Dataset Information

Inhibition of radiographic progression across levels of composite index-defined disease activity in patients with active psoriatic arthritis treated with intravenous golimumab: results from a phase-3, double-blind, placebo-controlled trial.

ABSTRACT:

Background

In the GO-VIBRANT trial of intravenous golimumab in psoriatic arthritis (PsA), golimumab significantly inhibited radiographic progression. In post hoc analyses, we evaluated changes in total PsA-modified Sharp/van der Heijde scores (SHS) across levels of composite index-defined disease activity following treatment.

Methods

In this phase-3, double-blind, placebo-controlled trial, 480 bio-naïve patients with active PsA randomly received intravenous golimumab 2?mg/kg (N?=?241; week 0, week 4, every 8 weeks [q8w]) or placebo (N?=?239; week 0, week 4, week 12, week 20) followed by golimumab (week 24, week 28, q8w) through week 52. Week 24 and week 52 SHS changes in patient subgroups, defined by levels of disease activity as assessed by several composite measures (minimal disease activity [MDA], very low disease activity [VLDA], Psoriatic ArthritiS Disease Activity Score [PASDAS], Disease Activity in Psoriatic Arthritis [DAPsA], Clinical Disease Activity Index [CDAI]), were evaluated post hoc in 474 patients with evaluable radiographic data. Partially (last-observation-carried-forward methodology) and completely (nonresponder methodology) missing data were imputed.

Results

Across indices, golimumab-treated patients demonstrated less radiographic progression than placebo-treated patients, regardless of disease activity state achieved via golimumab, from week 0 to 24 (e.g., mean changes in PsA-modified SHS were -?0.83 vs. 0.91, respectively, in patients achieving MDA and -?0.05 vs. 1.49, respectively, in those not achieving MDA). Treatment differences observed at week 24 persisted through week 52, despite placebo-randomized patients crossing over to golimumab at week 24 (e.g., mean changes in PsA-modified SHS from week 0 to 52 for golimumab- vs. placebo?golimumab-treated patients achieving MDA were -?1.16 vs. 1.19, respectively) and regardless of whether low disease activity was achieved (0.03 vs. 1.50, respectively, in those not achieving MDA). Consistent patterns were observed for disease activity assessed using VLDA, PASDAS, DAPsA, and CDAI composite endpoints.

Conclusions

The extent of structural damage inhibition afforded by up to 1?year of intravenous golimumab treatment paralleled levels of PsA activity, with greater progression of structural damage observed in patients with sustained higher disease activity. Among patients not achieving low levels of disease activity across several composite indices, golimumab-randomized patients appeared to exhibit far less progression of structural damage than placebo-randomized PsA patients, illustrating a potential disconnect between responses, wherein golimumab can inhibit structural damage independent of clinical effect.

Trial registration

ClinicalTrials.gov. NCT02181673. Registered 04 July 2014.

SUBMITTER: Mease P

PROVIDER: S-EPMC7059340 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Inhibition of radiographic progression across levels of composite index-defined disease activity in patients with active psoriatic arthritis treated with intravenous golimumab: results from a phase-3, double-blind, placebo-controlled trial.

Mease Philip P Husni M Elaine ME Kafka Shelly S Chakravarty Soumya D SD Harrison Diane D DD Lo Kim Hung KH Xu Stephen S Hsia Elizabeth C EC Kavanaugh Arthur A

Arthritis research & therapy 20200306 1

<h4>Background</h4>In the GO-VIBRANT trial of intravenous golimumab in psoriatic arthritis (PsA), golimumab significantly inhibited radiographic progression. In post hoc analyses, we evaluated changes in total PsA-modified Sharp/van der Heijde scores (SHS) across levels of composite index-defined disease activity following treatment.<h4>Methods</h4>In this phase-3, double-blind, placebo-controlled trial, 480 bio-naïve patients with active PsA randomly received intravenous golimumab 2 mg/kg (N = ...[more]

