Tofacitinib (2) – Xeljanz®

• Clinical trials
  • The ORAL STANDARD trial is a randomised, multicentre, double-blind, 52-week RCT with a parallel-group design.
  • The benefit assessment is therefore based on data from the two relevant study arms: tofacitinib + MTX (intervention arm) and adalimumab + MTX (comparison arm).
  • The second Phase III trial relevant to the benefit assessment, ORAL STRATEGY, is a randomised, multicentre, double-blind, parallel-group trial with a study duration of 12 months.

b2) Tofacitinib in combination therapy with MTX

• For bDMARD-naive patients for whom treatment with bDMARDs is indicated for the first time, the additional benefit of tofacitinib in combination with MTX compared with the appropriate comparator therapy, adalimumab + MTX, is not proven.
• In light of these considerations, based on the information in the dossier, the results of the benefit assessment and the addendum, the G-BA considers that the additional benefit of tofacitinib + MTX compared with the appropriate comparator therapy, adalimumab + MTX, for the treatment of patients with moderate to severe rheumatoid arthritis who are eligible for bDMARD therapy for the first time, is not proven.
• mortality
  • Overall mortality did not differ statistically significantly between the two treatment groups.
• Morbidity – Remission (CDAI ≤ 2.8; SDAI ≤ 3.3; Boolean definition according to ACR-EULAR)
  • Remission is defined as achieving a CDAI ≤ 2.8. At week 52, approximately the same number of patients achieved remission with tofacitinib+MTX or adalimumab+MTX (meta-analysis – overall RR: 1.14 [0.88; 1.49]; p-value = 0.324).
  • For the endpoint ‘remission’, in line with the results of the operationalisation as CDAI ≤ 2.8, neither the operationalisation as SDAI ≤ 3.3, nor the operationalisation using the Boolean definition according to ACR-EULAR show statistically significant differences between tofacitinib+MTX and adalimumab+MTX.
  • Overall, for the endpoint of remission, tofacitinib+MTX showed neither a positive nor a negative effect compared with adalimumab+MTX.
• Morbidity – Low disease activity (DAS28-4 ESR ≤ 3.2; DAS28-4 CRP ≤ 3.2, SDAI ≤ 11, CDAI ≤ 10)
  • For the endpoint of low disease activity (DAS28-4 ESR ≤ 3.2) the meta-analysis of the two studies, ORAL STANDARD and ORAL STRATEGY, shows a statistically significant effect to the detriment of the intervention arm (tofacitinib + MTX) compared with the comparator arm (adalimumab + MTX) (overall RR: 0.79 [0.65; 0.95]; p-value = 0.013).
  • However, the effect to the detriment of tofacitinib + MTX is not confirmed either by the operationalisation DAS28-4 C-reactive protein (DAS28-4 CRP) ≤ 3.2, nor by the operationalisations SDAI ≤ 11 or CDAI ≤ 10.
  • Overall, therefore, no advantage or disadvantage for tofacitinib + MTX compared with adalimumab + MTX can be inferred in terms of low disease activity.
• Morbidity – number of joints tender to pressure
  • The meta-analysis reveals no statistically significant difference between tofacitinib+MTX and adalimumab+MTX in the proportion of patients with ≤ 1 tender joint at week 52.
• Morbidity – number of swollen joints
  • In the meta-analytical assessment of the two studies, based on 28 joints, no statistically significant effect of tofacitinib plus MTX compared with adalimumab plus MTX was observed for the proportion of patients with ≤ 1 swollen joint at week 52.
• Morbidity – pain (VAS)
  • In the meta-analysis of the two studies, no statistically significant difference in the mean change was observed between tofacitinib plus MTX and adalimumab plus MTX.
• Morbidity – Disease activity (VAS via Patient Global Assessment of Arthritis [PatGA])
  • The meta-analysis showed no statistically significant difference in the mean change when comparing tofacitinib plus MTX with adalimumab plus MTX.
• Morbidity – Fatigue (improvement of ≥ 4 points on the FACIT-F)
  • For the patient-relevant endpoint of fatigue, assessed using the validated self-report instrument FACIT-F, the meta-analysis showed no statistically significant effect in the comparison of treatment arms regarding the proportion of patients with an improvement of ≥ 4 points at week 52.
• Morbidity – Physical functional status (improvement in HAQ-DI of ≥ 0.22 points)
  • For the patient-relevant endpoint of physical functional status (improvement in HAQ-DI of ≥ 0.22 points), the meta-analysis showed no statistically significant difference between the treatment groups.
• Morbidity – Sleep problems (Medical Outcome Study (MOS) sleep score)
  • No usable data are available for the ORAL STANDARD study regarding the endpoint of sleep problems (MOS sleep score). This endpoint was not assessed in the ORAL STRATEGY study.
• Morbidity – Health status (EQ-5D VAS)
  • For the mean change in the patient-relevant endpoint of health status, assessed using the EQ-5D VAS, the ORAL STRATEGY study showed no statistically significant advantage or disadvantage for tofacitinib+MTX compared with adalimumab+MTX. This endpoint was not assessed in the ORAL STANDARD study.
• Quality of life – Health Survey Short Form 36 (SF-36) (improvement of ≥ 5 points on the SF-36)
  • In the analyses of the proportion of patients showing an improvement of ≥ 5 points in the physical and mental health summary scores, the meta-analysis revealed no statistically significant effect in favour of either treatment regimen.
• Side effects – severe adverse events (SAE)
  • For the SAE endpoint, the meta-analysis shows no statistically significant advantage or disadvantage of tofacitinib+MTX compared with adalimumab+MTX.
• Side effects – discontinuation due to adverse events (AE), infections
  • For the patient-relevant endpoints of discontinuation due to AEs and infections, the meta-analysis revealed no statistically significant advantage or disadvantage of tofacitinib+MTX compared with adalimumab+MTX in either case.
• Overall assessment
  • In summary, for the endpoint categories of mortality, morbidity (remission, low disease activity, fatigue, pain, patient-reported disease activity, swollen and tender joints, physical functional status or health status), as well as quality of life, no statistically significant advantages or disadvantages for tofacitinib + MTX compared with the appropriate comparator therapy, adalimumab + MTX.
  • Nor, when viewed as a whole, can any advantages or disadvantages be identified for tofacitinib + MTX compared with the appropriate comparator therapy, adalimumab + MTX, in the category of side effects.

Courtesy translation only, please refer to the German original.