Differences and Similarities in Clinical and Functional Responses Among Patients Receiving Tofacitinib Monotherapy, Tofacitinib Plus Methotrexate, and Adalimumab Plus Methotrexate: A Post-hoc Analysis of Data From Oral Strategy

2021 ◽  
Author(s):  
Tsutomu Takeuchi ◽  
Roy Fleischmann ◽  
Noriko Iikuni ◽  
Harry Shi ◽  
Koshika Soma ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Activity Index ◽  
Cumulative Probability ◽  
Inadequate Response ◽  
Combination Therapies ◽  
Functional Responses ◽  
Strategy Study ◽  
Post Hoc Analysis ◽  
Probability Plots ◽  
Post Hoc

Abstract BackgroundThis post-hoc analysis assessed clinical and functional responses to tofacitinib monotherapy, tofacitinib + methotrexate (MTX), and adalimumab + MTX, in patients with rheumatoid arthritis enrolled in the ORAL Strategy study, including evaluation of patient-level data using cumulative probability plots.MethodsIn the 12-month, phase IIIb/IV ORAL Strategy study, patients with rheumatoid arthritis and an inadequate response to MTX were randomized to receive tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID + MTX, or adalimumab 40 mg every other week + MTX. In this post-hoc analysis, cumulative probability plots were generated for mean percent change from baseline (%∆) in Clinical Disease Activity Index (CDAI; clinical response) and mean change from baseline (∆) in Health Assessment Questionnaire-Disability Index (HAQ-DI; functional response) at month 12. Median C-reactive protein (CRP) levels by time period were summarized by CDAI remission (≤2.8) status at months 6 and 12. ResultsData for 1146 patients were analyzed. At month 12, cumulative probability plots for %∆CDAI and ∆HAQ-DI were similar across treatments in patients with greater response. At lower levels of response, patients receiving tofacitinib monotherapy did not respond as well as those receiving combination therapies. With tofacitinib + MTX, numerically higher baseline CRP levels and numerically larger post-baseline CRP reductions were seen in patients achieving CDAI remission at months 6 and 12 vs those who did not.ConclusionsThese results suggest that patients with a greater response did well, irrespective of which therapy they received. Patients with lesser response had better outcomes with combination therapies vs tofacitinib monotherapy, suggesting they benefitted from MTX. High pre‑treatment CRP levels may be associated with better response to tofacitinib + MTX. Trial registrationClinicalTrials.gov, NCT02187055. Registered 08 July 2014, https://clinicaltrials.gov/ct2/show/NCT02187055?term=NCT02187055&draw=2&rank=1

scholarly journals Differences and similarities in clinical and functional responses among patients receiving tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate: a post hoc analysis of data from ORAL Strategy

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Tsutomu Takeuchi ◽  
Roy Fleischmann ◽  
Noriko Iikuni ◽  
Harry Shi ◽  
Koshika Soma ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Activity Index ◽  
Cumulative Probability ◽  
Inadequate Response ◽  
Combination Therapies ◽  
Functional Responses ◽  
Strategy Study ◽  
Post Hoc Analysis ◽  
Probability Plots ◽  
Post Hoc

Abstract Background This post hoc analysis assessed clinical and functional responses to tofacitinib monotherapy, tofacitinib + methotrexate (MTX), and adalimumab + MTX, in patients with rheumatoid arthritis enrolled in the ORAL Strategy study, including evaluation of patient-level data using cumulative probability plots. Methods In the 12-month, phase IIIb/IV ORAL Strategy study, patients with rheumatoid arthritis and an inadequate response to MTX were randomized to receive tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID + MTX, or adalimumab 40 mg every other week + MTX. In this post hoc analysis, cumulative probability plots were generated for mean percent change from baseline (%∆) in the Clinical Disease Activity Index (CDAI; clinical response) and mean change from baseline (∆) in the Health Assessment Questionnaire-Disability Index (HAQ-DI; functional response) at month 12. Median C-reactive protein (CRP) levels by time period were summarized by CDAI remission (≤ 2.8) status at months 6 and 12. Results Data for 1146 patients were analyzed. At month 12, cumulative probability plots for %∆CDAI and ∆HAQ-DI were similar across treatments in patients with greater response. At lower levels of response, patients receiving tofacitinib monotherapy did not respond as well as those receiving combination therapies. With tofacitinib + MTX, numerically higher baseline CRP levels and numerically larger post-baseline CRP reductions were seen in patients achieving CDAI remission at months 6 and 12 vs those who did not. Conclusions These results suggest that patients with a greater response did well, irrespective of which therapy they received. Patients with lesser response had better outcomes with combination therapies vs tofacitinib monotherapy, suggesting they benefitted from MTX. High pre-treatment CRP levels may be associated with better response to tofacitinib + MTX. Trial registration ClinicalTrials.gov, NCT02187055. Registered on 08 July 2014.

