TABLE 3

List of Manufacturer’s Pooled Clinical Studies and CUP

Study ID and EnrollmentDesign Control TypeTest (and Reference) TreatmentStudy ObjectivesDiagnosis Inclusion CriteriaNumber of Patients by ArmSex and Median Age (Range)Safety Endpoint(s)
102
 Twenty patients planned to be included (10 in each stratification group); 23 patients included (10 in group 1, 13 in group 2)An open-label, multicenter,4 repeated-dose study;stratified by age: group 1, aged 35–90 d inclusive at inclusion; group 2, aged 91–150 d inclusive at inclusionTest: propranolol oral solution (Hemangiol), 3.75 mg/mL, 3 mg/kg per day at the end of titration; BID (morning and late afternoon) for 12 wkTo characterize PK of Hemangiol and propranolol metabolite (4-OH-propranolol) at steady-state in patients during treatment; to assess efficacy of Hemangiol on evolution of IH over 12 wk and to assess safety profileAge 35–150 d; proliferating IH requiring systemic therapy; function-threatening, in certain anatomic locations that often leave permanent scars or deformity, large facial IH, smaller IH in exposed areas, severe ulceration, pedunculated IHEntered: 23 patients (10 in group 1, 13 in group 2); completed: 22 patients (10 in group 1, 12 in group 2)Group 1: 3 males, 7 females, 69.7 d (50–89 d); group 2: 3 males, 10 females, 128.2 d (91–152 d)Endpoints based on the following evaluations: AEs, height, weight, head circumference, temperature, HR, BP, respiratory rate, pulmonary auscultation, liver palpation, global physical examinations, ECGs, laboratory examinations
201
Approximately 450 patients planned to be randomized overall (100:50 per Hemangiol arm:placebo arm); 460 patients randomized overall (55:99:103:101: 102; placebo:Hemangiol; 1 mg/kg per day for 3 mo, 1 mg/kg per day for 6 mo, 3 mg/kg per day for 3 mo, 3 mg/kg per day for 6 mo)Multidose, 2-stage, adaptive, seamless phase II/III design with regimen selection at end of the first stage. Stage 1: randomized, 4 Hemangiol arms and placeboa; stage 2: randomized, placebo, and best regimen of Hemangiol from stage 1; primary analysis at week 24Test: propranolol oral solution (Hemangiol) 1 or 3 mg/kg per day BID for 3 or 6 mo. Reference: placebo oral solution BID for 3 or 6 mo; total treatment duration was 6 moTo identify appropriate dose and duration of Hemangiol treatment, demonstrate superiority over placebo on the basis of resolution of target IH at week 24. Safety profile of Hemangiol. Long-term follow-up of patients for 72 wk after study treatment discontinuation.Aged 35–150 d, inclusive; presence of proliferating IH (target hemangioma) requiring systemic therapy present anywhere on body except diaper area; largest diameter at least 1.5 cmRandomized and treated: 456 patients (55 in placebo group; 98, 102, 100, 101 in Hemangiol regimens 1, 2, 3, and 4). Completed (24 wk): 323 patients (19 in placebo group; 63, 88, 65, 88 in Hemangiol regimens 1, 2, 3, and 4)131 males, 325 females, 103.9 d (35–152 d); 167 patients in 35- to 90-d group; 289 patients in >90-d groupEndpoints based on the following evaluations: AEs, height, weight, head circumference, temperature, HR, BP, respiratory rate, pulmonary auscultation, liver palpation, global physical examination, ECG measurements, laboratory examinations, two-dimensional cardiac ultrasounds, and neurodevelopment assessments
301
 Eleven patients enrolledOpen-label uncontrolled study at French centersTest: propranolol oral solution (Hemangiol) 2 or 3 g/kg per day BID for 6 moAllow the use of propranolol in infants still requiring this systemic treatment after participation in study 102 or 201 (French centers); safety profile and effect on resolution of IHReceived treatment in study 102 or 201 and completed end of study visit within ≤6 mo; proliferating IH requiring systemic therapy with propranolol in investigator’s opinionN = 11; 2 mg/kg per day: 4 patients; 3 mg/kg per day: 7 patients10 females, 1 male; aged 101–397 dEndpoints based on the following evaluations: AEs, height, weight, head circumference, temperature, HR, BP, respiratory rate, pulmonary auscultation, liver palpation, global physical examination, ECG measurements, neurodevelopment evaluation
CUP
 1661Compassionate use; open-label, noncontrolledHemangiol; planned doses in protocol: 1–3 mg/kg per day; median: 2.0 mg/kg per dayAllow compassionate useInfants with proliferating IH that was life-threatening or gave rise to a functional risk, and ulcerative IH not responding to simple treatment and who could not be included in the ongoing clinical studiesNA1227 females, 401 males (of 1628); 3.8 mo (1 d to 6.4 y)Collection of safety data; reporting was the responsibility of the treating physician
  • BID, twice daily; NA, not applicable; PK, pharmacokinetics.

  • a Regimen 1: 3 mo, 1 mg/kg per day followed by 3 mo of placebo; regimen 2: 6 mo, 1 mg/kg per day; regimen 3: 3 mo, 3 mg/kg per day followed by 3 mo of placebo; regimen 4: 6 mo, 3 mg/kg per day; placebo group: 6 mo of placebo. Stratified by age (35–90 d, 91–150 d) and IH localization (facial, nonfacial).