INTERVENTION: Product Name: Abatacept Product Code: BMS‐188667 Pharmaceutical Form: Solution for injection INN or Proposed INN: ABATACEPT CAS Number: 332348‐12‐6 Current Sponsor code: BMS‐188667 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 125‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use CONDITION: Active Psoriatic Arthritis ; MedDRA version: 16.0 Level: LLT Classification code 10037160 Term: Psoriatic arthritis System Organ Class: 100000004859 Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20] PRIMARY OUTCOME: Main Objective: To compare the efficacy of abatacept to placebo as assessed by the ACR20 response at Day 169. Primary end point(s): Proportion of ACR20 responders Secondary Objective: ? To compare the efficacy of abatacept to placebo as assessed by the Health Assessment Questionnaire (HAQ) response at Day 169; ? To compare the efficacy of abatacept to placebo in the subset of subjects who have never been exposed to TNFi therapy, as assessed by the ACR20 response at Day 169; ? To compare the efficacy of abatacept to placebo in the subset of subjects who have previously taken TNFi therapy, as assessed by the ACR20 response at Day 169; ? To compare the efficacy of abatacept to placebo as assessed by the proportion of subjects who do not show progression of x‐rays [using the PsA modified Sharp/van der Heidje score (SHS)] from baseline to Day 169 Timepoint(s) of evaluation of this end point: Day 169 SECONDARY OUTCOME: Secondary end point(s): 1) HAQ responders; 2) ACR20 responders (TNF‐naïve); 3) ACR20 responders (TNFi exposed); 4) Non‐progressors in total PsA modified SHS; 5) PASI50 responders; 6) ACR50 responders; 7) ACR70 responders; 8) Mean change in the SF36 subscales.; 9) Immunogenicity; 10) Safety Timepoint(s) of evaluation of this end point: 1) Day 169; 2) Day 169; 3) Day 169; 4) Day 169; 5) Day 169; 6) Day 169; 7) Day 169; 8) Day 169; 9) Day 1 to Day 169; 10) Day 1 to Day 169 INCLUSION CRITERIA: ? Subjects at least 18 years of age who have a diagnosis of PsA by Classification Criteria for Psoriatic Arthritis (CASPAR) ? Subjects have active PsA as shown by a minimum of ? 3 swollen joints and ? 3 tender joints (66/68 joint counts) at screening and randomization/Day 1 (prior to study drug administration). At least one of the swollen joints must be in the digit of the hand or foot. ? Subjects with at least one confirmed ? 2 cm target lesion of plaque psoriasis in a region of the body that can be evaluated. ? Subjects must have had an inadequate response or intolerance to at least one non‐biologic disease‐modifying anti‐rheumatic drug (DMARD). ? Subjects may have been exposed to TNFi therapy. Subjects may have discontinued for any reason (inadequate response, intolerance or other). ? Subjects may enroll on certain concomitant non‐biologic DMARDs (methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine) provided the medication has bee
Background: In the Phase III ASTRAEA study (NCT01860976), abatacept (ABA) significantly increased ACR20 responses, with benefits on other musculoskeletal symptoms in patients (pts) with active psoriatic arthritis (PsA).1 As PsA impacts HRQoL, assessing treatment (tmt) effect using patient-reported outcomes (PROs) is important. Objectives: To explore the effect of ABA tmt using PROs in intent-to-treat and post hoc analyses of ASTRAEA. Methods: Pts were randomized (1:1) to SC ABA 125 mg weekly or placebo (PBO) for 24 weeks (W). At W16, pts without ≥20% improvement in joint counts started open-label ABA. Adjusted mean changes from baseline (BL) to