Tixagevimab / Cilgavimab (1) – Evusheld®

• Clinical trials
  • The TACKLE trial is an ongoing, double-blind, randomised controlled trial comparing treatment with tixagevimab/cilgavimab with placebo in adult patients in the early stages of COVID-19.

a) Adults with COVID-19 who do not require supplementary oxygen therapy and who are at increased risk of a severe course of COVID-19 if infected with a viral variant against which tixagevimab/cilgavimab demonstrates significantly reduced or insufficient efficacy

• For the treatment of adult patients with COVID-19 who do not require additional oxygen therapy, who are at increased risk of a severe course of COVID-19, and who are infected with a viral variant against which tixagevimab/Cilgavimab has significantly reduced or no adequate efficacy, and the additional benefit is not proven.
• Tixagevimab/Cilgavimab therefore demonstrates significantly reduced or no efficacy against the Omicron variants (BA.2.75; BA.5; XBB.1 and their respective sub-lineages) (as demonstrated by in vitro neutralisation tests).
• Consequently, for adults infected with a SARS-CoV-2 variant for which there is evidence, or due to the current pandemic situation, that tixagevimab/Cilgavimab (currently Omicron variants) – no conclusion can be drawn regarding the additional benefit of treating COVID-19 with Tixagevimab/Cilgavimab.
• For this patient population (patient population a), an additional benefit of tixagevimab/cilgavimab over the appropriate comparator therapy is not proven.

b) Adults with COVID-19 who do not require supplemental oxygen therapy and who are at increased risk of a severe course of COVID-19 following infection with a viral variant against which tixagevimab/cilgavimab demonstrates sufficient efficacy

• For the treatment of adult patients with COVID-19 who do not require additional oxygen therapy, who are at increased risk of a severe course of COVID-19, and who are infected with a viral variant against which tixagevimab/Cilgavimab has sufficient efficacy, there is a hint of a minor additional benefit of Tixagevimab/Cilgavimab compared with the appropriate comparator therapy.
• The certainty of the study results for the present question is therefore reduced overall. Overall, significant uncertainties therefore remain regarding the transferability to the German healthcare context; when considered in the overall assessment of certainty, these justify the conclusion that there is an indication of additional benefit.
• mortality
  • No statistically significant difference was observed between the treatment groups for the endpoint of all-cause mortality.
• Morbidity – severe COVID-19
  • In the TACKLE study, the endpoint ‘severe COVID-19’ is defined as the occurrence of at least one of the following events by day 29: - Pneumonia (fever, cough, tachypnoea or dyspnoea and pulmonary infiltrates) - Hypoxaemia (oxygen saturation < 90% on room air and/or severe shortness of breath) - A WHO score of 5 or higher on the clinical progression scale for COVID-19
  • For the endpoint of severe COVID-19, there was a statistically significant advantage for tixagevimab/cilgavimab compared to the other treatment groups.
• Morbidity – admission to an intensive care unit for any reason
  • For the endpoint of admission to an intensive care unit for any cause, there was no statistically significant difference between the treatment groups.
• Morbidity – hospitalisation for any cause
  • For the endpoint of hospitalisation for any cause, there was a statistically significant advantage for tixagevimab/cilgavimab compared to the other treatment groups.
• Morbidity – return to normal health
  • For the endpoint ‘return to normal health’, there was no statistically significant difference between the treatment groups.
• Morbidity – COVID-19 symptoms
  • No suitable data are available for the endpoint ‘COVID-19 symptoms’. The analyses submitted by the pharmaceutical manufacturer cannot be meaningfully interpreted, as no conclusions can be drawn regarding the burden of symptoms on patients.
• Health-related quality of life
  • Endpoints relating to health-related quality of life were not assessed in the included study.
• Side effects – severe adverse events (SAEs)
  • No statistically significant difference was observed between the treatment groups for the SUE endpoint.
• Side effects – severe adverse events (AEs)
  • No suitable data are available for the endpoint ‘severe AEs’, as the severity of AEs was not assessed using an established classification system but according to categories defined by the pharmaceutical manufacturer.
• Side effects – Discontinuations due to adverse events (AEs)
  • No events occurred for the endpoint ‘withdrawal due to AEs’.
• Side effects – Hypersensitivity reactions and injection site reactions
  • There are therefore no suitable data available for the endpoint ‘hypersensitivity reactions and injection site reactions’.
• Overall assessment / Conclusion
  • In the mortality category, there was no statistically significant difference between the treatment groups for the endpoint of all-cause mortality.
  • The morbidity endpoints – severe COVID-19, hospitalisation for any cause, admission to an intensive care unit for any cause, and return to normal health – are used for the benefit assessment. For the endpoints ‘severe COVID-19’ and ‘hospitalisation for any cause’, statistically significant advantages were observed in favour of tixagevimab/cilgavimab. However, due to the partially overlapping definition of the two endpoints, double counting of events cannot be ruled out. For the other endpoints – admission to an intensive care unit for any cause and return to normal health – no statistically significant differences were observed between the treatment groups.
  • No endpoints were assessed in the health-related quality of life category. For the endpoints in the side effect category, there were neither advantages nor disadvantages for tixagevimab/cilgavimab.
  • In summary, positive effects are evident in the morbidity category, with no adverse effects to counterbalance them.
  • Taking an overall view of the results, based on the positive effects observed in the endpoints of severe COVID-19 and hospitalisation for any cause, a modest additional benefit compared with standard medical care is inferred for adults with COVID-19 for the treatment of infections with a viral variant against which tixagevimab/cilgavimab has sufficient neutralising activity, a minor additional benefit is inferred compared with treatment as clinically indicated.

c) Adolescents aged 12 to < 18 years with a body weight of at least 40 kg who have COVID-19, do not require additional oxygen therapy and are at increased risk of a severe course of COVID-19

• For the treatment of adolescent patients with COVID-19 who do not require additional oxygen therapy and who are at increased risk of a severe course of COVID-19, the additional benefit is not proven.
• No data are available for adolescents aged 12 to < 18 years with a body weight of at least 40 kg who do not require additional oxygen therapy and who are at increased risk of a severe course of COVID-19 (see study description for patient population b).
• For this age group, the additional benefit of tixagevimab/cilgavimab is therefore not proven.

Courtesy translation only, please refer to the German original.