Fingolimod (5) – Gilenya®

• Clinical trials
  • The PARADIGMS trial is a randomised, double-blind, active-controlled, parallel-group trial comparing fingolimod with interferon beta-1a (administered intramuscularly (i.m.)) in paediatric and adolescent patients with relapsing-remitting multiple sclerosis (RRMS).

a1) Children and adolescents aged ≥ 10 and < 18 years with highly active relapsing-remitting multiple sclerosis despite treatment with a complete and appropriate course of at least one disease-modifying therapy, for whom escalation of therapy is indicated.

• The additional benefit is not proven.
• No data were submitted for the assessment of the additional benefit of fingolimod compared with treatment at the doctor’s discretion for the management of previously treated children and adolescents with highly active relapsing-remitting multiple sclerosis for whom escalation of therapy is indicated.
• Consequently, no conclusions can be drawn regarding the additional benefit of fingolimod compared with the appropriate comparator therapy for this patient group.

a2) Children and adolescents aged ≥ 10 and < 18 years with highly active relapsing-remitting multiple sclerosis despite treatment with a complete and appropriate course of at least one disease-modifying therapy, for whom a change within the class of basic therapies is indicated.

• Hint for a non-quantifiable additional benefit.
• Overall, this therefore indicates a non-quantifiable additional benefit for fingolimod compared with interferon beta-1a.
• mortality
  • No deaths occurred during the blinded phase of the PARADIGMS trial.
• Morbidity – Confirmed relapses (EDSS-based)
  • Two measures are used to assess confirmed relapses (annual rate of confirmed relapses and time to first confirmed relapse). Both measures show an estimated effect in favour of fingolimod compared with interferon beta-1a.
  • However, a statistically significant advantage of treatment with fingolimod compared with treatment with interferon beta-1a is evident only for the endpoint ‘time to first confirmed relapse’.
  • No data on the median time to the first confirmed relapse are available for either treatment arm.
  • In contrast, no statistically significant difference was observed for the endpoint ‘annual rate of confirmed relapses’.
  • However, the endpoint “time to first confirmed relapse” does not allow conclusions to be drawn regarding the number of annual relapses, although this is of great importance to patients when assessing disease relapses.
  • Consequently, the extent of the advantage in terms of ‘time to first confirmed relapse’ cannot be quantified.
  • Overall, however, an advantage of fingolimod over interferon beta-1a is inferred for the relapse endpoint based on ‘time to first confirmed relapse’.
• Morbidity – Confirmed change in disability (EDSS-based)
  • To assess the confirmed change in disability, the operationalisations ‘confirmed disability progression’ and ‘confirmed improvement in disability’ are used.
  • For both operationalisations, there is no statistically significant difference between the treatment groups, meaning that neither an advantage nor a disadvantage can be inferred for treatment with fingolimod compared with treatment with interferon beta-1a.
• Health-related quality of life – PedsQL
  • Health-related quality of life was assessed using the PedsQL.
  • The PedsQL is a generic, validated questionnaire for self-assessment of health-related quality of life in children and adolescents.
  • For the benefit assessment, the continuous analyses of the total PedsQL score are used.
  • A statistically significant advantage of fingolimod over interferon beta-1a is evident for the mean difference pooled across the patient population following prior treatment.
  • To assess clinical relevance, Hedges’ g was estimated based on the effect estimates.
  • The calculation indicates an effect of the order of 1 standard deviation for the effect estimator (Hedges’ g: 0.97 [−0.02; 1.96]).
  • However, due to the minor sample size, the estimates for the 95% confidence interval are uncertain and, in terms of statistical significance, are not consistent with the result for the mean difference.
  • The confidence interval is therefore not useful for assessing the relevance of the effect.
  • Nevertheless, given the magnitude of the effect described (approximately 1 standard deviation), an advantage of fingolimod therapy over interferon beta for the described endpoint-1a therapy in terms of the health-related quality of life endpoint; however, the extent of this benefit is non-quantifiable due to the unclear clinical relevance.
• Side effects
  • The number of SUEs and therapy discontinuations due to AEs was minor in both treatment arms.
  • However, due to the very small number of patients, no reliable conclusions can be drawn regarding the potential for harm; consequently, the available data do not allow any advantage or disadvantage for fingolimod compared with interferon beta-1a to be inferred.
• Overall assessment
  • The benefit assessment was based on the randomised, double-blind, actively controlled PARADIGMS study, in which fingolimod was compared with interferon beta-1a (administered intramuscularly) in paediatric and adolescent patients with relapsing-remitting multiple sclerosis.
  • Patient population a2) comprises children and adolescents (aged ≥ 10 and < 18 years) with highly active relapsing-remittingrelapsing-remitting multiple sclerosis despite treatment with a full and appropriate course of at least one disease-modifying therapy, for which a change in basic therapy is indicated.
  • In the morbidity endpoint ‘confirmed relapses’, a statistically significant advantage was observed for treatment with fingolimod compared with treatment with interferon beta-1a in terms of the time to the first confirmed relapse.
  • However, this statistically significant advantage is not reflected in the annual relapse rate.
  • Consequently, no conclusions can be drawn regarding a reduction in the total number of relapses.
  • Consequently, the extent of the advantage of fingolimod cannot be quantified solely on the basis of the time to the first confirmed relapse.
  • There were no statistically significant differences between the treatment groups in the change in disability between baseline and the end of the study.
  • In the endpoint category of health-related quality of life, there is a statistically significant advantage of fingolimod compared with interferon beta-1a.
  • However, the assessment of the clinical relevance of this statistically significant advantage is subject to uncertainty, meaning that the extent of the advantage cannot be quantified.
  • In the endpoint category of side effects, neither advantages nor disadvantages for fingolimod compared with interferon beta-1a can be identified.
  • However, given the minor number of patients on which this assessment was based, the potential for harm associated with fingolimod cannot be conclusively assessed.
  • The extent of the statistically significant effects in favour of fingolimod in the morbidity endpoint ‘time to first confirmed relapse’ and in quality of life is classified as non-quantifiable.
  • Furthermore, the potential for harm associated with fingolimod cannot be conclusively assessed on the basis of the minor number of patients.

b1) Children and adolescents aged ≥ 10 and < 18 years with rapidly progressive severe relapsing-remitting multiple sclerosis, defined as two or more relapses with progression of disability within one year, and with one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesions compared with a recent MRI scan, who have not yet received any disease-modifying therapy.

