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SELECT-COMPARE - MTX inadequate responder patients2

A comparison of RINVOQ + MTX to adalimumab + MTX and placebo + MTX2

RINVOQ + MTX demonstrated significant remission vs adalimumab + MTX at all timepoints from Week 8 to Week 1563,4


SELECT-COMPARE: Remission (DAS28-CRP <2.6) rates over time (NRI)3,4

*nominal p≤0.001 RINVOQ + MTX vs PBO + MTX.
p≤0.001 RINVOQ + MTX vs PBO + MTX.
nominal p≤0.01 RINVOQ + MTX vs ADA + MTX.
§nominal p≤0.001 RINVOQ + MTX vs ADA + MTX.

Vertical line at Week 26 indicates the end of the placebo-controlled period.
#Vertical line at Week 48 indicates the start of the long-term extension phase.

The primary endpoint of SELECT-COMPARE: Clinical remission (DAS28-CRP <2.6) RINVOQ + MTX vs placebo + MTX at Week 12, was met (p<0.001).2

Treatment groups are by initial randomisation. Per protocol, patients were rescued (RINVOQ to ADA, PBO to RINVOQ, and ADA to RINVOQ) at Weeks 14, 18, or 22 based on improvement in SJC+TJC, or Week 26 based on CDAI LDA. All PBO patients not previously rescued (at Weeks 14, 18, or 22) were switched to RINVOQ at Week 26. Patients rescued at Week 26 (due to not meeting CDAI LDA) were imputed as non-responder for each subsequent visit. For binary endpoints shown by randomised treatment group, NRI was applied for rescue, premature discontinuation of study drug, and missing data. For continuous endpoints by randomised treatment group, LOCF was applied for rescue; missing data were not imputed.3

Data analyses are in patients with moderate to severe RA across all studies of RINVOQ’s Phase III EMA registrational programme.1,3

ADA = adalimumab; CDAI = clinical disease activity index; CRP = C-reactive protein; DAS28 = disease activity score 28 joints; LDA = low disease activity; LOCF = last observation carried forward; MTX = methotrexate; NRI = non-responder imputation; RA = rheumatoid arthritis; SJC = swollen joint count; TJC = tender joint count.

Upadacitinib versus Placebo or Adalimumab in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomised Controlled Trial. Fleischman et al., 2019.

RINVOQ + MTX demonstrated superiority to adalimumab + MTX at Week 12 in HAQ-DI and pain, with significance sustained to Week 1562,3,5

SELECT-COMPARE: HAQ-DI and pain LS mean change from baseline at Weeks 12, 72 and 156 (LOCF)2,3,5

                                            HAQ-DI                                                                     PAIN

Patients who switched from placebo PBO, ADA, or MTX on to RINVOQ were included in the RINVOQ analysis set from the start of RINVOQ treatment, while those who switched from RINVOQ to ADA were included in the ADA dataset from the start of ADA treatment3

*p≤0.001 RINVOQ + MTX vs placebo + MTX.
p<0.01 RINVOQ + MTX vs adalimumab + MTX.
nominal p≤0.01 RINVOQ + MTX vs adalimumab + MTX.
§p≤0.001 RINVOQ + MTX vs adalimumab + MTX.
nominal p≤0.001 RINVOQ + MTX vs adalimumab + MTX.

HAQ-DI is rated on a 0–3 scale; patient’s assessment of pain is scored on a 0–100 mm scale.3

The primary endpoint of SELECT-COMPARE: Clinical remission (DAS28-CRP <2.6) RINVOQ + MTX vs placebo + MTX at Week 12, was met (p<0.001).2

