Dolutegravir (2) – Tivicay®

• Clinical trials
  • The SINGLE trial was a randomised, controlled, double-blind, multicentre Phase III trial involving 844 treatment-naïve adults infected with HIV-1.
  • The SAILING trial was a randomised, double-blind, actively controlled Phase III trial in HIV-infected adults who had previously received antiretroviral therapy (ART), with treatment groups comprising dolutegravir (N = 360) and raltegravir (N = 364), each with individualised background therapy determined by their respective resistance profiles.

a) HIV-1-infected children aged ≥ 6 years to < 12 years who had not previously received antiretroviral therapy

• An additional benefit is not proven
• The pharmaceutical manufacturer has not provided any data in its dossier regarding the investigation of dolutegravir in treatment-naïve children aged ≥ 6 to < 12 years.
• Extending the additional benefit of dolutegravir observed in treatment-naive adults to the patient group of treatment-naive children is not justified on the basis of the SINGLE and SPRING-1 studies, which formed the basis for the benefit assessment in adults.
• During the commenting procedure, the pharmaceutical manufacturer submitted analyses of these patients. However, the data submitted are incomplete. Firstly, the patient characteristics are not presented. Secondly, the pharmaceutical manufacturer has not provided analyses for all patient-relevant endpoints. Analyses are missing for the endpoints of severe adverse events (AE) of grade 3–4 (Division of AIDS [DAIDS]), psychiatric disorders (System Organ Class [SOC]) and musculoskeletal, connective tissue and bone disorders (SOC).
• Overall assessment / Conclusion
  • Additional benefit is not proven. For treatment-naïve children aged ≥ 6 years to < 12 years, there is no proof of additional benefit.
  • Based on the current state of scientific knowledge, there are insufficient grounds to extrapolate the evidence from studies involving adult patients for the purpose of benefit assessment.

b) HIV-1-infected children aged ≥ 6 years to < 12 years who have previously received antiretroviral treatment

• The additional benefit is not proven
• Extending the additional benefit of dolutegravir observed in treatment-experienced adults to the patient group of pre-treated children is not justified on the basis of the SAILING study, particularly as the study populations in the adult and paediatric studies are not sufficiently comparable.
• It has not been demonstrated that, for the children in study 0193, integrase inhibitors represent the first-line treatment option in the context of patient-specific antiretroviral therapy; consequently, a comparison with the results of the benefit assessment for treatment-experienced adult patients is not possible.
• The prerequisite that raltegravir would be a sufficiently safe and appropriate comparator therapy for pre-treated children is not met.
• For the children studied in trial 1093, the rate of serious adverse events was 13 per cent (3 out of 23 patients), which was higher than the 9.2 per cent observed in adults (33 out of 375 patients), although the comparability of the rates is limited due to the minor number of cases in the paediatric study 1093.
• Furthermore, patient characteristics differ in terms of baseline viral load, which was higher in the paediatric studies than in the adult studies. This also complicates the reliable extrapolation of the evidence, as it is known from other HIV medicinal products that viral load influences efficacy.
• Overall assessment / Conclusion
  • For treatment-experienced children aged ≥ 6 years to < 12 years, there is no proof of additional benefit.
  • The extrapolation of evidence in line with the current state of scientific knowledge with regard to the benefit assessment has not been sufficiently and reliably substantiated.
  • The study submitted by the pharmaceutical manufacturer in the therapeutic indication was not sufficiently substantiated to support the extrapolation of evidence, particularly due to the differences between the adult and paediatric studies regarding the baseline characteristic ‘baseline viral load’ and, furthermore, due to the moderately increased rate of serious adverse events under dolutegravir compared with adults, was not suitable with sufficient certainty for extrapolating the additional benefit established for adult patients to children.

Courtesy translation only, please refer to the German original.