scholarly journals AB0259 EVALUATION OF THE EFFECT OF FILGOTINIB ON THE PHARMACOKINETICS OF ROSUVASTATIN, ATORVASTATIN, AND PRAVASTATIN

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1155.3-1156
Author(s):  
K. Anderson ◽  
C. Nelson ◽  
Q. Gong ◽  
M. Alani ◽  
T. Tarnowski ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Single Dose ◽  
Organic Anion ◽  
Janus Kinase ◽  
Lipid Lowering ◽  
Pharmacokinetic Parameters ◽  
Inadequate Response ◽  
Post Hoc Analysis ◽  
Cardiovascular Morbidity And Mortality ◽  
Post Hoc

Background:Filgotinib is an orally administered small molecule that preferentially inhibits Janus kinase 1 and is approved for use in Europe and Japan in adult patients with rheumatoid arthritis (RA) who have had an inadequate response to conventional therapies. Patients with RA are at a higher risk of cardiovascular morbidity and mortality relative to the general population1. Thus, it is important to understand potential drug-drug interactions of filgotinib with lipid-lowering agents such as statins. Based on in vitro studies, filgotinib is not expected to significantly increase exposure of statins via inhibition of the organic anion transporting peptide (OATP) at clinically relevant exposures. Hence, in Phase 2 and Phase 3 clinical studies, statins were allowed for use with filgotinib. A post-hoc analysis showed no increase in statin-induced AEs such as muscle or liver toxicities when statins were coadministered with filgotinib (“Concomitant Use of Statins in Filgotinib-Treated Patients with Rheumatoid Arthritis: A Post Hoc Analysis”, submitted to EULAR 2021).Objectives:The objectives of this study (NCT04608344) were to evaluate the effect of filgotinib on the pharmacokinetics of atorvastatin, pravastatin, and rosuvastatin, which are sensitive substrates for the OATP-1B1/1B3, and the short-term safety of administering filgotinib with or without statins.Methods:This was an open-label, randomized, two-way, crossover study in healthy adult volunteers (n = 27). Study participants received a single dose of atorvastatin (ATV 40 mg) and a single dose of a cocktail of pravastatin (PRA 40 mg)/rosuvastatin (ROS 10 mg), on two different occasions with washout in between, alone or in combination with filgotinib (200 mg QD for 11 days). Serial pharmacokinetic sampling was performed and pharmacokinetic parameters for each statin were calculated. Safety was assessed throughout the study. An analysis of variance using a mixed-effects model was applied to the natural logarithmic transformation of pharmacokinetic parameters (Cmax and AUCinf) for ATV, 2-OH-ATV (active metabolite of ATV), PRA, and ROS. Geometric-least squares means (GLSM) ratios and 90% confidence intervals (90% CI) of pharmacokinetic parameters were estimated for each analyte and were compared against pre-specified lack of pharmacokinetic alteration boundaries of 70 to 143%.Results:Of the 27 enrolled participants, 25 participants completed all study treatments. Most AEs and laboratory abnormalities were Grade 1 or 2 in severity; 1 participant discontinued due to a Grade 3 increase in creatine kinase and 1 participant discontinued due to difficulty in blood draws. Following coadministration of filgotinib with ATV, relative to ATV alone, ATV AUCinf was unaffected (GLSM ratio (90% CI): 0.91 (0.84, 0.99)), but ATV Cmax was slightly reduced (GLSM ratio (90% CI): 0.82 (0.69, 0.98)). 2-OH-ATV exposure (Cmax and AUCinf) were unaffected (GLSM ratio (90% CI): 0.98 (0.81, 1.18) for Cmax and 1.12 (1.02, 1.22) for AUCinf), and were within the pre-specified lack-of-effect bounds. Following coadministration with filgotinib, PRA AUCinf was unaffected (GLSM ratio (90% CI): 1.22 (1.06, 1.42)), but PRA Cmax was slightly higher (1.25 (1.01, 1.54)). ROS exposure (Cmax and AUCinf) were moderately higher upon coadministration with filgotinib (GLSM ratio (90% CI): 1.68 (1.43, 1.97) for Cmax and 1.42 (1.30, 1.56) for AUCinf), and these changes in rosuvastatin exposure are not considered to be clinically relevant.Conclusion:All study treatments were generally well tolerated. Co-administration with filgotinib did not have a clinically meaningful impact on the exposure of ATV, PRA, and ROS. These data support concomitant use of filgotinib with OATP substrates such as statins.References:[1]Piepoli MF, Hoes AW, Agewall S, et al. Eur Heart J. 2016;37(29): 2315-2381.Disclosure of Interests:Kacey Anderson Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Cara Nelson Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Qi Gong Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Muhsen Alani Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Thomas Tarnowski Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Ahmed A. Othman Shareholder of: Gilead Sciences, Employee of: Gilead Sciences

