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Twenty-eight-week results from the REALISTIC phase IIIb randomized trial: efficacy, safety and predictability of response to certolizumab pegol in a diverse rheumatoid arthritis population.

Weinblatt ME, Fleischmann R, van Vollenhoven RF, Emery P, Huizinga TW, Cutolo M, van der Heijde D, Duncan B, Davies O, Luijtens K, Dougados M - Arthritis Res. Ther. (2015)

Bottom Line: Adverse event rates were similar for placebo → CZP and CZP → CZP patients, with no new safety signals identified.Failure to achieve improvements in DAS28(ESR), SJC or CDAI within the first 12 weeks of CZP therapy was associated with a low chance of achieving LDA at week 28.No new safety signals were observed.

View Article: PubMed Central - PubMed

Affiliation: Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA. mweinblatt@partners.org.

ABSTRACT

Introduction: This 28-week, phase IIIb study assessed safety and maintenance of response to certolizumab pegol (CZP) in a diverse population of rheumatoid arthritis (RA) patients, stratified by prior anti-TNF exposure, concomitant methotrexate (MTX) use and disease duration. The ability to predict achievement of low disease activity (LDA) at week 28 from improvements in Disease Activity Score 28 (DAS28), erythrocyte sedimentation rate (ESR), swollen joint count (SJC) and Clinical Disease Activity Index (CDAI) up to week 12 was assessed.

Methods: The 28-week study population included all patients who completed the double-blind (DB) phase and entered the open-label (OL) phase, receiving 200 mg CZP every 2 weeks (Q2W) ≥16 weeks. In the 12-week DB period, patients with active RA and an inadequate response to ≥1 disease-modifying antirheumatic drug (DMARD) were randomized 4:1 to CZP (400 mg at weeks 0, 2 and 4 then 200 mg Q2W) or placebo (Q2W), stratified by prior anti-TNF use, concomitant use of MTX and disease duration (<2 years vs. ≥2 years).

Results: A total of 955 patients entered the OL phase. At week 28, similar clinical improvements were seen in those receiving CZP throughout (CZP → CZP; n = 771) and those receiving placebo during the DB phase and switching to CZP in the OL phase (placebo → CZP; n = 184) (ACR20 response rate = 59.7 % vs. 53.3 %; ACR50/ACR70 response rates were also similar). Effect of CZP treatment was similar regardless of prior anti-TNF use, disease duration and concomitant DMARDs, based on ACR20 response rates. The percentage of patients achieving DAS28(ESR) LDA at week 28 was calculated for DAS28(ESR), SJC or CDAI responders at earlier time points. Reductions from baseline (Δ) of DAS28(ESR) <1.2, ΔSJC <25 % or ΔCDAI <10 by week 12 were associated with <9 % chance of achieving LDA at week 28 regardless of prior anti-TNF exposure. Adverse event rates were similar for placebo → CZP and CZP → CZP patients, with no new safety signals identified.

Conclusions: A diverse population of RA patients with varying disease duration showed rapid and sustained clinical improvements on CZP treatment, regardless of prior anti-TNF or concomitant DMARD use. Failure to achieve improvements in DAS28(ESR), SJC or CDAI within the first 12 weeks of CZP therapy was associated with a low chance of achieving LDA at week 28. No new safety signals were observed.

Trial registration: ClinicalTrials.gov, NCT00717236 , 15 July 2008.

No MeSH data available.


Related in: MedlinePlus

Clinical response at week 28, stratified by baseline characteristics. a Week 28 ACR20/ACR50/ACR70 responses stratified by prior anti-TNF therapy. b DAS28(CRP) progression up to week 28 by prior anti-TNF therapy. c Week 28 ACR20/ACR50/ACR70 responses stratified by baseline DMARDs. d Week 28 ACR20/ACR50/ACR70 responses stratified by disease duration (OL set, imputed data). Footnote: ACR response rates were calculated using NRI if withdrawal was due to an AE or lack/loss of efficacy, and LOCF in case of any other reason. Least squares mean (change from baseline) in DAS28(CRP) was analyzed using MMRM. AE adverse event, CRP C-reactive protein, CZP certolizumab pegol, DAS28 Disease Activity Score in 28 joints, LOCF last observation carried forward, MMRM mixed-effects model for repeated measures, NRI nonresponder imputation, OL open-label, TNF tumor necrosis factor
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Fig3: Clinical response at week 28, stratified by baseline characteristics. a Week 28 ACR20/ACR50/ACR70 responses stratified by prior anti-TNF therapy. b DAS28(CRP) progression up to week 28 by prior anti-TNF therapy. c Week 28 ACR20/ACR50/ACR70 responses stratified by baseline DMARDs. d Week 28 ACR20/ACR50/ACR70 responses stratified by disease duration (OL set, imputed data). Footnote: ACR response rates were calculated using NRI if withdrawal was due to an AE or lack/loss of efficacy, and LOCF in case of any other reason. Least squares mean (change from baseline) in DAS28(CRP) was analyzed using MMRM. AE adverse event, CRP C-reactive protein, CZP certolizumab pegol, DAS28 Disease Activity Score in 28 joints, LOCF last observation carried forward, MMRM mixed-effects model for repeated measures, NRI nonresponder imputation, OL open-label, TNF tumor necrosis factor

