Propranolol (1) – Hemangiol®

• Clinical trials
  • To assess the additional benefit of propranolol in patients with proliferative infantile haemangioma requiring systemic therapy, the pharmaceutical manufacturer submitted the double-blind, placebo-controlled, multicentre, 5-arm Phase II/III registration trial V00400SB 201.
  • To assess the additional benefit of propranolol in patients with a haemangioma of greater severity (life- or function-threatening haemangioma or ulcerated haemangioma, which causes pain and/or does not respond to simple wound care measures), the pharmaceutical manufacturer has submitted data from a single-arm study (Study V00400SB 102) and from a Compassionate Use Programme (CUP) in France.

a) Patients with life-threatening or functionally debilitating haemangioma

• For patients with life-threatening or functionally debilitating haemangioma, or patients with ulcerated haemangioma that causes pain and/or does not respond to simple wound care measures, there is a hint of a non-quantifiable additional benefit.
• Overall, taking into account the limitations of the evidence available for this patient population in terms of the certainty of the findings, hints of additional benefit can be derived from the overall conclusion on additional benefit.
• Side effects
  • The additional benefit of propranolol compared with the appropriate comparator therapy (patient-specific treatment (in this case: glucocorticoids)) lies not only in a non-quantifiable additional benefit regarding the reduction in the target haemangioma at week 24, but also in a reduction in serious side effects—the extent of which is likewise non-quantifiable due to the uncertainties described—which may be accompanied by secondary complications caused by treatment with glucocorticoids, such as Cushing’s syndrome (moon face)⁴,⁵,⁷, osteoporosis, high blood pressure, gastrointestinal complaints, gastroenteritis, fungal infections, infections due to immunosuppression, therapy discontinuation due to adverse events, reduced linear growth/increased body weight, and hospitalisation due to severe dehydration.
  • In contrast, the side effects associated with treatment with propranolol are, in terms of their severity and significance for the patient—considered against the background of the overall severity of the disease—classified as minor and well controllable and treatable in terms of both extent and frequency, particularly with regard to serious side effects. Common adverse events associated with treatment with propranolol (across all studies and patient populations) include hypoglycaemia, bradycardia, infections and parasitic diseases, gastrointestinal disorders, sleep disturbances, hypotension and bronchospasm.
• Overall view
  • Overall, it is not possible to carry out a quantitative assessment of the extent of a treatment effect and thus to quantify the additional benefit of propranolol in patients with life-threatening or functionally debilitating haemangioma or with ulcerated haemangioma, which causes pain and/or does not respond to simple wound care measures.

Patients with ulcerated haemangioma that causes pain and/or does not respond to simple wound care measures

• For patients with life-threatening or functionally debilitating haemangioma, or patients with ulcerated haemangioma that causes pain and/or does not respond to simple wound care measures, there is a hint of a non-quantifiable additional benefit.
• Overall, taking into account the limitations of the evidence available for this patient population in terms of the certainty of the findings, hints of additional benefit can be derived from the overall conclusion regarding additional benefit.
• Side effects
  • The additional benefit of propranolol compared with the appropriate comparator therapy (patient-specific treatment (in this case: glucocorticoids)) lies not only in a non-quantifiable additional benefit regarding the reduction in the target haemangioma at week 24, but also in a reduction in serious side effects—the extent of which is likewise non-quantifiable due to the uncertainties described—which may be accompanied by secondary complications caused by treatment with glucocorticoids, such as Cushing’s syndrome (moon face)⁴,⁵,⁷, osteoporosis, high blood pressure, gastrointestinal complaints, gastroenteritis, fungal infections, infections due to immunosuppression, therapy discontinuation due to adverse events, reduced linear growth/increased body weight, and hospitalisation due to severe dehydration.
  • In contrast, the side effects associated with treatment with propranolol are, in terms of their severity and significance for the patient—considered against the background of the overall severity of the disease—classified as minor and well controllable and treatable in terms of both extent and frequency, particularly with regard to serious side effects. Common adverse events associated with treatment with propranolol (across all studies and patient populations) include hypoglycaemia, bradycardia, infections and parasitic diseases, gastrointestinal disorders, sleep disturbances, hypotension and bronchospasm.
• Overall view
  • Overall, it is not possible to carry out a quantitative assessment of the extent of a treatment effect and thus to quantify the additional benefit of propranolol in patients with life-threatening or functionally debilitating haemangioma or with ulcerated haemangioma, which causes pain and/or does not respond to simple wound care measures.