• Hint for a non-quantifiable additional benefit.
• Overall, this therefore indicates a non-quantifiable additional benefit for fingolimod compared with interferon beta-1a.
• mortality
  • No deaths occurred during the blinded phase of the PARADIGMS study.
• Morbidity – Confirmed relapses (EDSS-based)
  • Two operationalisations are used to assess confirmed relapses (annual rate of confirmed relapses and time to first confirmed relapse).
  • For both measures, the effect estimate favours fingolimod over interferon beta-1a.
  • However, a statistically significant advantage of fingolimod over interferon beta-1a is evident only in the ‘annual rate of confirmed relapses’.
• Morbidity – Confirmed change in disability (EDSS-based)
  • To assess the confirmed change in disability, the operationalisations ‘confirmed disability progression’ and ‘confirmed improvement in disability’ are used.
  • Whilst there is no statistically significant difference between the treatment groups for confirmed disability progression, there is a statistically significant advantage in favour of fingolimod over interferon beta-1a for improvement in disability.
• Health-related quality of life – PedsQL
  • Health-related quality of life was assessed using the PedsQL.
  • The PedsQL is a generic, validated questionnaire for self-assessment of health-related quality of life in children and adolescents.
  • No statistically significant difference was observed between the treatment groups; consequently, neither an advantage nor a disadvantage can be inferred for treatment with fingolimod compared with treatment with interferon beta-1a.
• Side effects
  • No statistically significant differences were observed between the two treatment groups for the SAE endpoint.
  • No therapy discontinuations due to AEs occurred.
  • However, due to the very small number of patients, no reliable conclusions can be drawn regarding the potential for harm; consequently, the available data do not allow for the identification of any advantage or disadvantage of fingolimod compared with interferon beta-1a.
• Overall assessment
  • The benefit assessment was based on the randomised, double-blind, actively controlled PARADIGMS study, in which fingolimod was compared with interferon beta-1a (administered intramuscularly) in paediatric and adolescent patients with relapsing-remitting multiple sclerosis.
  • The patient population (b1) comprises treatment-naïve children and adolescents (aged ≥ 10 and < 18 years) with rapidly progressing severe relapsing-remitting multiple sclerosis, defined as two or more relapses with disability progression within one year, and with one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesions compared with a recent MRI scan.
  • For the morbidity endpoint ‘confirmed relapses’, the annual relapse rate shows a statistically significant advantage for treatment with fingolimod compared with treatment with interferon beta-1a.
  • However, there is no statistically significant difference between the treatment groups in the time to the first confirmed relapse.
  • For the morbidity endpoint ‘change in disability’ between baseline and the end of the study, there is a statistically significant difference in the improvement in disability in favour of fingolimod compared with interferon beta-1a.
  • However, no statistically significant differences were observed between the two treatment groups in terms of disability progression.
  • Given that it is not proven with sufficient certainty that disability progression occurred in the included children and adolescents within the preceding twelve months, and that they therefore fully correspond to the target population, there are uncertainties to such an extent that the advantages in the endpoints ‘annual relapse rate’ and ‘improvement in disability’ cannot be conclusively assessed.
  • The extent of the additional benefit is therefore non-quantifiable for the relevant target population.
  • In the endpoint categories of health-related quality of life and side effects, there is no statistically significant difference between fingolimod and interferon beta-1a in either case.
  • The statistically significant effects in favour of fingolimod in the morbidity endpoints ‘annual relapse rate’ and ‘improvement in disability’ are non-quantifiable in terms of extent due to the existing uncertainties.
  • Furthermore, there was no proof that treatment with fingolimod has a positive effect on the quality of life of children and adolescents.
  • Moreover, the potential for harm associated with fingolimod cannot be conclusively assessed on the basis of the minor number of patients.
  • It follows that, based on the data presented, the overall advantages of fingolimod cannot be quantified.

b2) Children and adolescents aged ≥ 10 and < 18 years with rapidly progressive severe relapsing-remitting multiple sclerosis, defined as two or more relapses with disability progression within one year, and with one or more gadolinium-enhancing lesions on brain MRI or with a significant increase in T2 lesions compared with a recent MRI scan, despite disease-modifying therapy.

• The additional benefit is not proven.
• No relevant data are available for assessing the additional benefit of fingolimod compared with treatment at the clinician’s discretion for the treatment of children and adolescents with rapidly progressive severe relapsing-remitting multiple sclerosis despite treatment with disease-modifying therapy.
• The PARADIGMS study cannot be used to derive any additional benefit, as all children and adolescents included in the comparator arm of the study received interferon beta-1a regardless of prior treatment.
• Consequently, the appropriate comparator therapy, ‘treatment as directed by the doctor’, has not been implemented.
• Consequently, no conclusions can be drawn regarding the additional benefit of fingolimod compared with the appropriate comparator therapy for this patient group.

Courtesy translation only, please refer to the German original.