PMID: 32143685

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Project description:BackgroundIntravenous (IV) golimumab, a TNFi, is approved for treating rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). We analyzed pooled safety results from three phase 3 IV golimumab trials in these rheumatologic diseases and hypothesized that the safety profile of IV golimumab would be similar to that established for other TNFi, including subcutaneous golimumab.MethodsData from three double-blind, randomized trials of IV golimumab in patients with RA, PsA, and AS, each with a placebo-controlled period and an extension of active treatment, were included. Golimumab 2 mg/kg was administered at weeks 0 and 4, then every 8 weeks through week 100 (RA) or week 52 (PsA, AS). Concomitant low-dose, oral corticosteroids were permitted. Concomitant methotrexate was required in the RA trial and permitted in the PsA and AS trials; placebo patients crossed over to golimumab at weeks 24 (RA, PsA) and 16 (AS), respectively. Adverse events (AEs), including infections, serious infections, malignancies, and major adverse cardiovascular events (MACE), were assessed through week 112 (RA) or week 60 (PsA, AS).ResultsIn total, 539 patients were randomized to placebo, and 740 patients were randomized to golimumab; 1248 patients received ≥ 1 golimumab administration. Among the placebo and golimumab patients, respectively, during the placebo-controlled periods, 40.6% and 50.3% had an AE, 2.4% and 3.8% had a serious AE, and 0.4% and 0.8% had a serious infection. Among all golimumab-treated patients, the numbers of events/100 patient-years (95% CI) were as follows: AEs, 175.2 (169.0, 181.6); serious AEs, 12.7 (11.0, 14.5); serious infections, 3.4 (2.5, 4.4); active tuberculosis, 0.4 (0.1, 0.8); opportunistic infection, 0.2 (0.1, 0.6); malignancies, 0.4 (0.2, 0.9), and MACE, 0.5 (0.2, 1.0). There were no cases of lymphoma. Three (0.6%) placebo-treated patients and 6 (0.5%) golimumab-treated patients died during the studies. Concomitant methotrexate was associated with increased occurrence of elevated alanine transaminase levels and lower incidence of antibodies to golimumab. During the placebo-controlled periods, serious infections in the placebo and golimumab groups were more common in patients receiving concomitant low-dose oral corticosteroids vs. those not receiving corticosteroids.ConclusionsIV golimumab demonstrated a safety profile that was broadly consistent across these rheumatologic indications and with other TNFi, including subcutaneous golimumab. Concomitant methotrexate or corticosteroids were associated with an increase in specific AEs.Trial registrationsClinicalTrials.gov , NCT00973479 . Registered on September 9, 2009.Clinicaltrialsgov , NCT02181673 . Registered on July 4, 2014.Clinicaltrialsgov , NCT02186873 . Registered on July 10, 2014.

Project description:ObjectivesTo describe the extrapolation approaches used to support intravenous (IV) golimumab for polyarticular juvenile idiopathic arthritis (pJIA) and juvenile psoriatic arthritis (jPsA) and subcutaneous (SC) ustekinumab for jPsA.MethodsPharmacokinetic, clinical response, and safety data from trials of IV golimumab and SC ustekinumab in polyarticular-course JIA (pc-JIA) (GO-VIVA) or pediatric psoriasis (PsO) (CADMUS and CADMUS Jr) and data from pivotal, phase 3 trials of these agents in adults with similar diseases were used to support extrapolation in pJIA and jPsA. In the phase 3 GO-VIVA trial, patients with pc-JIA aged 2 to < 18 years received IV golimumab 80 mg/m2 at weeks 0, 4, then every 8 weeks (Q8W). In the phase 3, randomized, placebo-controlled CADMUS trial, patients with PsO aged ≥ 12 to < 18 years received ustekinumab at weeks 0, 4, then Q12W. In the phase 3 CADMUS Jr trial, patients with PsO aged ≥ 6 to < 12 years received ustekinumab at weeks 0, 4, then Q12W. The ustekinumab analyses used data only from patients who received the standard ustekinumab dosing regimen (≤ 60 kg: 0.75 mg/kg; > 60 to ≤ 100 kg: 45 mg; > 100 kg: 90 mg).ResultsIn the 127 patients with pc-JIA treated with IV golimumab (GO-VIVA), pharmacokinetic and exposure-response results were similar to those in adults with rheumatoid arthritis treated with IV golimumab. Additionally, pharmacokinetic and clinical response data from five patients with jPsA in GO-VIVA were comparable to those in adults with PsA treated with IV golimumab. No new safety signals were observed in GO-VIVA. Pharmacokinetic and clinical response data observed in the four pediatric patients with PsO and jPsA treated with ustekinumab in CADMUS and CADMUS Jr were similar to those in the 91 pediatric patients with PsO without jPsA in these trials and to those in adults with PsA treated with ustekinumab. Safety was extrapolated from CADMUS or CADMUS Jr; no new signals were observed.ConclusionsThese three sets of analyses corroborate similar exposure and efficacy of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in patients with jPsA to support extrapolation of established adult efficacy. The overall safety profiles of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in pediatric patients with PsO with or without jPsA were consistent with the safety profiles of these agents in the context of their clinical programs and cumulative use. Based on these analyses, the US Food and Drug Administration approved IV golimumab for polyarticular JIA and active PsA in patients 2 years and older and SC ustekinumab for pediatric PsA in patients 6 years and older, highlighting how use of an extrapolation approach can help streamline drug development for pediatric patient populations in whom larger clinical trials are not feasible.Clinical trial registrationGO-VIVA (NCT02277444) was registered at clinicaltrials.gov on 29 October 2014; CADMUS (NCT01090427) was registered on 22 March 2010; and CADMUS Jr (NCT02698475) was registered on 3 March 2016.

