Immunologi:

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    • SELECT-COMPARE: Study design

      A Phase 3 study investigating the efficacy and safety of RINVOQ 15 mg + MTX compared with placebo + MTX and adalimumab + MTX for the treatment of moderate to severe RA in patients who had an inadequate response to MTX2,4

      *Rescue criteria: At Weeks 14, 18, and 22, patients receiving adalimumab or placebo were switched to RINVOQ and patients receiving RINVOQ were switched to adalimumab if <20% improvement in tender joint count and swollen joint count vs baseline. At Week 26, all remaining placebo patients who were not rescued were switched to RINVOQ, and patients receiving RINVOQ or adalimumab were switched to adalimumab and RINVOQ, respectively, if CDAI >10.

       

      Primary 
      RINVOQ 15 mg + MTX vs Placebo + MTX at Week 12 for DAS28(CRP)

      Safety 
      Adverse events, serious adverse events, adverse events of special interests (e.g., serious infections, opportunistic infections, MACEs, VTEs, malignancies)

      CDAI: Clinical Disease Activity Index; DAS28 (CRP): disease activity score with 28 joint count (C-reactive protein); EOW: every other week; MACE: major adverse cardiovascular event; MTX: methotrexate; QD: once daily; VTE: venous thromboembolic event.

        

      Significantly greater remission rates vs placebo + MTX and adalimumab + MTX (DAS28)  

      SELECT-COMPARE: Remission (DAS28 [CRP] <2.6) rates at Week 12 (NRI)1,2

      † P≤0.001 vs placebo + MTX 
      ‡ P≤0.001 vs adalimumab + MTX  
      §Indicates multiplicity-controlled comparison of RINVOQ + MTX vs placebo + MTX.

       

      DAS28 (CRP) <2.6 for RINVOQ + MTX vs placebo + MTX at Week 12 was a primary endpoint controlled for multiplicity. DAS28 (CRP) <2.6 for RINVOQ + MTX vs adalimumab + MTX at Week 12 was a prespecified nonranked endpoint not controlled  for multiplicity; nominal P-value is provided.

      DAS28 (CRP): Disease activity score with 28-joint count (C-reactive protein); MTX: methotrexate; NRI: nonresponder imputation.

       

      RINVOQ 15 mg + MTX showed better effect vs adalimumab + MTX at Week 12:

      SELECT-COMPARE2

       

      Superiority for ACR50, Δ pain, and Δ HAQ-DI for RINVOQ + MTX vs adalimumab + MTX at Week 12 were ranked key secondary endpoints for FDA controlled for multiplicity. Δ HAQ-DI for RINVOQ + MTX vs placebo + MTX at Week 12 was a ranked key secondary endpoint for EMA controlled for multiplicity. All other data shown were prespecified nonranked endpoints not controlled for multiplicity; nominal P-values are provided.

      *P≤0.001 vs placebo + MTX 
      P≤0.001 vs adalimumab + MTX 
      P≤0.01 vs adalimumab + MTX 
      §Indicates muliplicity-controlled superiority comparison of RINVOQ + MTX vs adalimumab + MTX.

      IIIndicates muliplicity-controlled comparison of RINVOQ + MTX vs placebo + MTX.

      ACR50: improvement of at least 50% in the American College of Rheumatology core criteria; ANCOVA: analysis of covariance; EMA: European Medicines Agency; FDA: Food and Drug Administration; HAQ-DI: Health Assesment Questionnaire Disabliity Index; MTX: methotrexate; NRI: nonresponder imputation; VAS: visual analogue scale.

       

      RINVOQ 15 mg: Joint protection over time

      SELECT-COMPARE: Inhibition of structural joint damage progression at Week 26 (linear extrapolation)1,2

      SELECT-COMPARE: Inhibition of structural joint damage progression at Week 48 (linear extrapolation)1,3

      Change in mTSS for RINVOQ + MTX vs placebo + MTX at Week 26 was a ranked secondary endpoint controlled for multiplicity. All other data shown for RINVOQ + MTX vs placebo + MTX were prespecified nonranked endpoints not controlled for multiplicity; nominal P-values are provided. No statistical comparisons were made between RINVOQ and adalimumab groups for radiographic endpoints.

      *P≤0.001 vs placebo + MTX 
      Indicates multiplicity-controlled comparison of RINVOQ + MTX vs placebo + MTX.

      Treatment groups are by initial randomization. For the placebo group, all data at Week 48 were imputed by linear extrapolation. X-ray data collected at treatment switching or at discontinuation of placebo (for patients who discontinued placebo) were used for extrapolation. Specifically, for placebo patients who switched to RINVOQ at Week 26, the Week 26 x-ray was used for extrapolation to impute the data at Week 48. For patients randomized to RINVOQ or adalimumab who were rescued, data at Week 48 were also imputed by linear extrapolation using x-ray data collected at treatment switching.1-3

      LS: least squares; mTSS: modified total Sharp score; MTX: methotrexate; MTX-IR: inadequate response to MTX.

       

      SELECT-COMPARE: Adverse events through 26 weeks of treatment2*

      *Adverse events were collected and summarized up to Week 26 and censored as follows: For patients who remained on initially randomized treatment up to Week 26, all events up to Week 26 were included; for patients who met the rescue criteria at Week 14, 18 or 22, events that occurred starting the day of initiation of rescue treatment were excluded. 
      One patient randomized to RINVOQ received only a placebo injection before discontinuing and is included in the placebo group for safety assessments. 
      Deaths: In the placebo + MTX group, there was 1 cardiovascular (CV) death and 1 death due to Pneumocystis jirovecii pneumonia. In the adalimumab + MTX group, there was 1 death due to craniocerebral injury and 1 CV death. 
      §Only 1 case of latent tuberculosis was reported (in the RINVOQ + MTX group). 
      IIHepatic disorders: Primarily liver function test elevation. 
      Gastrointestinal perforation (identified using GI perforation Standardized MedDRA Queries): not spontaneous perforations but 1 peritonitis and 1 anal abscess. 
      #Malignancies: In the placebo + MTX group, there was 1 cervical carcinoma and 1 basal cell carcinoma. In the adalimumab + MTX group, there was 1 basal cell carcinoma.
      **Major adverse cardiovascular events (adjudicated): In the placebo + MTX group, there were 2 nonfatal myocardial infarctions and 1 CV death. In the adalimumab + MTX group, there was 1 nonfatal stroke and 1 CV death.
      ††Only patients who continued on initially randomized study drug are included in the analysis.

      CPK: creatine phosphokinase; LS: least squares; MTX: methotrexate.

       

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      Referanser

      1. RINVOQ SPC avsnitt 5.1, sist oppdatert 21.05.2021.
      2. Fleischmann R, Pangan AL, Song IH, et al. Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase 3, double-blind, randomized controlled trial [published online July 9, 2019]. Arthritis Rheumatol. doi:10.1002/art.41032 
      3. Fleischmann RM, Genovese MC, Enejosa JV, et al. Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response [published online July 30, 2019]. Ann Rheum Dis. doi:10.1136/annrheumdis-2019-215764
      4. Supplementary Figure 1, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.41032/abstract

       

      NO-RNQ-210031v1.0juni/2021