Nintedanib (Ofev, 3) – Ofev®

• Clinical trials
  • The SENSCIS trial was a randomised, controlled, double-blind, multinational Phase III trial. In the SENSCIS trial, a total of 580 patients were randomised in a 1:1 ratio to the intervention arm (nintedanib + best supportive care (BSC); N=290) or the control arm (placebo + BSC; N=290).

Adult patients with interstitial lung disease associated with systemic sclerosis (SSc-ILD)

• The additional benefit is not proven.
• In its overall assessment, the G-BA therefore concludes that additional benefit from nintedanib compared with BSC is not proven for the treatment of adult patients with SSc-ILD.
• mortality
  • For the endpoint of overall survival, the SENSCIS 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)
  • For the endpoint of annual FVC decline [ml], the SENSCIS study showed 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 supplementary purposes only.
• Morbidity – Functional Assessment of Chronic Illness Therapy (FACIT) – Dyspnoea
  • The FACIT-Dyspnoea questionnaire is used to assess the severity of breathlessness and its functional impact on various activities of daily living. The FACIT-Dyspnoea questionnaire consists of the breathlessness score and the functional limitations score.
  • For the shortness of breath score, no statistically significant difference was found between the treatment groups in the SENSCIS study.
  • For the functional limitations score, a statistically significant disadvantage was observed for nintedanib + BSC compared with placebo + BSC. However, the 95% confidence interval for Hedges’ g does not lie entirely outside the irrelevance range, meaning that the clinical relevance of the effect observed in the mean difference cannot be assessed.
• Quality of life – St George’s Respiratory Questionnaire (SGRQ)
  • Health-related quality of life was assessed in the SENSCIS study using the SGRQ as a change from baseline at the end of the study. The SGRQ comprises the domains of symptoms, activity and daily living. A reduction in the score indicates an improvement.
  • 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 – is considered to be insufficiently validated. Instead, the IQWiG considers the mean difference in change from the start to the end of the study for the total SGRQ score.
  • No statistically significant difference was observed between the treatment groups for the total SGRQ score.
  • Regardless of whether responder analyses based on a response criterion (reduction of ≥ 4 points) can be taken into account for this indication, the study shows no statistically significant difference between the treatment groups for the SGRQ endpoint.
• Side effects
  • For the endpoint of serious adverse events (SAEs), the SENSCIS study showed no statistically significant difference between nintedanib + BSC and placebo + BSC.
  • For the endpoint of discontinuation due to adverse events, the SENSCIS study identified a statistically significant disadvantage compared with nintedanib + BSC compared with placebo + BSC, which was primarily due to diarrhoea. With the exception of diarrhoea, no information is available on the severity of the AEs that led to therapy discontinuation.
  • With regard to specific AEs, the SENSCIS 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.
  • For the endpoints ‘Metabolic and nutritional disorders’ (SOC) and ‘Vascular disorders’ (SOC), a statistically significant disadvantage of nintedanib + BSC compared with placebo + BSC was observed in the SENSCIS study. However, it is questionable whether the side effect in the SOC ‘vascular disorders’ should be classified as a side effect or whether it may reflect symptoms of the disease SSc-ILD.
  • The ADRs in the SOCs ‘Gastrointestinal disorders’, ‘Metabolic and nutritional disorders’ and ‘Vascular disorders’ were, for the most part, not serious. The ADRs in the PT ‘Diarrhoea’, on the other hand, are classified as serious side effects (CTCAE ≥ 3).
  • Overall, there are adverse effects associated with nintedanib compared with BSC.
• Overall assessment
  • Overall, there are negative effects for nintedanib compared with BSC in the endpoints ‘VAS bowel problems’ of the SHAQ and discontinuation due to AEs.
  • Given the gastrointestinal side effects reported for nintedanib, it is reasonable to assume that the observed negative effect in the ‘morbidity’ category of the SHAQ’s VAS for bowel problems is also, at least in part, attributable to the side effects of nintedanib and not solely to changes in disease-specific symptoms.
  • In view of the positive marketing authorisation decision and having weighed up the available data, the G-BA concludes in this case that the identified disadvantages of nintedanib + BSC compared with placebo + BSC do not lead to the conclusion that there is less benefit. In its overall assessment, the G-BA therefore concludes that additional benefit from nintedanib compared with BSC is not proven for the treatment of adult patients with SSc-ILD.

Courtesy translation only, please refer to the German original.