Amikacin (liposomal) (1) – Arikayce liposomal®

• Clinical trials
  • CONVERT is a multicentre, open-label, randomised trial designed to investigate the efficacy and safety of liposomal amikacin for inhalation as an adjunct to combination therapy (multi-drug regime, MDR)(N = 224) compared with MDR alone (N = 112) in adult patients with pulmonary Mycobacterium avium complex(MAC) infection and without cystic fibrosis.

Adult patients with lung infections caused by non-tuberculous mycobacteria (NTM) belonging to the Mycobacterium avium complex (MAC), with limited treatment options, who do not have cystic fibrosis

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• Overall, given the strength of the evidence, only a hint of added benefit can be assumed.
• mortality
  • The mortality data presented for month 8 show only minor numbers of deaths (3 in each study arm: amikacin+MDR: 1.3%; MDR: 2.7%); however, no effect estimators were provided.
  • In the mortality category, there are no hints to suggest any advantages or disadvantages of amikacin.
• Morbidity – freedom from pathogens
  • Evidence of pathogen-free status is based on patients’ sputum samples. Consequently, the endpoint must be regarded as a laboratory parameter and constitutes a surrogate parameter that is not, in itself, relevant to the patient.
  • No data on surrogate validation were provided. In the present therapeutic indication, freedom from the pathogen is a necessary prerequisite for improvement in pulmonary MAC infection, which is why the endpoint can be considered as a supplementary factor in the benefit assessment.
  • For a robust assessment as part of the benefit assessment, additional comparative data would be required, showing at least an improvement in symptoms or quality of life associated with pathogen-free status. However, no such data were provided.
  • The primary study endpoint in the statistical analysis plan applicable to the European authorisation procedure was defined as the proportion of individuals who achieved sustained pathogen-free status three months after discontinuation of the entire course of treatment.
  • Statistically significant effects in favour of amikacin were observed. The proportion of patients who were pathogen-positive at baseline and pathogen-free after 12 months of treatment was 18.3%. Three months after the end of treatment, 16.1% of patients were still pathogen-free, and by the end of the 12-month follow-up period, this figure had fallen to 13.4%.
  • The endpoints of relapses and new infections were only evaluated descriptively in the study and are not used for benefit assessment.
• Morbidity – 6-minute walk test
  • The walking distance covered within 6 minutes, assessed in accordance with the American Thoracic Society guidelines, is considered relevant to patients.
  • The potential for bias in the analysis of the 6-minute walk test is assessed as high, as it is unclear whether the blinding of study staff for the 6-minute walk test could be maintained in this otherwise unblinded study, and due to the significantly higher proportion of missing values in the intervention arm.
  • Overall, the analyses carried out showed no statistically significant difference between the study arms.
  • The analyses of the 6-minute walk distance showed no statistically significant differences between the treatment arms.
• Morbidity – EQ-5D VAS
  • Patients’ assessment of their own health status is a patient-relevant endpoint, and assessment using the visual analogue scale (VAS) of the EQ-5D questionnaire is considered adequate.
  • However, due to a difference of more than 15% in the proportion of missing values (24% in the intervention arm and 6% in the control arm at month 6), the results are considered to be highly biased.
  • The pharmaceutical manufacturer did not carry out any imputation of missing values. The endpoint cannot therefore be conclusively assessed and cannot be used for the benefit assessment.
• Quality of life – St George’s Respiratory Questionnaire (SGRQ)
  • Health-related quality of life was assessed in the study using the St George’s Respiratory Questionnaire (SGRQ).
  • However, due to a difference of more than 15% in the proportion of missing values (25% in the intervention arm and 7% in the control arm at month 6), the results are considered to be highly biased.
  • The pharmaceutical manufacturer did not carry out any imputation of missing values. The endpoints cannot therefore be conclusively assessed and cannot be used for the benefit assessment.
• Side effects
  • Up to the analysis point at month 8, the study revealed statistically significant differences to the detriment of amikacin therapy in terms of severe adverse events (AEs, CTCAE grade ≥ 3) and adverse events leading to therapy discontinuation.
  • No data are available on the severe AEs that occurred at month 8; it therefore remains unclear which severe AEs (at SOC or PT level) account for the difference between the study arms.
  • There are no statistically significant differences in serious AEs (SAEs).
  • Among the AEs with an incidence of ≥ 10% in at least one treatment arm, there are numerical disadvantages for amikacin (differences of at least 10% between the treatment arms) in the SOC ‘Respiratory, thoracic and mediastinal disorders’ (in this case, dysphonia, cough and dyspnoea in the PT data), ‘Gastrointestinal disorders’, ‘General disorders and administration site conditions’ and ‘Nervous system disorders’. No statistical analysis was provided.
  • Furthermore, among AEs of particular interest with an incidence of ≥ 10% in at least one treatment arm, numerical disadvantages were also observed for the events bronchospasm, haemoptysis, ototoxicity, infectious exacerbation of the underlying condition and other respiratory events. No statistical analysis was provided.
  • Up to month 8, an increased incidence of side effects is observed with amikacin.

Courtesy translation only, please refer to the German original.