Project description:ObjectiveReport on radiographic effects and maintenance of clinical benefit with intravenous golimumab 2 mg/kg+methotrexate (MTX) for up to week (wk) 52 in active rheumatoid arthritis (RA).MethodsPatients (n=592) with active RA (≥6/66 swollen, ≥6/68 tender joints, C reactive protein (CRP) ≥1.0 mg/dL and positive for rheumatoid factor and/or anticyclic citrullinated protein antibody at screening) despite MTX ≥3 months (stable dose of 15-25 mg/week for ≥4 weeks) participated in this multicentre, international, randomised, double blind, placebo controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg or placebo infusions at weeks 0 and 4 and then every 8 weeks; patients continued their stable MTX regimen. Placebo patients started golimumab 2 mg/kg at wk16 (early escape; <10% improvement in tender and swollen joints) or wk24 (crossover by design). Week 24 and wk52 radiographic (van der Heijde-Sharp (vdH-S) scores), clinical efficacy and safety data up to 1 year are reported here.ResultsSignificant and rapid clinical improvement was observed up to wk24 of intravenous golimumab therapy. Golimumab+MTX treated patients demonstrated less radiographic progression than placebo treated patients at wk24 (vdH-S score mean change 0.03 vs 1.09; p<0.001) and wk52 (0.13 vs 1.22; p=0.001). Among patients with ≥20% improvement in the American College of Rheumatology response criteria or who achieved a 'good' or 'moderate' response according to the 28 joint Disease Activity Score employing CRP at wk24, approximately 80% maintained this response up until wk52. Through an average of 43.5 weeks of follow-up, 64.6% of patients receiving golimumab+MTX reported adverse events, most commonly non-serious infections.ConclusionsIn patients with active RA despite MTX, intravenous golimumab+MTX yielded significant inhibition of structural damage at wk24 and wk52, and sustained clinical improvement in signs and symptoms with no new safety signals up to 1 year.ClinicaltrialsgovNCT00973479, EudraCT 2008-006 064-11.

Project description:ObjectiveTo assess pooled golimumab safety up to year 3 of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) trials.MethodsGolimumab 50 and 100 mg, administered subcutaneously (SC) every 4 weeks (q4wk), were assessed in patients with active RA (methotrexate-naïve, methotrexate-experienced and anti-TNF (tumour necrosis factor)-experienced), PsA or AS, despite conventional therapy. Placebo control continued up to week (wk) 24 (wk 52, methotrexate-naïve), with early escape at wk 16 (wk 28, methotrexate-naïve); subsequently, all patients received golimumab 50 or 100 mg q4wk. After the blinded controlled period, golimumab doses could be adjusted per investigator discretion. Pooled safety analyses reported herein include data from placebo-controlled and uncontrolled study periods up to wk 160. Determinations of incidences/100 patient-years (pt-yrs) for rare events also included RA patients from a phase IIb trial.ResultsAcross five phase III trials of SC golimumab, 639 patients received placebo and 2226 received golimumab 50 mg (n=1249) and/or 100 mg (n=1501) up to wk 160 (patients may be included in more than one group because non-responders were allowed early escape); 1179 patients were treated for ≥156 weeks. For placebo, golimumab 50 mg and golimumab 100 mg, respective adverse event incidences/100 pt-yrs (95% CIs) up to wk 160 were: 0.28 (0.01 to 1.56), 0.30 (0.12 to 0.62), 0.41 (0.23 to 0.69) for death; 5.31 (3.20 to 8.30), 3.03 (2.36 to 3.82), 5.09 (4.36 to 5.90) for serious infection; 0.00 (0.00 to 0.84), 0.17 (0.05 to 0.44), 0.35 (0.18 to 0.62) for tuberculosis; 0.00 (0.00 to 0.84), 0.13 (0.03 to 0.38), 0.24 (0.10 to 0.46) for opportunistic infection; 0.00 (0.00 to 0.84), 0.00 (0.00 to 0.13), 0.12 (0.03 to 0.30) for demyelination; and 0.00 (0.00 to 0.84), 0.04 (0.00 to 0.24), 0.18 (0.06 to 0.38) for lymphoma.ConclusionsSC golimumab safety up to 3 years remained consistent with that of other TNF antagonists. Golimumab 100 mg showed numerically higher incidences of serious infections, demyelinating events and lymphoma than 50 mg; safety follow-up up to year 5 continues.