Treatment groups are by initial randomisation. Per protocol, patients were rescued (RINVOQ to ADA, PBO to RINVOQ, and ADA to RINVOQ) at Weeks 14, 18, or 22 based on improvement in SJC+TJC, or Week 26 based on CDAI LDA. All PBO patients not previously rescued (at Weeks 14, 18, or 22) were switched to RINVOQ at Week 26. Patients rescued at Week 26 (due to not meeting CDAI LDA) were imputed as non-responder for each subsequent visit. For binary endpoints shown by randomised treatment group, NRI was applied for rescue, premature discontinuation of study drug, and missing data. For continuous endpoints by randomised treatment group, LOCF was applied for rescue; missing data were not imputed.3

Data analyses are in patients with moderate to severe RA across all studies of RINVOQ’s Phase III EMA registrational programme.1,3

ADA = adalimumab; CDAI = clinical disease activity index; CRP = C-reactive protein; DAS28 = disease activity score 28 joints; HAQ-DI = Health Assessment Questionnaire Disability Index; LS = least-squares; LDA = low disease activity; LOCF = last observation carried forward; MTX = methotrexate; NRI = non-responder imputation; RA = rheumatoid arthritis; SJC = swollen joint count; TJC = tender joint count.

Upadacitinib versus Placebo or Adalimumab in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomised Controlled Trial. Fleischmann et al., 2019.

SELECT-COMPARE: SF-36 domain scores at Week 128

p≤0.001 RINVOQ + MTX vs PBO + MTX all domains
p<0.001 RINVOQ + MTX vs ADA 40 mg + MTX: RP, BP, GH; p=0.005: VT; p=0.007: SF; p=0.03: PF domains

Graphs adapted from source material

The 36-Item Short Form Health Survey (SF-36) consists of two aggregate [Physical (PCS) and Mental Component Summary (MCS)] scores based on eight domains, measured on a scale of 0-100 where a higher score indicates better health.8

For SF-36(PCS), RINVOQ showed statistically significant improvements from baseline vs placebo at Week 12 (7.9 vs 3.6, p<0.05).

SF-36 for RINVOQ vs adalimumab at Week 12 and individual SF-36 scores were not prespecified endpoints, so the p values are descriptive only.

Domains include:

  • PF, physical functioning
  • RP, role-physical
  • BP, bodily pain
  • GH, general health
  • VT, vitality
  • SF, social functioning
  • RE, role-emotional
  • MH, mental health

 

The primary endpoint of SELECT-COMPARE: Clinical remission (DAS28-CRP <2.6) RINVOQ + MTX vs placebo + MTX at Week 12, was met (p<0.001).2

cMTX = continued methotrexate; CRP = C-reactive protein; DAS28 = disease activity score 28 joints; MTX = methotrexate.

Upadacitinib versus Placebo or Adalimumab in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomised Controlled Trial. Fleischman et al., 2019.

RINVOQ + MTX inhibited radiographic progression over time6,7

SELECT-COMPARE: Inhibition of structural joint damage progression at Week 266

SELECT-COMPARE: Inhibition of structural joint damage progression at Week 96#7

Graphs adapted from source material. Results based on reading session 2. The primary endpoint of SELECT-COMPARE: Clinical remission (DAS28-CRP <2.6) RINVOQ + MTX vs placebo + MTX at Week 12, was met.2

*p≤0.001 RINVOQ + MTX vs placebo + MTX. Nominal p=NS RINVOQ + MTX vs adalimumab + MTX. #p values not reported for Week 96 data.

Treatment groups are by initial randomisation. X-ray data collected at treatment switching or at discontinuation of placebo (for patients who discontinued placebo) were used for extrapolation.5 At Week 26, all patients receiving placebo + MTX who were not previously rescued at Weeks 14, 18, or 22 were switched to RINVOQ + MTX, regardless of response. X-rays of both hands and feet were collected at baseline, Week 26, Week 48, and Week 96.7

Patients who switched from placebo, adalimumab or MTX on to RINVOQ were included in the RINVOQ analysis set from the start of RINVOQ treatment, while those who switched from RINVOQ to adalimumab were included in the adalimumab data set from the start of adalimumab treatment.