Patients with haemangioma where there is a risk of permanent scarring or disfigurement

• For patients with haemangiomas where there is a risk of permanent scarring or disfigurement, there is an indication of a major additional benefit.
• The G-BA classifies the extent of the additional benefit of propranolol in patients with a haemangioma where there is a risk of permanent scarring or disfigurement as major, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in treating the condition. Compared with the appropriate comparator therapy, this constitutes, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a sustained and, compared with the appropriate comparator therapy, (patient-specific treatment (watch-and-wait approach)), as a cure for the condition is achieved.
• mortality
  • No deaths occurred over the entire observation period (96 weeks). The results regarding mortality can only be interpreted qualitatively due to the varying proportions of patients who participated in the follow-up and the associated uncertainty regarding the actual duration of observation for each patient. It can therefore only be inferred for this endpoint that propranolol did not result in any greater harm in terms of mortality compared with the watch-and-wait approach. An additional benefit of propranolol for the endpoint of mortality compared with the appropriate comparator therapy is therefore not proven.
• Morbidity – Complete/near-complete regression of the visible component of the target haemangioma at week 24
  • The operationalisation underlying the evaluation of this endpoint allowed only for an assessment of the change in the visible (superficial) component of the target haemangioma; consequently, this endpoint was specified in this regard, deviating from the designation provided by the pharmaceutical manufacturer.
  • Based on the per-protocol analysis, a statistically significant advantage in favour of propranolol was observed (RR 31.91; 95% CI [4.55; 223.96]; p < 0.001). Patients who discontinued treatment prematurely, as well as those who took unauthorised medication, were classified in this analysis as patients in whom treatment had failed.
  • Overall, this means that, despite a high potential for bias, the additional benefit of propranolol for this endpoint is not downgraded overall, owing to the differing proportions of patients in the study arms who were classified as treatment failures. For the endpoint of complete/near-complete regression of the visible component of the target haemangioma at week 24, an additional benefit of propranolol compared with the appropriate comparator therapy (watch-and-wait approach) is inferred on the basis of these results and the associated cure; this additional benefit is of major extent.
• Morbidity – complications of the target haemangioma (functional impairment, ulcerations and bleeding)
  • For the endpoint ‘complications of the target haemangioma’ – the following were considered: functional cardiac impairment, ocular impairment, obstruction of the visual axis, airway obstruction/stenosis, each of which is accompanied by symptoms, as well as ulcerations and haemorrhages requiring therapeutic intervention – the results can only be interpreted qualitatively due to the markedly different treatment durations between the study arms.
  • Based on the crude proportions of patients experiencing an event, no statistically significant difference was observed between the treatment arms; there is neither a greater nor a less benefit ((RR 0.73; 95% CI [0.17; 3.13]; p=0.788). An additional benefit of propranolol over the appropriate comparator therapy is therefore not proven for this patient-relevant endpoint.
• Morbidity – Complete regression of the non-target haemangioma (on the face; not on the face)
  • No usable data were available for the endpoints ‘complete regression of the non-target haemangioma (on the face)’ and ‘regression of the non-target haemangioma (not on the face)’, as the number of events could not be clearly derived from the information in the study report in accordance with the ITT principle. The additional benefit of propranolol compared with the appropriate comparator therapy with regard to the complete regression of the non-target haemangioma is not proven.
• quality of life
  • Health-related quality of life was not assessed in study V00400SB 201. An additional benefit of propranolol cannot therefore be inferred for this endpoint. However, the absence of these data has no bearing on the benefit assessment of propranolol, particularly given that the study involving infants examined a patient population in which such a survey would not be expected.
• Side effects – Adverse events
  • Due to the marked differences in treatment duration between the study arms in study V00400SB 201, the results regarding adverse events could only be interpreted qualitatively. 97 of the 101 patients in the propranolol arm (96%) and 43 of 55 (78.2%) of the patients in the comparator arm experienced at least one adverse event.
• Conclusion
  • The G-BA classifies the extent of the additional benefit of propranolol in patients with a haemangioma where there is a risk of permanent scarring or disfigurement as ‘major’ on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in treating the condition. Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a sustained and, compared with the appropriate comparator therapy, (treatment tailored to the individual patient (watch-and-wait approach)), as a cure for the condition is achieved.

Courtesy translation only, please refer to the German original.