile of propranolol in this indication.
Detailed description
Primary objective The primary objective of this study is 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.
Interventions
DRUGPropranolol
Propranolol (1 or 3 mg/kg/day for 3 or 6 months)
DRUGPlacebo
Treatment with placebo for 6 months
Sponsors
Pierre Fabre Dermatology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Days to 150 Days
Healthy volunteers
No
Inclusion criteria
* Proliferating IH (target hemangioma) requiring systemic therapy anywhere on the body except on the diaper area with largest diameter of at least 1.5 cm
Exclusion criteria
\- 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 has previously been treated for IH, including any surgical and/or medical procedures (e.g. laser therapy) * The patient is known to have a hypersensitivity to propranolol and/or any other beta-blockers * One or more of the following types of IH are present: * Life-threatening IH * Function-threatening IH (e.g. those causing impairment of vision, respiratory compromise caused by airway lesions, etc.) * Ulcerated IH (whatever the localisation) with pain and lack of response to simple wound care measures * 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 (left ventricular systolic function) ≤40% and/or cardiomyopathy and/or hereditary arrhythmia disorder
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Interim Analysis : Complete/Nearly Complete Resolution of the Target Infantile Hemangioma at Week 24 Compared to Baseline Based on the Intra-patient Blinded Centralized Independent Qualitative Assessments of Week 24 Photographs. | 6 months |
| Primary Analysis : Complete/Nearly Complete Resolution of the Target Infantile Hemangioma at W24 Compared to Baseline Based on the Intra-patient Blinded Centralized Independent Qualitative Assessments of W24 Photographs. | 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Success/Failure Based on the Investigator Qualitative Assessment of Complete Resolution at W48. | 6 months | Time to first sustained improvement based on centralized qualitative assessments of paired patient-visits |
Countries
Australia, Canada, Czechia, France, Germany, Hungary, Italy, Lithuania, Mexico, New Zealand, Peru, Poland, Romania, Russia, Spain, United States
Participant flow
Pre-assignment details
512 patients were included in the study (informed Consent Form signed). Among these 510 patients, 460 were randomized and 52 were screen failure * At least one inclusion criterion not met in 26 cases * Parent's decision in 12 cases * Other reasons in 15 cases. One patient was not included for two reasons (Parent's decision and other reason)
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo: Treatment with placebo for 6 months | 55 |
| Propranolol 1mg/kg/d 3 Months Propranolol oral solution 1mg/kg/day for 3 months, then placebo for 3 months | 98 |
| Propranolol 1 mg/kg/d 6 Months Propranolol oral solution 1mg/kg/day for 6 months | 102 |
| Propranolol 3 mg/kg/d 3 Months Propranolol oral solution 3mg/kg/day for 3 months, then placebo for 3 months | 100 |
| Propranolol 3 mg/kg/d 6 Months Propranolol oral solution 3mg/kg/day for 6 months | 101 |
| Total | 456 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 32 | 30 | 7 | 25 | 9 |
| Overall Study | Other reasons | 4 | 4 | 8 | 9 | 5 |
| Overall Study | Treatment Intolerance | 0 | 2 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Propranolol 1mg/kg/d 3 Months | Propranolol 1 mg/kg/d 6 Months | Propranolol 3 mg/kg/d 3 Months | Propranolol 3 mg/kg/d 6 Months | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 103.91 DAYS STANDARD_DEVIATION 31.06 | 103.58 DAYS STANDARD_DEVIATION 33.07 | 102.65 DAYS STANDARD_DEVIATION 30.12 | 107.53 DAYS STANDARD_DEVIATION 30.14 | 101.63 DAYS STANDARD_DEVIATION 31 | 103.85 DAYS STANDARD_DEVIATION 31.02 |
| Infantile hemangioma localization FACE | 40 participants | 71 participants | 72 participants | 64 participants | 71 participants | 318 participants |
| Infantile hemangioma localization NONE FACE | 15 participants | 27 participants | 30 participants | 36 participants | 30 participants | 138 participants |
| Region of Enrollment Australia | 1 participants | 5 participants | 14 participants | 5 participants | 7 participants | 32 participants |
| Region of Enrollment Canada | 2 participants | 5 participants | 6 participants | 3 participants | 2 participants | 18 participants |
| Region of Enrollment Czech Republic | 2 participants | 1 participants | 3 participants | 1 participants | 1 participants | 8 participants |
| Region of Enrollment France | 21 participants | 25 participants | 18 participants | 22 participants | 28 participants | 114 participants |
| Region of Enrollment Germany | 8 participants | 17 participants | 9 participants | 17 participants | 9 participants | 60 participants |
| Region of Enrollment Hungary | 1 participants | 2 participants | 4 participants | 2 participants | 2 participants | 11 participants |
| Region of Enrollment Italy | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants | 2 participants |
| Region of Enrollment Lithuania | 1 participants | 7 participants | 4 participants | 1 participants | 5 participants | 18 participants |
| Region of Enrollment Mexico | 0 participants | 2 participants | 0 participants | 3 participants | 0 participants | 5 participants |
| Region of Enrollment New Zealand | 0 participants | 0 participants | 1 participants | 1 participants | 3 participants | 5 participants |