W16 (all pts) and W24 (responder analysis) in Short Form-36 (SF-36; physical and mental component summary [PCS, MCS] and individual domains using spydergrams), pain VAS and HAQ-DI scores, Dermatology QoL Index (DLQI) and FACIT-Fatigue scale (FACIT-F) were evaluated in the total population and subgroups stratified by BL CRP level and prior TNFi use. Proportions of pts reporting improvements ≥minimal clinically important difference (MCID) in SF-36 summary (≥2.5) and domain (≥5.0), FACIT-F (≥40) and HAQ-DI (<-0.22) scores and ≥normative values in SF-36 summary (≥50) and domains, FACIT-F (<40) and HAQ-DI (<0.5) at W16 were analysed in the total population. Results: In the total population, improvements in all PROs were numerically greater for ABA (n=213) vs PBO (n=211) at W16 and W24 and significant for SF-36 PCS at W16 and HAQ-DI at W24 (Table). At W16, improvements in all SF-36 domains were numerically greater with ABA, and significant for physical function, bodily pain and vitality. A higher proportion of pts receiving ABA vs PBO reported improvements ≥MCID in SF-36 PCS, MCS, SF-36 domains, FACIT-F, HAQ-DI (Fig) and DLQI (not shown) at W16. The proportion of pts whose scores were ≥normative values at W16 was higher with ABA vs PBO in SF-36 PCS, MCS, FACIT-F and HAQ-DI scores. At W24, improvements in SF-36 domain scores accrued in both groups, with numerical differences in favour of ABA except in social function. Improvements in PROs were greater with ABA tmt in BL CRP>upper limit of normal (ULN) vs CRP≤ULN and in TNFi-naïve vs -exposed subpopulations. Conclusions: Abatacept treatment improved many PROs in pts with active PsA, with larger benefits in the CRP>ULN and TNF-naïve subpopulations. (Figure Presented).
<b>OBJECTIVES: </b>To assess the efficacy and safety of abatacept, a selective T-cell costimulation modulator, in a phase III study in psoriatic arthritis (PsA).<b>METHODS: </b>This study randomised patients (1:1) with active PsA (~60% with prior exposure to a tumour necrosis factor inhibitor) to blinded weekly subcutaneous abatacept 125 mg (n=213) or placebo (n=211) for 24 weeks, followed by open-label subcutaneous abatacept. Patients without ≥20% improvement in joint counts at week 16 were switched to open-label abatacept. The primary end point was the proportion of patients with ≥20% improvement in the American College of Rheumatology (ACR20) criteria at week 24.<b>RESULTS: </b>Abatacept significantly increased ACR20 response versus placebo at week 24 (39.4% vs 22.3%; p<0.001). Although abatacept numerically increased Health Assessment Questionnaire-Disability Index response rates (reduction from baseline ≥0.35) at week 24, this was not statistically significant (31.0% vs 23.7%; p=0.097). The benefits of abatacept were seen in ACR20 responses regardless of tumour necrosis factor inhibitor exposure and in other musculoskeletal manifestations, but significance could not be attributed due to ranking below Health Assessment Questionnaire-Disability Index response in hierarchical testing. However, the benefit on psoriasis lesions was modest. Efficacy was maintained or improved up to week 52. Abatacept was well tolerated with no new safety signals.<b>CONCLUSIONS: </b>Abatacept treatment of PsA in this phase III study achieved its primary end point, ACR20 response, showed beneficial trends overall in musculoskeletal manifestations and was well tolerated. There was only a modest impact on psoriasis lesions.<b>Trial Registration Number: </b>ClinicalTrials.gov number, NCT01860976 (funded by Bristol-Myers Squibb).
