Ivacaftor (10) – Kalydeco®

• Clinical trials
  • To assess the additional benefit of ivacaftor in patients with cystic fibrosis who carry an R117H mutation in the CFTR gene, the pharmaceutical manufacturer submitted the pivotal, multicentre, randomised, double-blind, placebo-controlled Phase III trial VX11-770-110 (hereinafter referred to as Study 110), in which ivacaftor plus best standard care (BSC) was compared with placebo plus BSC.

Patients with cystic fibrosis aged 18 years and over who carry an R117H mutation in the CFTR gene

• Overall, for adult patients (> 18 years) with an R117H mutation in the CFTR gene, there is a hint of a minor additional benefit of ivacaftor compared with BSC.
• The G-BA classifies the extent of the additional benefit of ivacaftor as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease as a whole.
• The certainty of the findings is limited, in particular due to the incomplete implementation of the appropriate comparator therapy, best supportive care.
• Taken as a whole, these uncertainties regarding the certainty of the findings provide a hint of additional benefit.
• mortality
  • No deaths occurred in Study 110.
• Morbidity – Forced expiratory volume in one second (FEV1%)
  • Forced expiratory volume in one second (FEV1), expressed as a percentage of the standardised normal value (FEV1%), was measured as an absolute change.
  • In Study 110, a statistically significant difference in FEV1% was observed in favour of IVA + BSC compared with placebo + BSC.
  • There are differing views on the clinical relevance of FEV1% to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Body Mass Index (BMI)
  • BMI is used to assess body weight in relation to height.
  • However, for the endpoint ‘absolute change in BMI’, Study 110 did not show a statistically significant difference between the treatment groups; furthermore, the patients included already had a BMI within the normal range at the start of the study.
  • No conclusions regarding additional benefit can be drawn from this.
• Morbidity – Pulmonary exacerbations
  • Pulmonary exacerbations, particularly those leading to hospital admission, represent a clinically relevant endpoint and are to be regarded as patient-relevant.
  • For the endpoints of pulmonary exacerbations and hospitalisation due to pulmonary exacerbations, no statistically significant differences were observed between IVA + BSC and placebo + BSC.
  • The endpoint of intravenous antibiotic therapy due to pulmonary exacerbations does not allow for any further conclusions (e.g. regarding severe exacerbations), as intravenous administration also depends on the spectrum of pathogens and does not correlate solely with the severity of the pulmonary exacerbation.
• Health-related quality of life measured using the Cystic Fibrosis Questionnaire-Revised (CFQ-R)
  • Quality of life was assessed using the validated, disease-specific CFQ-R (patient version).
  • The domains of physical well-being, emotional state, vitality, social limitations, role functioning, body image, eating disorders, treatment burden and subjective health assessment are associated with health-related quality of life.
  • Statistically significant differences between IVA + BSC and placebo + BSC were observed in the domains of physical well-being, emotional state, vitality, social restrictions and eating disorders.
  • To assess the relevance of the results, the standardised mean difference in the form of Hedges’ g is considered in each case. Its 95% confidence interval lies entirely outside the irrelevance range of –0.2 to 0.2 in the domains of emotional state and vitality, meaning that a relevant effect can be assumed for these domains.
  • Effect modifications are observed in the ‘emotional state’ domain for the characteristic ‘Pseudomonas aeruginosa infection status’, and in the ‘vitality’ and ‘social limitations’ domains for the characteristic ‘gender’.
  • As these effect modifications are only evident in individual endpoints related to quality of life and there is no medical rationale, particularly for endpoints in the quality of life category, the entire relevant population is considered.
  • Overall, this results in a relevant advantage for ivacaftor in the quality of life category for the endpoints ‘emotional state’ and ‘vitality’ (assessed using the CFQ-R).
• Side effects
  • No statistically significant differences were observed for the endpoints of AEs, SAEs and therapy discontinuations due to AEs.
  • Among the specific AEs, a statistically significant disadvantage of IVA + BSC compared with placebo + BSC was observed for the endpoint ‘oropharyngeal pain’ (Preferred Term).
• Overall assessment
  • For the benefit assessment of ivacaftor for the treatment of cystic fibrosis (CF) in patients aged 18 years and over who carry an R117H mutation in the CFTR gene, the direct comparison between IVA + BSC and placebo + BSC from Study 110 was used.
  • No deaths occurred in Study 110.
  • In the morbidity category, a statistically significant effect in favour of ivacaftor, assessed as clinically relevant, was observed for the endpoint ‘respiratory symptoms’ (measured using the CFQ-R).
  • No relevant effects were observed for the other morbidity endpoints relevant to the assessment (pulmonary exacerbations, gastrointestinal symptoms and weight problems).
  • In the quality of life category, statistically significant advantages, assessed as clinically relevant, were observed in the ‘emotional well-being’ and ‘vitality’ domains of the CFQ-R questionnaire.
  • In the category of side effects, there were no statistically significant differences in the overall rates of adverse events, serious adverse events or therapy discontinuations due to adverse events.
  • The advantages observed in respiratory symptoms and in the quality-of-life endpoints of emotional well-being and vitality result in an additional benefit for ivacaftor compared with the appropriate comparator therapy, best supportive care (BSC).
  • The G-BA classifies the extent of the additional benefit of ivacaftor as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease as a whole.
  • In particular, no positive effects were observed on serious symptoms such as pulmonary exacerbations; therefore, the observed advantages are not considered sufficient to constitute a considerable additional benefit.

Courtesy translation only, please refer to the German original.