| Region of Enrollment Peru | 1 participants | 5 participants | 9 participants | 8 participants | 12 participants | 35 participants |
| Region of Enrollment Poland | 4 participants | 4 participants | 6 participants | 8 participants | 4 participants | 26 participants |
| Region of Enrollment Romania | 2 participants | 2 participants | 1 participants | 0 participants | 2 participants | 7 participants |
| Region of Enrollment Russian Federation | 0 participants | 1 participants | 0 participants | 1 participants | 1 participants | 3 participants |
| Region of Enrollment Spain | 5 participants | 9 participants | 14 participants | 17 participants | 14 participants | 59 participants |
| Region of Enrollment United States | 6 participants | 13 participants | 13 participants | 11 participants | 10 participants | 53 participants |
| Sex: Female, Male Female | 38 Participants | 68 Participants | 70 Participants | 79 Participants | 70 Participants | 325 Participants |
| Sex: Female, Male Male | 17 Participants | 30 Participants | 32 Participants | 21 Participants | 31 Participants | 131 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 40 / 55 | 88 / 98 | 92 / 102 | 92 / 100 | 96 / 101 | 27 / 33 | 66 / 85 | 70 / 91 | 65 / 87 | 75 / 95 |
| serious Total, serious adverse events | 3 / 55 | 5 / 98 | 3 / 102 | 9 / 100 | 5 / 101 | 5 / 33 | 6 / 85 | 5 / 91 | 5 / 87 | 7 / 95 |
Outcome results
Primary
Interim Analysis : Complete/Nearly Complete Resolution of the Target Infantile Hemangioma at Week 24 Compared to Baseline Based on the Intra-patient Blinded Centralized Independent Qualitative Assessments of Week 24 Photographs.
Time frame: 6 months
Population: Among the 190 first randomized patients who entered the stage 1 of the study, 2 patients were not treated because of parent'/legal guardian's decision: 1 in the 1mg/kg/day 6 months arm and 1 in the 3 mg/kg/day 3 months arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Interim Analysis : Complete/Nearly Complete Resolution of the Target Infantile Hemangioma at Week 24 Compared to Baseline Based on the Intra-patient Blinded Centralized Independent Qualitative Assessments of Week 24 Photographs. | 8.0 percentage of participants |
| Propranolol 1mg/kg/d 3 Months | Interim Analysis : Complete/Nearly Complete Resolution of the Target Infantile Hemangioma at Week 24 Compared to Baseline Based on the Intra-patient Blinded Centralized Independent Qualitative Assessments of Week 24 Photographs. | 9.8 percentage of participants |
| Propranolol 1 mg/kg/d 6 Months | Interim Analysis : Complete/Nearly Complete Resolution of the Target Infantile Hemangioma at Week 24 Compared to Baseline Based on the Intra-patient Blinded Centralized Independent Qualitative Assessments of Week 24 Photographs. | 37.5 percentage of participants |
| Propranolol 3 mg/kg/d 3 Months | Interim Analysis : Complete/Nearly Complete Resolution of the Target Infantile Hemangioma at Week 24 Compared to Baseline Based on the Intra-patient Blinded Centralized Independent Qualitative Assessments of Week 24 Photographs. | 7.7 percentage of participants |
| Propranolol 3 mg/kg/d 6 Months | Interim Analysis : Complete/Nearly Complete Resolution of the Target Infantile Hemangioma at Week 24 Compared to Baseline Based on the Intra-patient Blinded Centralized Independent Qualitative Assessments of Week 24 Photographs. | 62.8 percentage of participants |
Comparison: The interim analysis was carried out after the first 188 patients have completed their W24 visit or been withdrawn prematurely from study therapy. For each propranolol arm, individual hypotheses H0,i: θi≤0p-value: <0.0001One-sided Z-tests
Primary
Primary Analysis : Complete/Nearly Complete Resolution of the Target Infantile Hemangioma at W24 Compared to Baseline Based on the Intra-patient Blinded Centralized Independent Qualitative Assessments of W24 Photographs.
Time frame: 6 months
Population: After the interim analysis results, the Independent Committee recommendations was to continue the trial with the 3 mg/kg/day6 months arm and the placebo arm. 55 randomized and treated patients in the placebo arm and 102 randomized patients in the 3 mg/kg/day6 months arm,1 was not treated because no unit of the assigned treatment available on site.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Primary Analysis : Complete/Nearly Complete Resolution of the Target Infantile Hemangioma at W24 Compared to Baseline Based on the Intra-patient Blinded Centralized Independent Qualitative Assessments of W24 Photographs. | 3.6 percentage of participants |
| Propranolol 1mg/kg/d 3 Months | Primary Analysis : Complete/Nearly Complete Resolution of the Target Infantile Hemangioma at W24 Compared to Baseline Based on the Intra-patient Blinded Centralized Independent Qualitative Assessments of W24 Photographs. | 60.4 percentage of participants |
Comparison: The objective is to test the superiority of the selected arm using the approach of Posch et al.~The primary analysis was performed on the intent-to-treat population: all treated patients in Stage 1 and all treated patients in stage 2 randomized to placebo or the selected arm.p-value: <0.0001combination tests
Secondary
Success/Failure Based on the Investigator Qualitative Assessment of Complete Resolution at W48.
Time to first sustained improvement based on centralized qualitative assessments of paired patient-visits
Time frame: 6 months