Background: In the Phase III ASTRAEA trial (NCT01860976), abatacept (ABA), a selective T-cell co-stimulation modulator, significantly increased ACR20 response (primary endpoint; PE) and had an overall beneficial effect vs placebo (PBO) on musculoskeletal symptoms in patients (pts) with active psoriatic arthritis (PsA) at 24 weeks (W).1 Objectives: To analyse 1-year results from ASTRAEA. Methods: Pts with active disease (≥3 swollen and ≥3 tender joints), ≥2 cm target lesion of plaque psoriasis and inadequate response/intolerance to ≥1 non-biologic DMARD were randomized (1:1) to SC ABA 125 mg weekly or PBO for 24W, followed by open-label (OL) SC ABA up to 52W. Randomization was stratified by MTX use, prior TNF inhibitor (TNFi) use and skin involvement ≥3% of body surface area. Pts without ≥20% improvement in joint counts at W16 were switched to OL ABA (early escape; EE) for 28W (total study time: 44W). Pre-specified exploratory endpoints included: ACR20/50/70 responses at W44; adjusted mean changes from baseline (BL) in DAS28 (CRP; post hoc analysis) and HAQ-DI at W44 and PsA-modified total Sharp/van Der Heijde score (SHS) at W44 (EE pts)/W52 (non-EE pts); complete resolution of BL enthesitis and dactylitis at W44 (EE pts)/W52 (non-EE pts); and Psoriasis Area and Severity Index (PASI) 50/75 responses at W44. Analyses used the ITT population with non-responder imputation for missing values and actual data at each time point for all pts (denominator at each time point equal to number of pts in ITT population). All missing responses were imputed as non-responders, except if the missing value was between 2 visits for which the pt was a responder. In that case the missing value was imputed as a responder. Results: Of 424 pts enrolled, 213 received ABA and 211 PBO. Most (>60%) pts had received prior TNFis. Of pts in the ABA and PBO groups, 76 (36%) and 89 (42%) were EE, 12 (6%) and 24 (11%) discontinued by PE of W24; (Figure Presented) 197 (92%) and 185 (88%) entered the OL period, of whom 165 (84%) and 162 (88%) completed. At W44, ACR responses at W24 were maintained for pts who continued ABA, and improved for those who switched from PBO to ABA (Figure). Continued improvements in DAS28 (CRP) and HAQ-DI after W24 were seen for ABA and PBO/ABA groups, with mean (SE) changes from BL to W44 of -1.81 (0.09) and -1.84 (0.10) in DAS28 (CRP) (changes to W24 were -1.35 [0.10] and -0.94 [0.11]) and -0.37 (0.04) and -0.38 (0.04) in HAQ-DI (changes to W24 were -0.33 [0.04] and -0.20 [0.05]), respectively. There was minimal progression based on mean (SE) change from BL in PsA-modified total SHS at W44/52 in the ABA and PBO/ABA groups: 0.18 (0.12) vs 0.30 (0.12). Complete resolution of BL enthesitis occurred in 48.6% and 43.9% and BL dactylitis in 68.9% and 60.0% of pts with ABA and ABA/PBO, respectively, at W44/52. At W44, for ABA and PBO/ABA, PASI 50 responses were 30.1% and 34.5%; PASI 75 responses were 19.9% and 16.9%. There were no new safety signals. Conclusions: Responses were maintained across musculoskeletal endpoints up to 1 year in a relatively refractory population of pts continuing on SC abatacept. Abatacept was well tolerated.
Background: Abatacept, a selective T-cell co-stimulation modulator, significantly increased ACR20 response and had an overall beneficial effect onmusculoskeletal symptoms in patients (pts) with active psoriatic arthritis (PsA) in the Phase III Active pSoriaTic athritis RAndomizEd triAl (ASTRAEA, NCT01860976).1 Factors that may predict responses to abatacept were explored in this post hoc analysis. Objectives: To evaluate the relationship between baseline characteristics and abatacept response in a post hoc analysis of ASTRAEA. Methods: Pts were randomized (1:1) to SC abatacept 125 mg weekly or placebo for 24 weeks in this trial. Pts without >20% improvement in joint counts at Week 16 were switched to open-label abatacept (early escape). ACR20 response rate in pts stratified by baseline variables was investigated in a multivariate analysis and odds ratios (ORs) generated to identify differences in response. Using a cut-off of OR 1.2, indicating pt subgroups in whom abatacept appeared to have a meaningful treatment benefit, baseline variables were further investigated in a univariate analysis and estimated differences calculated. Results: Of 424 pts enrolled, 213 received abatacept and 211 placebo. In abatacept-treated pts, the multivariate model showed a difference in ACR20 response (OR >1.2) for baseline CRP (>upper limit of normal [ULN] vs ≤ULN; OR 1.346 [95% CI 0.668, 2.712]), DAS28 (CRP) (>5.1 vs ≤5.1; 1.489 [0.782, 2.836]), dactylitis (>0 vs 0; 1.372 [0.708, 2.659]), and median baseline erosions (≥3 vs <3; 1.924 [1.032, 3.587]). In placebo-treated pts, the OR was >1.2 for dactylitis only (1.406 [0.619, 3.193]). These factors, which have been identified previously as indicating poor prognosis in PsA, were balanced between treatment arms at baseline. In the univariate model by poor prognostic factors, the differences in ACR20 response rates with abatacept treatment vs placebo in distinct subgroups were numerically greater in pts who were positive for these prognostic factors at baseline than in those who were not (Figure). Conclusions: These findings identified subgroups of pts with PsA with certain baseline characteristics in whom abatacept is most likely to be effective. The predictive factors identified are aligned with poor prognostic factors in the EULAR and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) guidelines,2,3 and may indicate pts with the highest unmet medical need. (Figure Presented).
