Fenfluramin (2) – Fintepla®

• Clinical trials
  • Study 1601 is a multicentre, randomised, double-blind, phase III study with a parallel-group design (1:1:1) designed to investigate the efficacy and safety of fenfluramine compared with placebo in patients with Lennox-Gastaut syndrome.

Individuals aged 2 years and over with seizures associated with Lennox-Gastaut syndrome

• In summary, the additional benefit of fenfluramine is assessed as follows: a hint of a considerable additional benefit
• Overall, there is a hint of considerable additional benefit for fenfluramine.
• In its overall assessment of the available results on patient-relevant endpoints, the G-BA classifies the extent of the additional benefit of fenfluramine for the treatment of individuals aged 2 years and over with seizures associated with Lennox-Gastaut syndrome, as ‘considerable’ on the basis of the criteria set out in Section 5(8) in conjunction with Section 5(7), first sentence, number 2 of the AM-NutzenV.
• The strength of the evidence is classified as ‘hint’, as the study duration for this therapeutic indication is to be regarded as short, and the sustainability of the effects as well as the long-term effects on the safety of fenfluramine—particularly with regard to the risk of cardiovascular side effects—cannot be conclusively assessed.
• mortality
  • In Study 1601, Part 1, one death occurred in the intervention group.
  • No conclusion can be drawn regarding the extent of the additional benefit in the ‘Mortality’ category.
• Morbidity – frequency of epileptic seizures
  • The number of epileptic seizures was recorded daily by the carer or the trial participant in a diary, specifying the type and duration.
  • For the endpoint ‘frequency of epileptic seizures’, the pharmaceutical manufacturer provided analyses of drop attacks, motor seizures and non-motor seizures.
  • Motor seizures were defined as all generalised tonic-clonic (primary and secondary), tonic, atonic, tonic-atonic, clonic and focal seizures associated with observable motor signs, as well as hemiclonic seizures.
  • In Study 1601, a statistically significant advantage in favour of fenfluramine over placebo was observed in the change in the frequency of all countable motor seizures (normalised to 28 days) and in the proportion of subjects with a reduction in seizure frequency of > 0 %, ≥ 25 per cent and ≥ 50 per cent, respectively, each showed a statistically significant advantage for fenfluramine over placebo.
  • In the analyses using response thresholds of ≥ 75 per cent and ≥ 100 per cent, no statistically significant difference was observed between the treatment arms.
  • The non-motor seizures reported included all countable absences, myoclonic seizures, focal seizures without observable motor signs, infantile spasms and epileptic spasms.
  • No statistically significant difference was observed between the treatment groups, either in the change in the frequency of non-motor seizures (normalised to 28 days) or in the proportion of participants with a reduction in the frequency of non-motor seizures of > 0%, ≥ 25%, ≥ 50 per cent, ≥ 75 per cent and 100 per cent.
  • Falls are classified as clinically relevant in their own right, particularly due to the serious injuries that can result from a fall. In Study 1601, however, ‘fall-related seizures’ were defined not only as seizures that led to a fall, but also as seizures that, had the patient’s position been different, would have led to a fall. As potential falls are classified as not relevant to the assessment of the ‘falls’ endpoint, and no separate analysis of the falls that actually occurred was submitted by the pharmaceutical manufacturer, this endpoint is not used for the present benefit assessment.
• quality of life
  • Health-related quality of life was assessed using the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire, which was developed for patients aged 4 to 18 years.
  • In study 1601, no statistically significant differences in quality of life were demonstrated between treatment with fenfluramine and placebo.
• Side effects
  • For the population under evaluation, the study revealed no statistically significant differences between the treatment arms in the assessment of serious and severe adverse events.
  • There was no statistically significant difference between fenfluramine and placebo in the overall rates of side effects. In detail, when considering AEs with an incidence of ≥ 10% for the SOC ‘Infections and parasitic diseases’ and for the PT ‘Decreased appetite’, a statistically significant disadvantage for fenfluramine compared with placebo was observed in each case.
• Overall assessment
  • For the benefit assessment of fenfluramine in the treatment of individuals aged 2 years and over with seizures associated with Lennox-Gastaut syndrome, results are available from the 14-week randomised, double-blind and placebo-controlled treatment phase of Study 1601.
  • One death occurred in the intervention arm during the study. No conclusion can be drawn regarding the extent of the additional benefit in the mortality category.
  • In the morbidity category, a reduction in seizure frequency in the therapeutic indication is of high clinical relevance and represents an important therapeutic goal. For the endpoint ‘motor seizures’, a statistically significant advantage in favour of fenfluramine over placebo was observed both in the change in the frequency of motor seizures (normalised to 28 days) and in the proportion of participants with a reduction in seizure frequency of > 0 %, ≥ 25 per cent and ≥ 50 per cent, respectively. The results regarding the clinical global impression, assessed by the treating physician using the CGI-I, support this advantage. Treatment with fenfluramine showed a statistically significant advantage over placebo in terms of improvement in the clinical global impression.
  • For the endpoint ‘non-motor seizures’, however, no statistically significant differences were observed between the two treatment arms. Similarly, for the endpoint ‘executive function as measured by the BRIEF’, no statistically significant difference was observed between the two treatment groups in any age group. Overall, the advantages demonstrated in the morbidity endpoint category are assessed as considerable in extent.
  • In the quality of life category, the analyses of the QOLCE questionnaire revealed no statistically significant differences between fenfluramine and placebo in any instance.
  • In the ‘Side Effects’ category, no statistically significant differences were observed between the two treatment arms for either severe or serious AEs.

Courtesy translation only, please refer to the German original.