Immunologi:
Våra terapiområden

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      SELECT-COMPARE: Study design

      A Phase 3 study investigating the efficacy and safety of RINVOQ + 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

      select-compare-chart-1

      *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) <2.6 (EMA) or ACR20 (FDA)

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

      • Patients ≥18 years of age were eligible to participate. 
      • Diagnosis of RA for ≥3 months fulfilling the 2010 ACR/EULAR classification for RA with active disease (≥6 swollen joints of 66, ≥6 tender joints of 68 examined, hsCRP ≥5 mg/L), and at least one of the following at screening: ≥3 erosions on x-rays of hands and feet, or ≥1 erosion and positivity for RF or ACCP.
      • Patients must have had an inadequate response to MTX. 
      • Patients with prior exposure to at most 1 bDMARD (except adalimumab) were eligible (up to 20% of total study number of patients) if they had either limited exposure (<3 months) or had to discontinue the bDMARD due to intolerability.
      • Patients with inadequate response to prior bDMARDs or prior exposure to a JAK inhibitor were excluded.

      ACCP: anti-cyclic citrullinated protein; ACR: American College of Rheumatology; ACR20: improvement of at least 20% in the American College of Rheumatology core criteria; bDMARD: biological disease-modifying antirheumatic drug; CDAI: Clinical Disease Activity Index; DAS28 (CRP): disease activity score with 28 joint count (C-reactive protein); EMA: European Medicines Agency;  EOW: every other week; EULAR: European League Against Rheumatism; FDA: Food & Drug Administration; hsCRP: high-sensitivity C-reactive protein; MACE: major adverse cardiovascular event; MTX: methotrexate; QD: once daily; RF: rheumatoid factor; VTE: venous thromboembolic event.

        

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      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

      rinvoq-select-compare-remission-rates_retouched_sv
      select-compare-chart-key

       

      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.


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

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

       

      STUDY DESIGN
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      Remission (DAS28 [CRP] <2.6) rates through year 3 (NRI)1,2,3,4,5

      COMPARE w156 remission-das28

      ††DAS28 (CRP) <2.6 for RINVOQ + MTX vs placebo + MTX at Week 12 was a primary multiplicity-controlled endpoint. All other data shown between Week 12 and 48 were prespecified nonranked non-multiplicity controlled endpoints; nominal P-values are provided. Treatment groups are by initial randomization. For binary endpoints shown by randomized treatment group, non-responder imputation (NRI) was applied for rescue, premature discontinuation of study drug, and missing data. Data from Week 60 onwards were nonranked non-multiplicity controlled endpoints obtained from the ongoing long-term extension of SELECT-COMPARE.

       

      STUDY DESIGN
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      RINVOQ + MTX was superior to adalimumab + MTX at Week 12 on: 

      SELECT-COMPARE2

      SELECT_COMPARE (002)

       

      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.

       

      STUDY DESIGN
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      RINVOQ: Joint protection over time

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

      select-compare-chart-5

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

      select-compare-chart-6

      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.

       

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

      compare-table

      *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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      SELECT-COMPARE: Treatment-emergent adverse event summary through 156 weeks5

      COMPARE adverse-events-156-weeks

      *Exposure adjusted incidence rates (EAIR) are reported for malignancy, MACE, VTE, and death; exposure adjusted event rates (EAER) are reported for the remaining events. Data include all patients receiving RINVOQ or ADA, including rescue groups, with assignment based on drug exposure at the time of event. One treatment-emergent adjudicated GI perforation (preferred term: anal fistula) was identified in the RINVOQ-treatment group.

      †Majority of cases on RINVOQ were non-serious and involved 1 or 2 dermatomes. Three events were reported as ophthalmic HZ (2 on RINVOQ and 1 on ADA). No events were reported as having central nervous system or other noncutaneous involvement.

      ‡Opportunistic infections (excluding TB, HZ, and oral candidiasis): RINVOQ: 4 esophageal candidiasis, 2 oral fungal infection, 1 bronchopulmonary aspergillosis, 1 fungal pharyngitis, 1 GI candidiasis, and 1 meningitis listeria. ADA: 1 esophageal candidiasis and 1 sinusitis fungal. Event rates for oral candidiasis were 0.2 and 0.3 E/100PY for RINVOQ and ADA, respectively.

      §Malignancies, excluding NMSC: RINVOQ: 3 lung cancer, 3 malignant melanoma, 2 breast cancer; all other malignancies occurred in a single patient, including colon cancer, myxoid liposarcoma, laryngeal cancer, glioblastoma, endometrial adenocarcinoma, gastric adenocarcinoma, squamous cell carcinoma of the oral cavity, metastatic squamous cell carcinoma, adenocarcinoma, and malignant neoplasm of unknown primary site. ADA: 2 lung cancer, 1 malignant melanoma, 3 colon cancer, and 1 B-cell lymphoma.

      IIMACE (includes CV death, non-fatal MI, non-fatal stroke): RINVOQ: 2 non-fatal strokes, 4 non-fatal MIs, 4 CV deaths; ADA: 3 non-fatal strokes, 1 CV death.

      ¶VTE: RINVOQ: 1 venous thromboembolic death, 3 non-fatal DVT, 3 non-fatal PE, 2 concurrent DVT and PE; ADA: 4 PE, 1 DVT.

      #Hepatic disorders: majority were ALT/AST elevations, with no Hy’s law case identified.