CRP = C-reactive protein; DAS28 = disease activity score 28 joints; LS = least squares; mTSS = modified total sharp score; MTX = methotrexate.

Upadacitinib versus Placebo or Adalimumab in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomised Controlled Trial. Fleischmann et al., 2019.

Study design

A Phase III 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 MTX2,3,6

*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 + MTX vs PBO + MTX at Week 12: DAS28-CRP <2.6

Key secondary 

RINVOQ + MTX vs PBO + MTX at Week 12: DAS28-CRP ≤3.2, Change from baseline in DAS28-CRP, HAQ-DI, SF-36 PCS, CDAI ≤10, Change in morning stiffness duration, Change in FACIT-F

RINVOQ + MTX vs PBO + MTX at Week 26: Change in mTSS, % with mTSS ≤0 

RINVOQ + MTX vs adalimumab + MTX at Week 12: DAS28-CRP ≤3.2 

 

  • 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 anti-CCP antibodies
  • 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

Anti-CCP antibodies = anti-cyclic citrullinated protein; ACR = American College of Rheumatology; bDMARD = biological disease-modifying antirheumatic drug; CDAI = clinical disease activity index; CRP = C-reactive protein; DAS28 = disease activity score 28 joints; EOW = every other week; EULAR = European League Against Rheumatism; FACIT-F = Functional Assessment of Chronic Illness Therapy-Fatigue; HAQ-DI = Health Assessment Questionnaire Disability Index; hsCRP = high-sensitivity C-reactive protein; mTSS = modified total sharp score; MTX = methotrexate; PBO = placebo; OD = once daily; RA = Rheumatoid Arthritis; RF = rheumatoid factor; SF-36 PCS = Short Form (36) Health Survey Physical Component Score.

Upadacitinib versus Placebo or Adalimumab in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomised Controlled Trial. Fleischmann et al., 2019.


SELECT-NEXT - csDMARD inadequate responder patients9

A comparison of RINVOQ + csDMARD(s) to placebo + csDMARD(s)9

RINVOQ + csDMARD(s) demonstrated a significantly greater DAS28-CRP remission rate and Lower Disease Activity rate than placebo + csDMARD(s) at Week 12 (NRI)9

Graphs adapted from source material. Primary endpoint of DAS28-CRP <3.2 RINVOQ + csDMARD(s) vs placebo + csDMARD(s) was met at Week 12.9

LDA is defined as DAS28-CRP ≤3.2 and remission as DAS28-CRP <2.6.

*p≤0.0001 RINVOQ + csDMARD(s) vs placebo + csDMARD(s).

CRP = C-reactive protein; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; DAS28 = disease activity score 28 joints; LDA = low disease activity.

RINVOQ + csDMARD(s) demonstrated significantly greater ACR response rates vs placebo + csDMARD(s) at Week 12 (NRI)9

Graphs adapted from source material. Primary endpoint of DAS28-CRP <3.2 RINVOQ + csDMARD(s) vs placebo + csDMARD was met at Week 12.9

*p≤0.0001 RINVOQ + csDMARD(s) vs placebo + csDMARD(s).

ACR20/50/70 = American College of Rheumatology ≥20 %/50%/70% improvement; CRP = C-reactive protein; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; DAS28 = disease activity score 28 joints.

Study Design

A Phase III study investigating the efficacy and safety of RINVOQ + csDMARDs compared to placebo + csDMARDs in patients with moderate to severe RA and an inadequate response to csDMARDs9

Upadacitinib 30 mg OD is not an approved dose in RA.

Permitted background csDMARDs were oral and parenteral MTX, sulfasalazine, hydroxychloroquine, chloroquine, and leflunomide; up to 2 concomitant background csDMARDs were allowed, with the exception of the combination of MTX and leflunomide.

