Nintedanib (Ofev, 1) – Ofev®

• Clinical trials
  • The INPULSIS trials comprise two identically designed, multicentre, randomised, double-blind, placebo-controlled Phase IIIstudies investigating the efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis over a period of 52 weeks.

a) Adult patients with idiopathic pulmonary fibrosis (IPF)

• For adult patients with idiopathic pulmonary fibrosis (IPF), nintedanib offers a minor additional benefit.
• The G-BA classifies the extent of the additional benefit of nintedanib 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.
• mortality
  • Time to all-cause death and time to respiratory death
  • The proportion of patients who died within the 52-week observation period in the respective study arms did not differ statistically significantly in the INPULSIS-1 and INPULSIS-2 trials.
  • A total of 5.5% of patients in the nintedanib arm and 7.8% of patients in the placebo arm died during the study (hazard ratio (HR): 0.70; 95% confidence interval (CI): [0.43; 1.12]; p = 0.13), with 3.8% and 5.0% of patients, respectively, dying as a result of a respiratory event (HR: 0.74; 95% CI: [0.41; 1.33]; p = 0.31).
  • In the INPULSIS trials, no statistically significant difference was found between the intervention and control arms for the endpoint of mortality.
• Morbidity – time to first (adjudicated) acute exacerbation
  • The time to first acute exacerbation was defined as the time between randomisation and the occurrence of a major acute deterioration in the patient’s clinical condition caused by the underlying IPF.
  • With regard to the proportion of patients who experienced an acute exacerbation within 52 weeks, statistically significant advantages of nintedanib over placebo were observed in the INPULSIS-2 study (HR: 0.38; 95% CI: [0.19; 0.77]; p = 0.005; adjudicated: HR: 0.20; 95% CI: [0.07; 0.56]; p = 0.002), but not in the INPULSIS-1 trial (HR: 1.15; 95% CI: [0.54; 2.42]; p = 0.6728; adjudicated: HR: 0.55; 95% CI: [0.20; 1.54]; p = 0.2551).
  • In the pooled analysis of events across both studies, there was an advantage with regard to adjudicated exacerbations confirmed or suspected by the IAC (HR: 0.33; 95% CI: [0.12; 0.90]; p = 0.0299).
  • However, the certainty of evidence for the endpoint of adjudicated acute exacerbations is limited, as there is a high potential for bias at the endpoint level.
  • Despite the heterogeneity of the effects in the two studies with identical designs, INPULSIS-1 and -2, the G-BA assumes that nintedanib provides additional benefit with regard to acute exacerbations of IPF.
• Health-related quality of life – quality of life (St George’s Respiratory Questionnaire (SGRQ))
  • Health-related quality of life was assessed in the INPULSIS studies using the St George’s Respiratory Questionnaire (SGRQ), a questionnaire validated for chronic lung diseases.
  • At 52 weeks, a statistically significantly minor decrease in the proportion of patients in the INPULSIS-2 study receiving nintedanib resulted in a deterioration of at least 4 points compared with those on placebo (risk ratio (RR): 1.49; 95% CI: [1.05; 2.11]; p = 0.0218).
  • The change in mean difference (MWD) was also statistically significant (MWD: –2.69; 95% CI: [–4.95; –0.43]; p = 0.0197). In the INPULSIS-1 study, however, there was no statistically significant difference between the treatment arms.
  • The results for the IPF-specific version of the SGRQ are not suitable for determining additional benefit due to the unclear validity of the data calculated from the SGRQ data using a transformation equation.
• Side effects
  • The positive effects of nintedanib are offset by adverse events.
  • In the INPULSIS-1 study (RR: 1.09; 95% CI: [1.03; 1.15]; p < 0.001) and in the pooled analysis of the results from both studies (RR: 1.06; 95% CI: [1.03; 1.11]; p = 0.001), there was a statistically significant difference to the detriment of nintedanib in terms of the overall rate of adverse events.
  • Similarly, in the INPULSIS-1 trial, a statistically significantly higher proportion of patients in the intervention arm had to discontinue treatment due to an adverse event (RR: 1.95; 95% CI: [1.24; 3.06]; p = 0.002).
  • With regard to other overall rates (including CTCAE grade ≥ 3 adverse events and serious adverse events), either no usable data were available or no statistically significant difference was identified.
  • The study protocol defined the gastrointestinal side effects diarrhoea, nausea, vomiting, loss of appetite and weight loss a priori as adverse events of particular interest.
  • With the exception of loss of appetite (RR: 1.23; 95% CI: [0.66; 2.29]; p = 0.521) and weight loss (RR: 1.27; 95% CI: [0.67; 2.42]; p = 0.467) in the INPULSIS-1 trial, the adverse events of particular interest occurred statistically significantly more frequently across all trials and in the pooled analysis when patients were treated with nintedanib.
  • Overall, the side effects are considered to be significant for patients.
• Conclusion
  • However, when the available results on mortality, morbidity and quality of life are considered together with the findings on side effects, nintedanib does not demonstrate a clear improvement in treatment-related benefit that has not previously been achieved – in particular, no prolongation of survival, no noticeable relief of the disease for patients, and no significant reduction in serious side effects.
  • Therefore, a classification as ‘considerable additional benefit’ is not justified.
  • In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this constitutes a previously unattained moderate—and not merely minor—improvement in treatment-related benefit, as a reduction in disease symptoms in terms of the time to the first adjudicated exacerbation, supported by positive results regarding health-related quality of life.

Courtesy translation only, please refer to the German original.