Nintedanib (Ofev, 4) – Ofev®

• Clinical trials
  • The INBUILD trial was a randomised, controlled, double-blind Phase III trial.
  • In the INBUILD trial, a total of 663 patients were randomised in a 1:1 ratio to the intervention arm (nintedanib + best supportive care (BSC); N=332) or the control arm (placebo + BSC; N=331).

Adult patients with other chronic, progressive, fibrosing interstitial lung diseases (ILDs) [excluding idiopathic pulmonary fibrosis (IPF) and interstitial lung disease associated with systemic sclerosis (SSc-ILD)]

• Consequently, based on the criteria set out in Section 5(7) of the AM-NutzenV, and taking into account the severity of the disease, the written submissions and the oral hearing, the G-BA has determined that, for adult patients with chronic PF-ILD, that treatment with nintedanib provides a minor additional benefit.
• Overall, in terms of certainty of evidence, there is an indication of additional benefit.
• mortality
  • For the endpoint of overall survival, the INBUILD study showed no statistically significant difference between the treatment groups.
  • 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)
  • The endpoint ‘annual decline in forced vital capacity (FVC)’ was assessed as the primary endpoint at week 52 in the INBUILD study.
  • For the endpoint ‘annual decline in FVC [ml]’, the INBUILD study demonstrated a statistically significant advantage of nintedanib + BSC compared with placebo + BSC.
  • FVC is a surrogate endpoint. The data submitted by the pharmaceutical manufacturer for surrogate validation of the patient-relevant endpoint of mortality are insufficient to infer any additional benefit for the mortality endpoint based on FVC, due to shortcomings in data collection and methodological deficiencies.
  • Due to the insufficient validation, the results for this endpoint are presented for information purposes only.
• quality of life
  • Quality of life in adult patients with chronic PF-ILD was assessed in the INBUILD study using the Living with Pulmonary Fibrosis (L-PF) and Pulmonary Fibrosis Impact on Quality of Life Scale (PF-IQOLS) instruments.
  • The L-PF questionnaire is derived from the L-IPF, which was developed for patients with IPF and is itself a further development of the questionnaire ‘A Tool to Assess Quality of Life in IPF’ (ATAQ-IPF).
  • The analyses submitted by the pharmaceutical manufacturer are based on version 1.0 of the L-PF questionnaire, comprising 44 items. This questionnaire is considered to be insufficiently validated.
  • Furthermore, the analyses submitted by the pharmaceutical manufacturer during the commenting procedure regarding the various response criteria are incomplete. For the response threshold of 15 per cent of the scale range, analyses are missing for the ‘Fatigue’ score as a sub-score of the symptoms module. Overall, the analyses of the L-PF are therefore not usable for the present assessment.
  • No usable data were submitted in the quality of life category.
• Side effects
  • For the endpoint of serious adverse events (SAE), the INBUILD study showed no statistically significant difference between nintedanib + BSC and placebo + BSC.
  • For the endpoint of discontinuation due to AEs, the INBUILD study identified a statistically significant disadvantage compared with nintedanib + BSC compared with placebo + BSC, which was primarily due to diarrhoea.
  • With regard to specific adverse events, the INBUILD study identified a statistically significant disadvantage of nintedanib + BSC compared with placebo + BSC for the endpoint ‘gastrointestinal disorders’ (System Organ Class (SOC)). This effect is largely attributable to the Preferred Term (PT) ‘diarrhoea’ included in this SOC, for which a statistically significant disadvantage of nintedanib + BSC compared with placebo + BSC was also observed.
  • In addition, a statistically significant disadvantage was observed for the PT ‘reduced appetite’, which is included in the SOC ‘Metabolic and nutritional disorders’. For the endpoint ‘reduced appetite’, an effect modification was observed based on the characteristic of age. For patients aged ≥ 65, there was no statistically significant difference between the treatment arms. For patients aged < 65, a statistically significant disadvantage of nintedanib compared with BSC was observed.
  • For the endpoint ‘liver and biliary disorders’ (SOC), the INBUILD study found a statistically significant disadvantage of nintedanib + BSC compared with placebo + BSC.
  • The side effects (AEs) in the SOC ‘Gastrointestinal disorders’ and in the PT ‘Decreased appetite’ were, for the most part, not serious. By contrast, the side effects in the PT ‘Diarrhoea’ (CTCAE ≥ 3) and in the SOC ‘Liver and biliary disorders’ are classified as serious side effects.
  • In the ‘Side Effects’ category, the overall assessment for nintedanib is negative compared with BSC.
• Overall assessment
  • The randomised, controlled, double-blind Phase III INBUILD trial was presented for the benefit assessment of nintedanib in the treatment of adult patients with other chronic progressive fibrosing interstitial lung diseases (PF-ILDs). The INBUILD study provides results on mortality, morbidity and side effects.
  • For the endpoint of overall survival, the INBUILD study showed no statistically significant difference between the treatment groups.
  • In the morbidity category, a statistically significant advantage of nintedanib + BSC over placebo + BSC was observed for the composite endpoint of acute exacerbation or death.
  • For the endpoint of symptoms, assessed using the K-BILD total score, the INBUILD study showed no statistically significant difference between the treatment groups.
  • For the EQ-5D VAS endpoint, which measures health status, no statistically significant difference was observed between the treatment groups.
  • No usable data were presented in the quality of life category.
  • In the side effects category, no statistically significant difference was observed in the INBUILD study between nintedanib + BSC and placebo + BSC for the endpoint of serious adverse events (SAEs).
  • For the endpoint ‘discontinuation due to adverse events’, a statistically significant disadvantage compared with nintedanib + BSC compared with placebo + BSC was observed in the INBUILD study, which was primarily due to diarrhoea.
  • In detail, adverse effects of nintedanib + BSC compared with placebo + BSC were observed for specific adverse events.
  • In the category of side effects, there are overall side effects for nintedanib compared with BSC.
  • Having weighed up the available data, the G-BA concludes that there is a minor additional benefit of nintedanib compared with BSC for the treatment of adult patients with chronic PF-ILD.

Courtesy translation only, please refer to the German original.