*From Week 12 onward, patients initially randomised to placebo at baseline were switched to RINVOQ 15 mg or upadacitinib 30 mg per prespecified randomised assignment. Patients assigned to RINVOQ 15 mg or upadacitinib 30 mg continued their assigned dose.

Primary

RINVOQ + csDMARD(s) vs PBO + csDMARD(s) at Week 12: DAS28-CRP ≤3.2

Key secondary

RINVOQ + csDMARD(s) vs PBO + csDMARD(s) at Week 12: % of pts achieving DAS28-CRP <2.6, CDAI ≤10; Changes from baseline in DAS28-CRP, HAQ-DI, FACIT-F, SF-36 PCS, morning stiffness duration

  • 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 (at least 6 swollen joints out of 66, at least 6 tender joints out of 68, and hsCRP of 3 mg/L or more)
  • Received csDMARDs for ≥3 months and on a stable dose for ≥4 weeks before study entry
  • Patients must have had an inadequate response to at least 1 prior csDMARD (MTX, sulfasalazine, or leflunomide)
  • Patients with prior exposure to at most 1 bDMARD 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
  • No prior exposure to a JAK inhibitor or prior inadequate response to bDMARDs

ACR = American College of Rheumatology; bDMARD = biological disease-modifying antirheumatic drug; CDAI = Clinical Disease Activity Index; CRP = C-reactive protein; csDMARD = conventional synthetic disease-modifying antirheumatic drug; DAS28 = disease activity score 28 joints; EULAR = European League Against Rheumatism; FACIT-F = Functional Assessment of Chronic Illness Therapy-Fatigue; HAQ-DI = Health Assessment Questionnaire without Didability Index; hsCRP = high-sensitivity C-reactive protein; JAK = janus kinase; MTX = methotrexate; PBO = Placebo; OD = once daily; RA = Rheumatoid Arthritis;
SF-36 PCS = Short Form (36) Health Survey Physical Component Score.

Safety and Efficacy of Upadacitinib in Patients with Rheumatoid Arthritis and Inadequate Response to Conventional Synthetic Disease-Modifying Anti-Rheumatic drugs: A Randomised, Double-Blind, Placebo-Controlled Phase III Trial. Burmester et al., 2018.

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References

  1. RINVOQ (Upadactinib) SmPC.
  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, randomised controlled trial. Arthritis Rheumatol. 2019;71(11):1788–1800.
  3. Fleischmann R, Mysler E, Bessette L, et al. Long-term safety and efficacy of upadacitinib or adalimumab in patients with rheumatoid arthritis: results at 3 years from the SELECT-COMPARE study. 2021 EULAR E-Congress; POS0087.
  4. Data on File: ABVRRTI72704.
  5. Fleischmann R, Song I-H, Enejosa J et al. Long-term safety and effectiveness of upadacitinib or adalimumab in patients with rheumatoid arthritis: Results at 72 weeks from the SELECT-COMPARE study. Presented at the European Congress of Rheumatology, 3-6 June 2020.
  6. 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. Ann Rheum Dis. 2019; 0:1-9.
  7. Peterfy CG, Strand V, Genovese MC, et al. Radiographic Outcomes in Patients With Rheumatoid Arthritis Receiving Upadacitinib as Monotherapy or in Combination With Methotrexate: Results at 2 Years From the SELECT-COMPARE and SELECT-EARLY Studies. 2020 EULAR E-Congress;THU0211.
  8. Strand V, Tundia N, Bergman M, et al. Upadacitinib improves patient-reported outcomes vs placebo or adalimumab in patients with rheumatoid arthritis: results from SELECT-COMPARE. Rheumatology (Oxford). 2021 Feb 16:keab158. doi: 10.1093/rheumatology/keab158. Epub ahead of print. PMID: 33590829.
  9. Burmester GR, Kremer JM, van den Bosch F, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT) a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10139):2503–2512.

UK-UPAD-210317. Date of preparation: January 2022.

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