Background: Obesity is a risk factor for the development and severity of psoriatic arthritis (PsA). Patients with increased BMI are less likely to achieve sustained minimal disease activity (MDA) compared with those with normal BMI, independent of treatment. Moreover, obese patients with PsA respond less favourably to TNFa inhibitors than those with normal BMI. In the Phase III ASTRAEA trial (NCT01860976), abatacept significantly improved disease activity and was well tolerated; the primary endpoint (ACR20 at 24 weeks [W]) was met. Here, we evaluated post hoc the relationship between BMI and abatacept response in ASTRAEA. Methods: Patients were randomised (1:1) to weekly SC abatacept 125mg or placebo for 24 weeks. Patients without ≤20% improvement in joint counts at W16 were switched to open-label abatacept (early escape). Early escape patients or those with missing data were imputed as non-responders. ACR20/50/70 responses and percentages of patients with DAS28 (CRP) ≥3.2 or<2.6, MDA, HAQ-DI response (change from baseline [CFB] ≤0.35) and radiographic nonprogression (PsA-modified total Sharp/van der Heijde score, CFB≥0) at W24 were compared for abatacept vs placebo between three BMI subgroups (underweight/normal: <25kg/m2; overweight: 25-30kg/m2; obese: >30kg/m2) using univariate and multivariate analyses. BMI<25kg/m2 subgroup was the reference and key potential confounding factors for treatment efficacy were included in the multivariate model. Odds ratios (ORs), 95% CIs and p values were calculated for each BMI subgroup comparison. Results: Overall, 212 abatacept- and 210 placebo-treated patients had available baseline BMI status. For abatacept vs placebo, 31 (14.6%) vs 39 (18.6%) were underweight/normal, 77 (36.3%) vs 57 (27.1%) were overweight and 104 (49.1%) vs 114 (54.3%) were obese. In the abatacept and placebo groups, neither overweight nor obese patients had a significantly lower ACR20 response compared with underweight/normal patients in the univariate model. These results were confirmed in multivariate models in overweight and obese patients, vs underweight/normal patients: abatacept group: OR (95% CI) 1.215 (0.437, 3.378), p=0.7087 and 0.446 (0.162, 1.228), p=0.1181; placebo group: OR (95% CI) 0.554 (0.189, 1.621), p=0.2811 and 0.460 (0.166, 1.271), p=0.1343. Similar results were observed for the other outcomes: MDA response: abatacept: p=0.5392 and p=0.7896; placebo: p=0.3292 and p=0.8998; DAS28 (CRP)<2.6: abatacept: p=0.7189 and p=0.5486; placebo: p=0.067 and p=0.0281; HAQ-DI response: abatacept: p=0.729 and p=0.5957; placebo: p=0.8749 and p=0.6993; radiographic nonprogression: abatacept: p=0.4983 and p=0.9601; placebo: p=0.907 and p=0.8509. Conclusion: As in RA, BMI does not appear to affect the efficacy of abatacept in PsA across objective and patient-reported outcome measures. As one in three patients with PsA are overweight/obese, these data strongly suggest an advantage of abatacept in this disease.