Mentions: At week 28, patients stratified by prior and non-prior anti-TNF use showed similar ACR20, ACR50 and ACR70 response rates in the placebo → CZP and CZP → CZP groups, although there was a numerical trend for slightly higher response rates in the anti-TNF naïve patients (Fig. 3a). ACR20 response rates in patients with vs. without prior anti-TNF were 55.2 % vs. 62.4 % for CZP → CZP patients and 54.9 % vs. 52.2 % for placebo → CZP patients; ACR50 response rates in patients with vs. without prior anti-TNF were 30.4 % vs. 39.3 % for CZP → CZP patients and 25.4 % vs. 34.5 % in placebo → CZP patients). Patients with and without prior anti-TNF use also experienced similar improvements in DAS28(CRP) (Fig. 3b; Table S1 in Additional file 1). ACR20 response rates were also generally similar in the placebo → CZP and CZP → CZP groups when patients were stratified by the number and type of concomitant DMARDs used (0 vs. 1 vs. ≥2 DMARDs; with vs. without MTX use at baseline) (Fig. 3c), although with a trend for numerically higher response rates in patients receiving concomitant DMARD therapy compared to CZP monotherapy (Fig. S1 in Additional file 1). Stratifying patients by their disease duration (<2 vs. ≥2 years) also showed similar response rates. (Fig. 3d). Finally, a trend for improved ACR20 response rates with increasing baseline RF levels (<14 IU/mL (upper limit of normal), 14–50 IU/mL (approximately 3× upper limit of normal [ULN]) and >50 IU/mL) was observed (Fig. S2 in Additional file 1).Fig. 3


Twenty-eight-week results from the REALISTIC phase IIIb randomized trial: efficacy, safety and predictability of response to certolizumab pegol in a diverse rheumatoid arthritis population.

Weinblatt ME, Fleischmann R, van Vollenhoven RF, Emery P, Huizinga TW, Cutolo M, van der Heijde D, Duncan B, Davies O, Luijtens K, Dougados M - Arthritis Res. Ther. (2015)

Clinical response at week 28, stratified by baseline characteristics. a Week 28 ACR20/ACR50/ACR70 responses stratified by prior anti-TNF therapy. b DAS28(CRP) progression up to week 28 by prior anti-TNF therapy. c Week 28 ACR20/ACR50/ACR70 responses stratified by baseline DMARDs. d Week 28 ACR20/ACR50/ACR70 responses stratified by disease duration (OL set, imputed data). Footnote: ACR response rates were calculated using NRI if withdrawal was due to an AE or lack/loss of efficacy, and LOCF in case of any other reason. Least squares mean (change from baseline) in DAS28(CRP) was analyzed using MMRM. AE adverse event, CRP C-reactive protein, CZP certolizumab pegol, DAS28 Disease Activity Score in 28 joints, LOCF last observation carried forward, MMRM mixed-effects model for repeated measures, NRI nonresponder imputation, OL open-label, TNF tumor necrosis factor
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4644627&req=5