Project description:BackgroundGuselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2 trial of 739 bilogico-naïve patients with active PsA, guselkumab 100 mg resulted in less radiographic progression, assessed via change from baseline in PsA-modified van der Heijde-Sharp (vdH-S) score, compared with placebo at week (W) 24 when given at W0, W4, and then every 4 weeks (Q4W) or Q8W. The least squares mean differences from placebo were -0.66 for guselkumab Q4W (p=0.011) and -0.43 for guselkumab Q8W (p=0.072). Reports suggest baseline C-reactive protein (CRP) and joint erosions are strongly prognostic of poor outcomes, especially radiographic progression, in PsA patients. We designed a trial (APEX) to further assess the effect of guselkumab on radiographic progression in patients with active PsA and risk factors for radiographic progression.MethodsPatients are eligible for APEX if they have had PsA for ≥6 months and active disease (≥3 swollen and ≥3 tender joints, CRP ≥0.3 mg/dL) despite prior therapy with conventional synthetic disease-modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs, with ≥2 joints with erosions on baseline radiographs (hands and feet). The primary and major secondary endpoints are the proportion of patients achieving ≥20% improvement in American College of Rheumatology response criteria (ACR20) response at W24 and change from baseline at W24 in PsA-modified vdH-S score, respectively. Sample sizes of 350/250/350 for guselkumab Q8W/guselkumab Q4W/placebo are expected to provide >99% power to detect significant differences in W24 ACR20 response rates for each guselkumab group vs placebo, as well as ≥90% (Q4W vs placebo) and ≥80% (Q8W vs placebo) power to detect a significant difference in PsA-modified vdH-S score change at W24. A Cochran-Mantel-Haenszel test and analysis of covariance will compare treatment efficacy for the primary and major secondary endpoints, respectively.DiscussionDISCOVER-2 findings informed the design of APEX, a Phase 3b study intended to further evaluate the impact of guselkumab in patients with active PsA and known risk factors for radiographic progression.Trial registrationThis trial was registered at ClinicalTrials.gov, NCT04882098 . Registered on 11 May 2021.

Project description:ObjectiveTo evaluate the safety, efficacy, pharmacokinetics, immunogenicity, and radiographic progression through 2 years of treatment with intravenous (IV) golimumab plus methotrexate (MTX) in an open-label extension of a phase III trial of patients with active rheumatoid arthritis (RA) despite MTX therapy.MethodsIn the phase III, double-blind, randomized, placebo-controlled GO-FURTHER trial, 592 patients with active RA were randomized (2:1) to intravenous golimumab 2 mg/kg plus MTX (Group 1) or placebo plus MTX (Group 2) at weeks 0 and 4, then every 8 weeks thereafter; placebo patients crossed over to golimumab at week 16 (early escape) or week 24 (crossover). The final golimumab infusion was at week 100. Assessments included American College of Rheumatology 20%, 50%, 70% (ACR20, ACR50, ACR70) response criteria, 28-joint count disease activity score using the C-reactive protein level (DAS28-CRP), physical function and quality of life measures, and changes in the modified Sharp/van der Heijde scores (SHS). Safety was monitored through week 112.ResultsIn total, 486 patients (82.1%) continued treatment through week 100, and 68.1%, 43.8%, and 23.5% had an ACR20/50/70 response, respectively, at week 100. Clinical response and improvements in physical function and quality of life were generally maintained from week 24 through 2 years. Mean change from baseline to week 100 in SHS score was 0.74 in Group 1 and 2.10 in Group 2 (P = 0.005); progression from week 52 to week 100 was clinically insignificant in both groups. A total of 481 patients completed the safety followup through week 112; 79.1% had an adverse event, and 18.2% had a serious adverse event.ConclusionClinical response to IV golimumab plus MTX was maintained through week 100. Radiographic progression following golimumab treatment was clinically insignificant between week 52 and week 100. No unexpected adverse events occurred through week 112, and the safety profile was consistent with anti-tumor necrosis factor therapy.

Dataset Information

Inhibition of radiographic progression across levels of composite index-defined disease activity in patients with active psoriatic arthritis treated with intravenous golimumab: results from a phase-3, double-blind, placebo-controlled trial.

Background

Methods

Results

Conclusions

Trial registration

Publications

Inhibition of radiographic progression across levels of composite index-defined disease activity in patients with active psoriatic arthritis treated with intravenous golimumab: results from a phase-3, double-blind, placebo-controlled trial.

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