Ivacaftor (5) – Kalydeco®

a) Patients with cystic fibrosis carrying a G551D mutation in the CFTR gene, aged between 6 and 11 years

• Hint for a non-quantifiable additional benefit
• Taken together, based on the results of study 103, and taking into account the results of study 102 in patients aged 12 years and over, Ivacaftor demonstrates an additional benefit over the appropriate comparator therapy, the extent of which is non-quantifiable due to the limited available evidence.
• With regard to the certainty of the finding (probability of additional benefit), there is, on the whole, a hint of additional benefit.
• mortality
  • No deaths occurred in Study 103.
• morbidity
  • Pulmonary exacerbations and hospitalisation due to pulmonary exacerbations
  • No data are available for estimating the effect for the endpoints of pulmonary exacerbations and hospitalisation due to pulmonary exacerbations, each operationalised on the basis of event rates (number of events per patient-year). For the further analyses of patients with at least one event, there is no statistically significant difference between the treatment groups for either endpoint.
  • Forced expiratory volume in one second (FEV1 %)
  • There is a statistically significant difference in favour of ivacaftor + BSC compared with placebo + BSC for both the absolute and relative change in the FEV1 value over 48 weeks.
  • There are differing views on the clinical relevance of FEV1 %. This does not affect the overall conclusion regarding the extent of the additional benefit.
  • Symptoms measured using the Cystic Fibrosis Questionnaire-Revised (CFQ-R)
  • In the ‘Respiratory System and Gastrointestinal Symptoms’ domain, no statistically significant difference between the treatment groups was observed for either the patient version or the parent/carer version.
  • In the ‘weight problems’ domain of the parent/carer version, a statistically significant advantage of IVA + BSC over placebo + BSC was observed. However, the 95% confidence interval for Hedges’ g does not lie entirely outside the irrelevance range, meaning that the clinical relevance of this effect cannot be assessed.
  • Body Mass Index (BMI) and BMI z-score
  • In Study 103, a statistically significant advantage was observed for the BMI z-score in favour of ivacaftor + BSC compared with placebo + BSC; however, the extent of this advantage cannot be conclusively assessed.
  • Sweat chloride concentration (mmol/l)
  • A statistically significant difference in favour of ivacaftor + BSC compared with placebo + BSC was observed for the absolute change in sweat chloride concentration in the overall population (including children with a body weight < 25 kg).
• quality of life
  • Health-related quality of life measured using the CFQ-R
  • In the domains assessed for health-related quality of life using the CFQ-R, no statistically significant differences between treatment groups were observed in either the patient version or the parent/carer version.
• Side effects
  • The data on SAE are not usable, as no information is available on the nature of the events recorded for the relevant patient population (children with a body weight of 25 kg or more) . Furthermore, the SAE data for the overall population include, amongst other things, events that can be attributed to both side effects and morbidity and therefore cannot be assessed.
  • No data are available for estimating the effect size regarding the overall rate of AE events.
  • For the endpoint ‘discontinuation due to AEs’, there is no statistically significant difference between the treatment groups.
  • In the ‘side effects’ category, there is no statistically significant difference between the treatment arms when viewed as a whole.
• Overall assessment
  • For the re-benefit assessment following the exceeding of the 50 million euro turnover threshold for ivacaftor in the treatment of cystic fibrosis in patients aged 6 to 11 years who carry the G551D mutation in the CFTR gene, the pivotal, multicentre, randomised, double-blind, placebo-controlled Phase III trial 103 was submitted. This trial provided data on mortality, morbidity, quality of life and side effects.
  • No deaths occurred in Study 103.
  • For the endpoints of pulmonary exacerbations, hospitalisation due to pulmonary exacerbations, and the symptom domains assessed using the patient version of the CFQ-R, there were no statistically significant differences between the treatment arms. In the parent/carer version, in the ‘weight problems’ domain, a statistically significant difference was observed in favour of ivacaftor; however, the clinical relevance of this effect cannot be assessed.
  • For the BMI z-score endpoint, there is a statistically significant advantage in favour of ivacaftor compared with the comparator arm, although the extent of this advantage cannot be conclusively assessed. BMI and the BMI z-score are important in this indication, as developmental disorders and impaired nutrient absorption are among the typical signs of cystic fibrosis. This endpoint is considered a patient-relevant morbidity parameter, particularly in children with characteristic, disease-related growth disorders.
  • In the additional endpoints presented—FEV₁ and chloride concentration in sweat—statistically significant differences were observed in favour of ivacaftor compared with the control arm.
  • In the category of health-related quality of life, no statistically significant differences were observed between the treatment groups in the relevant domains of the CFQ-R, in either the patient or the parent/carer versions.
  • In the category of side effects, there was no statistically significant difference between the treatment arms when viewed as a whole.

b) Patients with cystic fibrosis with a G551D mutation in the CFTR gene aged 12 years and over