Fig3: Clinical response at week 28, stratified by baseline characteristics. a Week 28 ACR20/ACR50/ACR70 responses stratified by prior anti-TNF therapy. b DAS28(CRP) progression up to week 28 by prior anti-TNF therapy. c Week 28 ACR20/ACR50/ACR70 responses stratified by baseline DMARDs. d Week 28 ACR20/ACR50/ACR70 responses stratified by disease duration (OL set, imputed data). Footnote: ACR response rates were calculated using NRI if withdrawal was due to an AE or lack/loss of efficacy, and LOCF in case of any other reason. Least squares mean (change from baseline) in DAS28(CRP) was analyzed using MMRM. AE adverse event, CRP C-reactive protein, CZP certolizumab pegol, DAS28 Disease Activity Score in 28 joints, LOCF last observation carried forward, MMRM mixed-effects model for repeated measures, NRI nonresponder imputation, OL open-label, TNF tumor necrosis factor
Mentions: At week 28, patients stratified by prior and non-prior anti-TNF use showed similar ACR20, ACR50 and ACR70 response rates in the placebo → CZP and CZP → CZP groups, although there was a numerical trend for slightly higher response rates in the anti-TNF naïve patients (Fig. 3a). ACR20 response rates in patients with vs. without prior anti-TNF were 55.2 % vs. 62.4 % for CZP → CZP patients and 54.9 % vs. 52.2 % for placebo → CZP patients; ACR50 response rates in patients with vs. without prior anti-TNF were 30.4 % vs. 39.3 % for CZP → CZP patients and 25.4 % vs. 34.5 % in placebo → CZP patients). Patients with and without prior anti-TNF use also experienced similar improvements in DAS28(CRP) (Fig. 3b; Table S1 in Additional file 1). ACR20 response rates were also generally similar in the placebo → CZP and CZP → CZP groups when patients were stratified by the number and type of concomitant DMARDs used (0 vs. 1 vs. ≥2 DMARDs; with vs. without MTX use at baseline) (Fig. 3c), although with a trend for numerically higher response rates in patients receiving concomitant DMARD therapy compared to CZP monotherapy (Fig. S1 in Additional file 1). Stratifying patients by their disease duration (<2 vs. ≥2 years) also showed similar response rates. (Fig. 3d). Finally, a trend for improved ACR20 response rates with increasing baseline RF levels (<14 IU/mL (upper limit of normal), 14–50 IU/mL (approximately 3× upper limit of normal [ULN]) and >50 IU/mL) was observed (Fig. S2 in Additional file 1).Fig. 3

Bottom Line: Adverse event rates were similar for placebo → CZP and CZP → CZP patients, with no new safety signals identified.Failure to achieve improvements in DAS28(ESR), SJC or CDAI within the first 12 weeks of CZP therapy was associated with a low chance of achieving LDA at week 28.No new safety signals were observed.

View Article: PubMed Central - PubMed

Affiliation: Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA. mweinblatt@partners.org.

ABSTRACT

Introduction: This 28-week, phase IIIb study assessed safety and maintenance of response to certolizumab pegol (CZP) in a diverse population of rheumatoid arthritis (RA) patients, stratified by prior anti-TNF exposure, concomitant methotrexate (MTX) use and disease duration. The ability to predict achievement of low disease activity (LDA) at week 28 from improvements in Disease Activity Score 28 (DAS28), erythrocyte sedimentation rate (ESR), swollen joint count (SJC) and Clinical Disease Activity Index (CDAI) up to week 12 was assessed.

Methods: The 28-week study population included all patients who completed the double-blind (DB) phase and entered the open-label (OL) phase, receiving 200 mg CZP every 2 weeks (Q2W) ≥16 weeks. In the 12-week DB period, patients with active RA and an inadequate response to ≥1 disease-modifying antirheumatic drug (DMARD) were randomized 4:1 to CZP (400 mg at weeks 0, 2 and 4 then 200 mg Q2W) or placebo (Q2W), stratified by prior anti-TNF use, concomitant use of MTX and disease duration (<2 years vs. ≥2 years).

Results: A total of 955 patients entered the OL phase. At week 28, similar clinical improvements were seen in those receiving CZP throughout (CZP → CZP; n = 771) and those receiving placebo during the DB phase and switching to CZP in the OL phase (placebo → CZP; n = 184) (ACR20 response rate = 59.7 % vs. 53.3 %; ACR50/ACR70 response rates were also similar). Effect of CZP treatment was similar regardless of prior anti-TNF use, disease duration and concomitant DMARDs, based on ACR20 response rates. The percentage of patients achieving DAS28(ESR) LDA at week 28 was calculated for DAS28(ESR), SJC or CDAI responders at earlier time points. Reductions from baseline (Δ) of DAS28(ESR) <1.2, ΔSJC <25 % or ΔCDAI <10 by week 12 were associated with <9 % chance of achieving LDA at week 28 regardless of prior anti-TNF exposure. Adverse event rates were similar for placebo → CZP and CZP → CZP patients, with no new safety signals identified.

Conclusions: A diverse population of RA patients with varying disease duration showed rapid and sustained clinical improvements on CZP treatment, regardless of prior anti-TNF or concomitant DMARD use. Failure to achieve improvements in DAS28(ESR), SJC or CDAI within the first 12 weeks of CZP therapy was associated with a low chance of achieving LDA at week 28. No new safety signals were observed.

Trial registration: ClinicalTrials.gov, NCT00717236 , 15 July 2008.

No MeSH data available.


Related in: MedlinePlus