scholarly journals Clinical, Functional, and Radiographic Benefits of Longterm Adalimumab Plus Methotrexate: Final 10-year Data in Longstanding Rheumatoid Arthritis

2013 ◽  
Vol 40 (9) ◽  
pp. 1487-1497 ◽  
Author(s):  
Edward C. Keystone ◽  
Désirée van der Heijde ◽  
Arthur Kavanaugh ◽  
Hartmut Kupper ◽  
Shufang Liu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Disease Control ◽  
Activity Index ◽  
Controlled Trial ◽  
Joint Disease ◽  
Inadequate Response ◽  
Functional Responses ◽  
Open Label ◽  
Irreversible Damage

Objective.To examine the longterm effectiveness and safety of adalimumab in patients with longstanding rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX), and to assess the effect of a 1-year delay in initiation of combination therapy.Methods.DE019 was a 1-year randomized controlled trial (RCT) in which patients received adalimumab 20 mg weekly, adalimumab 40 mg every other week (eow), or placebo; all received concomitant MTX. Patients completing the RCT could receive open-label adalimumab 40 mg eow + MTX for an additional 9 years. Clinical, functional, and radiographic outcomes were assessed using composite measures of disease activity (e.g., American College of Rheumatology responses, 28-joint Disease Activity Score with C-reactive protein, Simplified Disease Activity Index), Health Assessment Questionnaire-Disability Index, and the modified total Sharp score (mTSS), respectively.Results.Of the 619 patients randomized, 457 entered the open-label extension; 202 completed 10 years. At Year 10, patients demonstrated effective disease control and inhibition of radiographic progression. Differences in clinical and functional responses between adalimumab + MTX and placebo + MTX observed during the RCT became less apparent at Year 10. Still, patients who initially received adalimumab + MTX had significantly lower mean ΔmTSS at Year 10 compared with patients who initially received placebo + MTX. No new safety signals arose following up to 10 years of adalimumab + MTX exposure.Conclusion.During up to 10 years of treatment with adalimumab + MTX, patients with longstanding RA experienced effective disease control with no change to the expected safety profile. A 1-year delay in receipt of adalimumab + MTX was associated with reduced effectiveness, suggesting that a window of opportunity to prevent irreversible damage exists even in a population with established RA.

Outcomes of Passable and Non-passable Strictures in Clinical Trials of Crohn’s Disease: A Post-hoc Analysis

2021 ◽  
Author(s):  
Neeraj Narula ◽  
Emily C L Wong ◽  
Parambir S Dulai ◽  
John K Marshall ◽  
Jean-Frederic Colombel ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Activity Index ◽  
Disease Activity Index ◽  
Symptom Improvement ◽  
Logistic Regression Models ◽  
Post Hoc Analysis ◽  
Endoscopic Remission ◽  
Post Hoc ◽  
The Impact