• Hint of a considerable additional benefit
• Taking the findings as a whole, a considerable additional benefit of ivacaftor compared with the appropriate comparator therapy can be inferred for patients aged 12 years and over in the present therapeutic indication.
• Due to the limitations mentioned above and given that only one study is available, the G-BA concludes that, at most, a hint of added benefit can be derived.
• mortality
  • No deaths occurred in Study 102.
• morbidity
  • Pulmonary exacerbations and hospitalisation due to pulmonary exacerbations
  • For the endpoint of pulmonary exacerbations, operationalised on the basis of event rates (number of events per patient-year), there is a statistically significant advantage of ivacaftor + BSC compared with placebo + BSC.
  • For the endpoint of hospitalisation due to pulmonary exacerbations, there were no statistically significant differences between the treatment groups.
  • Forced expiratory volume in one second (FEV1 %)
  • There is a statistically significant difference in favour of ivacaftor + BSC compared with placebo + BSC for both the absolute and relative change in the FEV1 value over 48 weeks.
  • There are differing views on the clinical relevance of FEV1%. This does not affect the overall conclusion regarding the extent of the additional benefit.
  • Symptoms measured using the Cystic Fibrosis Questionnaire-Revised (CFQ-R)
  • In the respiratory system domain, there is a statistically significant difference in favour of ivacaftor + BSC compared with placebo + BSC. The 95% confidence interval for Hedges’ g lies entirely outside the irrelevance threshold. This is interpreted as a clinically relevant effect.
  • In the domains of gastrointestinal symptoms and weight-related problems, no statistically significant differences were observed between the treatment groups.
  • Health status (EQ-5D VAS)
  • The assessment of health status using a VAS is considered to be relevant to patients. In Study 102, no statistically significant differences were observed between the treatment groups.
  • Body Mass Index (BMI) and BMI z-score
  • In Study 102, a statistically significant advantage was observed for the BMI z-score in favour of ivacaftor + BSC compared with placebo + BSC; however, the extent of this advantage cannot be conclusively assessed.
  • Sweat chloride concentration (mmol/l)
  • There was a statistically significant difference in the absolute change in sweat chloride concentration in favour of ivacaftor + BSC compared with placebo + BSC.
• quality of life
  • Health-related quality of life measured using the CFQ-R
  • In the domains of physical well-being, vitality and subjective health assessment, there are statistically significant differences in each case in favour of ivacaftor + BSC compared with placebo + BSC. In the domain of subjective health assessment in patients aged 14 years and over, the 95% confidence interval for Hedges’ g lies entirely outside the irrelevance range, meaning that the effect is interpreted as clinically relevant. In the domains of physical well-being and vitality (vitality in patients aged 14 years and over), there is evidence of an effect modification by the FEV1 at baseline. For patients with an FEV1 < 70% at the start of the study, the 95% confidence interval for Hedges’ g lies entirely outside the irrelevance range, meaning that a clinically relevant effect can only be assumed for these patients. For patients with an FEV1 of ≥ 70 %, there are no statistically significant differences between the treatment groups in either the well-being or vitality domains.
  • For the remaining domains, either there is no statistically significant difference between the treatment groups, or, where statistical significance is present, the clinical relevance of the effect cannot be assessed, as the 95% confidence interval for Hedges’ g lies, in some cases, within the irrelevance range.
• Side effects
  • The data on SAE are not usable, as, amongst other things, events were recorded that can be attributed to both side effects and morbidity and therefore cannot be assessed.
  • No data are available for estimating the effect in the results on the overall rate of AEs.
  • For the endpoint ‘discontinuation due to AEs’, there is no statistically significant difference between the treatment groups.
  • For the specific AEs of rash and dizziness, a statistically significant difference was observed in each case, to the detriment of ivacaftor + BSC compared with placebo + BSC.
• Overall assessment
  • For the benefit assessment following the exceeding of the 50 million euro threshold for ivacaftor for the treatment of cystic fibrosis in patients aged 12 years and over with a G551D mutation in the CFTR gene, the pivotal, multicentre, randomised, double-blind, placebo-controlled Phase III trial 102 was submitted. This trial provided data on mortality, morbidity, quality of life and side effects.
  • No deaths occurred in Study 102.
  • For the endpoints of pulmonary exacerbations and symptoms in the respiratory system domain, as assessed by the CFQ-R, there were statistically significant and clinically relevant advantages in favour of ivacaftor compared with the comparator arm.
  • For the BMI z-score endpoint, there was a statistically significant advantage in favour of ivacaftor compared with the comparator arm, although the extent of this advantage cannot be conclusively assessed.
  • Statistically significant differences in favour of ivacaftor compared with the comparator arm were also observed in the additional endpoints of FEV1 and change in sweat chloride concentration.
  • In the category of health-related quality of life, the domains of the CFQ-R corresponding to quality of life were assessed. For the domain of subjective health assessment in patients aged 14 years and over, a statistically significant and clinically relevant difference in favour of ivacaftor compared with placebo was observed. In the domains of physical well-being and vitality (the latter only for patients aged 14 and over), a statistically significant and clinically relevant difference was also observed in favour of ivacaftor compared with placebo.
  • In the ‘Side Effects’ category, statistically significant differences to the detriment of ivacaftor compared with placebo were observed for the specific AEs of dizziness and rash, with an extent that was no more than mild.

Courtesy translation only, please refer to the German original.