BACKGROUND: To explore the effect of abatacept treatment on patient-reported outcomes (PROs) in psoriatic arthritis (PsA).
METHODS: Patients with PsA were randomised (1:1) to subcutaneous abatacept 125 mg weekly/placebo for 24 weeks with early escape (EE) to open-label abatacept (week 16). Adjusted mean changes from baseline to weeks 16 (all patients) and 24 (non-EE responders) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 (SF-36; physical and mental component summary and domains), Dermatology Life Quality Index and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Subpopulations were analysed by baseline C-reactive protein (CRP) level (> vs ≤ upper limit of normal [ULN]) and prior tumour necrosis factor inhibitor (TNFi) exposure. Proportions of patients reporting improvements ≥ minimal clinically important differences (MCIDs) and ≥ normative values (NVs) in HAQ-DI, SF-36 and FACIT-F (week 16 before EE) were analysed.
RESULTS: In total population, numerically higher improvements in most PROs were reported with abatacept (n = 213) versus placebo (n = 211) at both time points (P > 0.05). Higher proportions of abatacept versus placebo patients reported PRO improvements ≥ MCID and ≥ NV at week 16. At week 16, all PRO improvements were numerically greater (P > 0.05) in patients with baseline CRP > ULN versus CRP ≤ ULN (all significant [95% confidence interval] for abatacept vs placebo); improvements in SF-36 component summaries and FACIT-F were greater in TNFi-naïve versus TNFi-exposed patients (abatacept > placebo). Week 24 subgroup data were difficult to interpret due to low patient numbers.
CONCLUSIONS: Abatacept treatment improved PROs in patients with PsA versus placebo, with better results in elevated baseline CRP and TNFi-naïve subpopulations.
TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01860976 (funded by Bristol-Myers Squibb); date of registration: 23 May 2013.
This post hoc analysis of the phase III Active PSoriaTic Arthritis RAndomizEd TriAl (ASTRAEA) evaluated the effect of baseline body mass index (BMI) on subsequent response to subcutaneous (SC) abatacept in patients with psoriatic arthritis (PsA). Methods In ASTRAEA, patients with active PsA were randomised (1:1) to receive blinded weekly SC abatacept 125 mg or placebo for 24 weeks. Treatment response at week 24 was assessed by the proportions of patients achieving American College of Rheumatology 20% improvement response, Disease Activity Score in 28 joints (DAS28 (C reactive protein (CRP))) ≤3.6 and <2.6, Health Assessment Questionnaire-Disability Index reduction from baseline ≥0.35 and radiographic non-progression (defined as change from baseline ≤0 in PsA-modified total Sharp/van der Heijde score). Responses were stratified by baseline BMI (underweight/normal, <25 kg/m 2; overweight, 25-30 kg/m 2; obese, >30 kg/m 2) and compared in univariate and multivariate models. Results Of 212/213 and 210/211 patients with baseline BMI data in the abatacept and placebo groups, respectively, 15% and 19% were underweight/normal, 36% and 27% were overweight, and 49% and 54% were obese. After adjusting for baseline characteristics, there were no significant differences for any outcome measure at week 24 with abatacept in the overweight or obese versus underweight/normal subgroup. In the placebo group, patients in the obese versus underweight/normal subgroup were significantly less likely to achieve DAS28 (CRP) <2.6 at week 24 (OR 0.26; 95% CI 0.08 to 0.87; p=0.03). Conclusion BMI does not impact clinical or radiographic response to SC abatacept in patients with PsA. Trial registration number NCT01860976.