Abstract Background and Aims There is paucity of evidence on the reversibility of Crohn’s disease [CD]-related strictures treated with therapies. We aimed to describe the clinical and endoscopic outcomes of CD patients with non-passable strictures. Methods This was a post-hoc analysis of three large CD clinical trial programmes examining outcomes with infliximab, ustekinumab, and azathioprine, which included data on 576 patients including 105 with non-passable strictures and 45 with passable strictures, as measured using the Simple Endoscopic Score for Crohn’s Disease [SES-CD]. The impact of non-passable strictures on achieving clinical remission [CR] and endoscopic remission [ER] was assessed using multivariate logistic regression models. CR was defined as a Crohn’s Disease Activity Index [CDAI] <150, clinical response as a CDAI reduction of ≥100 points, and ER as SES-CD score <3. Results After 1 year of treatment, patients with non-passable strictures demonstrated the ability to achieve passable or no strictures in 62.5% of cases, with 52.4% and 37.5% attaining CR and ER, respectively. However, patients with non-passable strictures at baseline were less likely to demonstrate symptom improvement compared with those with passable or no strictures, with reduced odds of 1-year CR (adjusted odds ratio [aOR] 0.17, 95% CI 0.03–0.99, p = 0.048). No significant differences were observed between patients with non-passable strictures at baseline and those with passable or no strictures in rates of ER [aOR 0.82, 95% CI 0.23–2.85, p = 0.751] at 1 year. Conclusions Patients with non-passable strictures can achieve symptomatic and endoscopic remission when receiving therapies used to treat CD, although they are less likely to obtain CR compared with patients without non-passable strictures. These findings support the importance of balancing the presence of non-passable strictures in trial arms.

scholarly journals Therapeutic potential of targeting Tfr/Tfh cell balance by low-dose-IL-2 in active SLE: a post hoc analysis from a double-blind RCT study

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Miao Miao ◽  
Xian Xiao ◽  
Jiayi Tian ◽  
Yunzhi Zhufeng ◽  
Ruiling Feng ◽  
...  
Keyword(s):  
Low Dose ◽  
Activity Index ◽  
Cell Subset ◽  
Immunoglobulin M ◽  
Controlled Clinical Trial ◽  
Double Blind ◽  
Post Hoc Analysis ◽  
Immune Balance ◽  
Cell Balance ◽  
Post Hoc

Abstract Objective To investigate the regulation of T follicular regulatory (Tfr) and T follicular (Tfh) cell subtypes by low-dose IL-2 in systemic lupus erythematosus (SLE) in a randomized, double-blind, placebo-controlled clinical trial. Methods A post hoc analysis was performed in a randomized cohort of SLE patients (n=60) receiving low-dose IL-2 therapy (n=30) or placebo (n=30), along with the standard of care treatment. The primary endpoint was the attainment of SLE responder index-4 (SRI-4) at week 12 in the trial. Twenty-three healthy controls were enrolled for T cell subset detection at the same time as the trial. The t-stochastic neighbor embedding (tSNE) analysis of CD4 T subsets based on immune cells flow cytometry markers was performed to distinguish Tfh, Tfh1, Tfh2, Tfh17, and Tfr cell subsets. Results Compared with HC, the frequency of Tfr (CXCR5+PD-1low Treg and CXCR5+PD-1high Treg) cells was significantly reduced, while the pro-inflammatory Tfh cells were increased in patients with SLE. The imbalanced Tfh cell was associated with several pathogenic factors (anti-dsDNA antibodies (r=0.309, P=0.027) and serum IL-17 (r=0.328, P=0.021)) and SLE Disease Activity Index (SLEDAI) score (r=0.273, P=0.052). Decreased CXCR5+PD-1low Treg/Tfh and CXCR5+PD-1low Treg/Tfh17 were both associated with increased immunoglobulin M (IgM) (r=−0.448, P=0.002 and r=−0.336, P=0.024, respectively). Efficacy of low-dose IL-2 therapy was associated with a restored Tfr/Tfh cell balance. Conclusion These data support the hypothesis that promotion of Tfr is associated with decreased disease activities and that low-dose IL-2 therapy can recover Tfr/Tfh immune balance. Trial registration number ClinicalTrials.gov Registries (NCT02465580).

scholarly journals Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial

2016 ◽  
Vol 76 (5) ◽  
pp. 840-847 ◽  
Author(s):  
Gerd R Burmester ◽  
Yong Lin ◽  
Rahul Patel ◽  
Janet van Adelsberg ◽  
Erin K Mangan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Active Rheumatoid Arthritis ◽  
Activity Index ◽  
Joint Disease ◽  
Phase Iii ◽  
Inadequate Response ◽  
Efficacy And Safety ◽  
Double Blind ◽  
End Point

ObjectivesTo compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response.MethodsMONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial. Patients received sarilumab (200 mg every 2 weeks (q2w)) or adalimumab (40 mg q2w) monotherapy for 24 weeks. The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24.ResultsSarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (−3.28 vs −2.20; p<0.0001). Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p≤0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037). Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis). Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab). Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences.ConclusionsSarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment. The safety profiles of both therapies were consistent with anticipated class effects.Trial registration numberNCT02332590.

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