Nintedanib (Ofev, 2) – Ofev®

• Clinical trials
  • Study 1199.187 is a randomised (1:1 ratio), controlled, double-blind Phase IIIb trial comparing nintedanib with placebo.

Adult patients with idiopathic pulmonary fibrosis

• mortality
  • For the endpoint of overall survival (time to death from any cause), the meta-analysis of the four studies INPULSIS-1, INPULSIS-2, 1199.187 and TOMORROW, no statistically significant difference was observed between nintedanib + BSC and placebo + BSC.
  • Consequently, the additional benefit of nintedanib + BSC compared with placebo + BSC for the endpoint of mortality is not proven.
• Morbidity – Annual decline in forced vital capacity (FVC)
  • For the endpoint of annual FVC decline [ml], the meta-analysis of the INPULSIS-1, INPULSIS-2 and 1199.187, a statistically significant advantage of nintedanib + BSC over placebo + BSC (MWD [95% CI]: 112.42 [79.06; 145.77]; p<0.0001).
  • FVC is a surrogate endpoint. The data submitted by the pharmaceutical manufacturer for the validation of the surrogate marker for the patient-relevant endpoint of mortality are insufficient, due to shortcomings in data collection and methodological deficiencies, to infer any additional benefit for the endpoint of mortality on the basis of FVC.
  • Due to the insufficient validation, the results for this endpoint are presented for supplementary purposes only.
• Quality of life – St George’s Respiratory Questionnaire (SGRQ)
  • Health-related quality of life was assessed in the INPULSIS-1, INPULSIS-2, TOMORROW and 1199.187 studies using the SGRQ to measure change at the end of the study.
  • In the IQWiG’s dossier assessment, the responder analyses submitted by the pharmaceutical manufacturer were not taken into account, as the response criterion used for this analysis – the MID – was deemed insufficiently validated.
  • For the SGRQ endpoint, significant differences were observed in the INPULSIS-2 study (MD [95% CI]: -2.69 [-4.95; -0.43]; p=0.020) and TOMORROW (MD [95% CI]: -6.12 [-10.57; -1.67]; p=0.007), a statistically significant advantage of nintedanib + BSC over placebo + BSC was demonstrated.
  • However, the 95% confidence interval for Hedges’ g in each case does not lie entirely outside the irrelevance range of –0.2 to 0.2, meaning that the clinical relevance of these effects cannot be assessed.
  • In the INPULSIS-1 and 1199.187 studies, no statistically significant difference was found between the treatment groups in either case.
  • For the SGRQ endpoint, the INPULSIS-2 study (RR [95% CI]: 1.49 [1.05; 2.11]; p=0.022) and TOMORROW (RR [95% CI]: 1.81 [1.01; 3.23]; p=0.048), a statistically significant advantage of nintedanib + BSC over placebo + BSC was observed in the responder analysis.
  • By contrast, the effect estimates from the INPULSIS-1 and 1199.187 studies suggest a disadvantage for nintedanib.
  • In summary, for the SGRQ endpoint—defined as a reduction of ≥ 4 points—there is neither an advantage nor a disadvantage for nintedanib.
• Side effects
  • For the endpoint of serious adverse events (SAEs), the meta-analysis of the INPULSIS-1, INPULSIS-2, TOMORROW and 1199.187, no statistically significant difference was observed between nintedanib + BSC and placebo + BSC.
  • For the endpoint of discontinuation due to adverse events, the meta-analysis of the INPULSIS-1, INPULSIS-2, TOMORROW and 1199.187 studies showed no statistically significant difference between the treatment groups.
  • With regard to specific adverse events, for the endpoint ‘gastrointestinal disorders’ (System Organ Class (SOC)), the meta-analysis of the INPULSIS-1, INPULSIS-2, TOMORROW and 1199.187, a statistically significant disadvantage of nintedanib + BSC compared with placebo + BSC was observed (RR [95% CI]: 1.92 [1.48; 2.49]; p=0.004).
  • This effect is largely attributable to the PTs (Preferred Terms) included in this SOC – diarrhoea, nausea, vomiting and upper abdominal pain – for each of which a statistically significant disadvantage of nintedanib + BSC compared with placebo + BSC was also observed.
• Overall assessment
  • A total of four RCTs were used for benefit assessment of nintedanib for the treatment of adult patients with idiopathic pulmonary fibrosis (the INPULSIS-1, INPULSIS-2, 1199.187 and TOMORROW studies).
  • For the endpoint of overall survival (time to death from any cause), the meta-analysis of the four studies INPULSIS-1, INPULSIS-2, 1199.187 and TOMORROW, no statistically significant difference was observed between nintedanib + BSC and placebo + BSC.
  • In the morbidity category, the meta-analyses conducted to compare nintedanib + BSC with placebo + BSC showed a statistically significant and clinically relevant benefit for the endpoints ‘time to first adjudicated acute exacerbation’ and ‘change in respiratory status (PGI-C (responder analysis))’ demonstrated a statistically significant and clinically relevant advantage.
  • For the health status endpoint (EQ-5D VAS), the meta-analysis showed an advantage of nintedanib + BSC over placebo + BSC; however, the clinical relevance of this statistically significant improvement cannot be assessed.
  • For the endpoints ‘need for oxygen therapy’, ‘6MWT’, ‘cough’ (CASA-Q) and ‘dyspnoea’ (SOBQ), no statistically significant difference was found between the treatment groups in any case.
  • In the quality of life category, for the SGRQ endpoint, there was no overall advantage or disadvantage of nintedanib + BSC compared with placebo + BSC, whether considering the mean differences or the SGRQ responders (reduction of ≥ 4 points).
  • In the side effects category, a statistically significant disadvantage of nintedanib + BSC compared with placebo + BSC was observed for the specific side effects relating to the endpoint ‘gastrointestinal disorders’ (SOC) in the meta-analysis of the INPULSIS-1, INPULSIS-2, TOMORROW and 1199.187, a statistically significant disadvantage of nintedanib + BSC compared with placebo + BSC was identified.
  • The advantage in the morbidity category for the endpoint ‘adjudicated acute exacerbation’ is classified as considerable and is further supported by the clinically relevant advantage in the endpoint ‘change in respiratory status (PGI-C)’ within the morbidity category.
  • However, the observed disadvantage of nintedanib in the ‘Side Effects’ category, as measured by the ‘Gastrointestinal disorders’ endpoint, does not lead to a downgrading of the extent of the additional benefit in the G-BA’s assessment.

Courtesy translation only, please refer to the German original.