      **CPK elevation: a majority were mild or moderate, asymptomatic, and transient.

      ††Deaths (including non-treatment emergent deaths defined as having occurred >30 days after last dose of RINVOQ or >70 days after last dose of ADA): RINVOQ: per CAC Decision, 4 CV deaths (CV; such as acute myocardial infarction, cardiac failure, sudden death) and 12 non-CV deaths including infections (sepsis, meningitis, nosocomial infection), cancers, and other non-CV causes of death (such as pelvic fracture) or undetermined/unknown causes. ADA: based on CAC decision, 2 CV deaths (such as left ventricular failure) and 7 non-CV deaths including infections (pneumonia), cancers, and other non-CV causes of death (such as craniocerebral injury) or undetermined/unknown cause.

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      Minimiinformation

      Se fullständig produktresumé

      RINVOQ® (upadacitinib), depottablett 15 mg, 30 mg, 45 mg (F), Rx, ATC-kod L04AA44 selektivt immunsuppressivt medel, JAK-hämmare. Indikationer: måttlig till svår aktiv reumatoid artrit hos vuxna med otillräckligt behandlingssvar på eller intolerans mot ett eller flera DMARDs i monoterapi eller i kombination med metotrexat. Aktiv psoriasisartrit hos vuxna med otillräckligt behandlingssvar på eller intolerans mot ett eller flera DMARDs, i monoterapi eller i kombination med metotrexat. Axial spondylartrit: – Aktiv icke-radiografisk axial spondylartrit hos vuxna med objektiva tecken på inflammation som anges av förhöjda nivåer av CRP och/eller MRI, som har otillräckligt behandlingssvar på NSAID. – Aktiv ankyloserande spondylit (radiografisk axial spondylartrit) hos vuxna med otillräckligt behandlingssvar på konventionell behandling. Måttlig till svår atopisk dermatit hos vuxna och ungdomar 12 år och äldre vilka är aktuella för systemisk behandling. Måttlig till svår aktiv ulcerös kolit eller Crohns sjukdom hos vuxna med otillräckligt behandlingssvar, förlorat behandlingssvar eller som varit intoleranta mot konventionell behandling eller biologiska läkemedel. Kontraindikationer: Överkänslighet mot den aktiva substansen eller mot något hjälpämne. Aktiv tuberkulos (TB) eller aktiv allvarlig infektion. Gravt nedsatt leverfunktion. Graviditet. Varningar och försiktighet: RINVOQ ska endast användas om inga lämpliga behandlingsalternativ är tillgängliga för patienter: som är 65 år eller äldre; med en anamnes på aterosklerotisk hjärt-kärlsjukdom eller andra kardiovaskulära riskfaktorer (t.ex. nuvarande eller tidigare långtidsrökare); med riskfaktorer för malignitet (t.ex. nuvarande eller tidigare malignitet). RINVOQ ska inte påbörjas hos patienter med aktiva, allvarliga infektioner, inkl. lokala infektioner och TB. Virusreaktivering, inkl. fall av reaktivering av herpesvirus (t.ex. herpes zoster), har rapporterats i kliniska studier. Påbörja inte eller avbryt tillfälligt behandling om onormala lab-värden som anemi, neutropeni, lymfopeni och levertransaminaser påträffas. RINVOQ associerades med ökade lipidparametrar i kliniska studier. Divertikulit och gastrointestinal perforation har rapporteras i kliniska prövningar och från klinisk erfarenhet. Patienter med aktiv Crohns sjukdom löper ökad risk att utveckla tarmperforation. VTE har rapporterats hos patienter på RINVOQ. Hos patienter med kända VTE-riskfaktorer ska RINVOQ användas med försiktighet. Allvarliga överkänslighetsreaktioner har rapporterats med RINVOQ. Fertilitet, graviditet och amning: Fertila kvinnor ska rådas använda effektiv preventivmetod under behandling och i minst 4 veckor efter avslutad behandling. RINVOQ är kontraindicerat under graviditet och ska inte användas under amning. För fullständig information om indikation, kontraindikationer, varningar och försiktighet, biverkningar, pris och dosering, se Fass.se. För information: kontakta AbbVie AB, 08 684 44 600. Datum för översyn av produktresumén: 19 december 2023. Begränsning av läkemedelsförmån: RINVOQ subventioneras 1) när behandling med TNF-hämmare gett otillräcklig effekt eller inte är lämplig 2) för patienter med atopisk dermatit när konventionell topikal eller systemisk behandling gett otillräcklig effekt eller inte är lämplig. 

      ▼Detta läkemedel är föremål för utökad övervakning.

      SE-RNQ-220026 v 7.0 Senast uppdaterad 2024-02-26

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      References

      1. RINVOQ produktresumé
      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. Arthritis Rheumatol. 2019 71: 1788-1800. 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. Flesichman R, Song IH, Enejosa J, et al. Long term safety and effectiveness of upadacitinib or adalimumab in patients with rheumatoid athritis: results at 72 weeks from the SELECT-COMPARE study. Ann Rheum Dis. 2020; 79: 323. 
      5. Fleischmann R; Mysler E, Bessette L, et al POS0087. Long-Term Safety and Efficacy of Upadacitinib or Adalimumab in Patients With Rheumatoid Arthritis: Results at 3 Years From the SELECT-COMPARE Study. Poster presented at EULAR 2021.

       

      SE-RNQ-220007 v 2.0 Senast uppdaterad 2022-10-12