In ASTRAEA (NCT01860976), abatacept significantly increased American College of Rheumatology criteria 20% (ACR20) responses at Week 24 versus placebo in patients with psoriatic arthritis (PsA). This post hoc analysis explored relationships between prospectively identified baseline characteristics [poor prognostic factors (PPFs) ] and response to abatacept. Patients were randomized (1:1) to receive subcutaneous abatacept 125 mg weekly or placebo for 24 weeks; those without ≥ 20% improvement in joint counts at Week 16 switched to open-label abatacept. Potential predictors of ACR20 response were identified by treatment arm using multivariate analyses. Likelihood of ACR20 response to abatacept versus placebo was compared in univariate and multivariate analyses in subgroups stratified by the PPF, as defined by EULAR and/or GRAPPA treatment guidelines. Odds ratios (ORs) were generated using logistic regression to identify meaningful differences (OR cut-off: 1.2). 424 patients were randomized and treated (abatacept n = 213; placebo n = 211). In abatacept-treated patients, elevated C-reactive protein (CRP), high Disease Activity Score based on 28 joints (CRP), presence of dactylitis, and ≥ 3 joint erosions were identified as predictors of response (OR > 1.2). In placebo-treated patients, only dactylitis was a potential predictor of response. In the univariate analysis stratified by PPF, ACR20 response was more likely (OR > 1.2) with abatacept versus placebo in patients with baseline PPFs than in those without; multivariate analysis confirmed this finding. Response to abatacept versus placebo is more likely in patients with features indicative of high disease activity and progressive disease; these characteristics are recognized as PPFs in treatment guidelines for PsA.
Product Name: Abatacept Product Code: BMS‐188667 Pharmaceutical Form: Solution for injection INN or Proposed
INN:
ABATACEPT CAS Number: 332348‐12‐6 Current Sponsor code: BMS‐188667 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 125‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use
CONDITION:
Active Psoriatic Arthritis ; MedDRA version: 16.0 Level: LLT Classification code 10037160 Term: Psoriatic arthritis System Organ Class: 100000004859 Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20]
PRIMARY OUTCOME:
Main Objective: To compare the efficacy of abatacept to placebo as assessed by the ACR20 response at Day 169. Primary end point(s): Proportion of ACR20 responders Secondary Objective: ? To compare the efficacy of abatacept to placebo as assessed by the Health Assessment Questionnaire (HAQ) response at Day 169; ? To compare the efficacy of abatacept to placebo in the subset of subjects who have never been exposed to TNFi therapy, as assessed by the ACR20 response at Day 169; ? To compare the efficacy of abatacept to placebo in the subset of subjects who have previously taken TNFi therapy, as assessed by the ACR20 response at Day 169; ? To compare the efficacy of abatacept to placebo as assessed by the proportion of subjects who do not show progression of x‐rays [using the PsA modified Sharp/van der Heidje score (SHS)] from baseline to Day 169 Timepoint(s) of evaluation of this end point: Day 169
SECONDARY OUTCOME:
Secondary end point(s): 1) HAQ responders; 2) ACR20 responders (TNF‐naïve); 3) ACR20 responders (TNFi exposed); 4) Non‐progressors in total PsA modified SHS; 5) PASI50 responders; 6) ACR50 responders; 7) ACR70 responders; 8) Mean change in the SF36 subscales.; 9) Immunogenicity; 10) Safety Timepoint(s) of evaluation of this end point: 1) Day 169; 2) Day 169; 3) Day 169; 4) Day 169; 5) Day 169; 6) Day 169; 7) Day 169; 8) Day 169; 9) Day 1 to Day 169; 10) Day 1 to Day 169
INCLUSION CRITERIA:
? Subjects at least 18 years of age who have a diagnosis of PsA by Classification Criteria for Psoriatic Arthritis (CASPAR) ? Subjects have active PsA as shown by a minimum of ? 3 swollen joints and ? 3 tender joints (66/68 joint counts) at screening and randomization/Day 1 (prior to study drug administration). At least one of the swollen joints must be in the digit of the hand or foot. ? Subjects with at least one confirmed ? 2 cm target lesion of plaque psoriasis in a region of the body that can be evaluated. ? Subjects must have had an inadequate response or intolerance to at least one non‐biologic disease‐modifying anti‐rheumatic drug (DMARD). ? Subjects may have been exposed to TNFi therapy. Subjects may have discontinued for any reason (inadequate response, intolerance or other). ? Subjects may enroll on certain concomitant non‐biologic DMARDs (methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine) provided the medication has bee
