Jenny Devenport

Tocilizumab as monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs: twenty-four-week results of an open-label, clinical practice study.

To assess the safety and tolerability of tocilizumab (TCZ) as monotherapy or in combination with nonbiologic disease‐modifying antirheumatic drugs (DMARDs) in patients with moderate to severe rheumatoid arthritis (RA) who had an inadequate response at study entry to their current treatment with biologic agents or DMARDs.

The effects of tocilizumab on osteitis, synovitis and erosion progression in rheumatoid arthritis: results from the ACT-RAY MRI substudy

Objective To examine the imaging-detected mechanism of reduction of structural joint damage progression by tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) using MRI. Methods In a substudy of a randomised, double-blind, phase 3b study (ACT-RAY) of biologic-naïve patients with RA who were methotrexate (MTX)-inadequate responders, 63 patients were randomised to continue MTX or receive placebo (PBO), both in combination with TCZ 8 mg/kg every 4 weeks, with optional additional disease-modifying antirheumatic drugs at week 24 if Disease Activity Score of 28 joints < 3.2. The most symptomatic hand was imaged with 0.2 Tesla extremity MRI at weeks 0, 2, 12 and 52. MR images were scored using Outcome Measures in Rheumatology–Rheumatoid Arthritis Magnetic Resonance Imaging Score. Predictors of week 52 erosion progression were determined by logistic regression analysis. Results TCZ + PBO (n=32) demonstrated mean improvements in synovitis from baseline to weeks 2 (−0.92; p=0.0011), 12 (−1.86; p<0.0001) and 52 (−3.35; p<0.0001), while TCZ + MTX (n=31) had mean improvements in synovitis at week 12 (−0.88; p=0.0074), but not week 52 (−1.00; p=0.0711). TCZ+PBO demonstrated mean reductions in osteitis at weeks 12 (−5.10; p=0.0022) and 52 (−8.56; p=0.0006), while TCZ+MTX had mean reductions at weeks 2 (−0.21; p<0.05) and 12 (−3.63; p=0.0008), but not week 52 (−2.31; p=0.9749). Mean erosion scores did not worsen in either group. MRI erosion scores at weeks 12 and 52 correlated strongly with radiography erosion scores at week 52 (r>0.80). Baseline synovitis and worsening of osteitis predicted erosion progression. Conclusions Rapid suppression of synovitis and osteitis with reduction in structural joint damage progression occurred with TCZ, as monotherapy or in combination with MTX, through week 52.

Relationship Between Baseline and Early Changes in C‐Reactive Protein and Interleukin‐6 Levels and Clinical Response to Tocilizumab in Rheumatoid Arthritis

To clarify the relevance of measuring interleukin‐6 (IL‐6) and C‐reactive protein (CRP) levels in order to predict clinical response to tocilizumab (TCZ) in rheumatoid arthritis patients.

AB0286 A Cluster-Randomized Trial of a Behavioral Intervention to Incorporate a Treat-To-Target Approach in the Clinical Care of Rheumatoid Arthritis Patients

Background A treat-to-target (T2T) approach to the care of patients with rheumatoid arthritis (RA) has been advocated, which involves regular assessment of disease activity using validated metrics, frequent follow-up visits for patients with moderate to high disease activity, and escalation of therapy when patients have inadequate therapeutic response as assessed by standard disease activity scores. Objectives The goal of this abstract is to examine whether cluster randomization will result in comparable patients for a behavioral intervention trial designed to assess the impact of implementing a structured T2T approach vs routine care. Methods This trial cluster-randomized 31 rheumatology practices based on practice size from the Corrona network of private and academic rheumatology sites to either the T2T intervention (n=16) or usual care (n=15) between July 29, 2011, and July 30, 2013. RA patients with moderate or high disease activity, defined as Clinical Disease Activity Index (CDAI) >10, and no contraindication to T2T were enrolled by the practices and followed for 12 months. In the T2T group, medications were to be accelerated based on disease activity levels with visits occurring as frequently as monthly in those with active disease. Treatment acceleration was defined as a new initiation or increase to the dose or frequency of a prescribed biologic or non-biologic DMARD, or changing route of methotrexate from oral to subcutaneous. In contrast, the usual care subjects were seen at least every 3 months with medication changes per the treating provider. The co-primary endpoints were achievement of low disease activity, defined as CDAI of ≤10, and an assessment of feasibility of implementing T2T in rheumatology practices (e.g., rates of treatment acceleration, frequency of visits, time to next visit conditional on disease activity, and probability of acceleration conditional on disease activity). Results There were 249 patients enrolled from the T2T practices and 289 from usual care practices. The two groups were similar in terms of mean age, gender, and race but not for ethnicity (Table). Patients were also similar in terms of education level, employment status, insurance type and clinical features (disease duration, rheumatoid factor seropositivity, tender joint count, swollen joint count, disease activity, and patient pain); however, functional status was different. Both groups had similar proportions of subjects receiving prednisone and methotrexate as well as similar dosing for those taking these medications. Study retention at 12 months (time window is 9 to 15 months after enrollment) was 83% of the usual care subjects and 79% of the T2T subjects. Conclusions This cluster-randomized approach to implementing a behavioral intervention successfully identified similar patients for the two treatment arms for a study of T2T. Acknowledgements The Corrona T2T study is sponsored by Corrona, LLC, with support from a development and subscription agreement/contract with Genentech and additional support from AbbVie. Disclosure of Interest L. Harrold Employee of: University of Massachusetts Medical School, G. Reed Employee of: Corrona, LLC, J. T. Harrington Shareholder of: AbbVie, Amgen, BMS, GlaxoSmithKline, Johnson & Johnson, Pfizer and Roche, Consultant for: AbbVie, Amgen, Antares, AstraZeneca, Celgene, Horizon, Iroko, Pfizer, Roche and UCB, Speakers bureau: AbbVie, Amgen, Pfizer, Roche and UCB, C. Barr Employee of: Corrona, LLC, K. Saunders Employee of: Corrona, LLC, A. Gibofsky: None declared, J. Greenberg Shareholder of: Corrona, LLC, Consultant for: AstraZeneca, Celgene, Novartis and Pfizer, Employee of: Corrona, LLC, A. John Employee of: Genentech, Inc, J. Devenport Employee of: Genentech, Inc, J. Kremer Shareholder of: Corrona, LLC, Grant/research support from: Genentech, Inc, Consultant for: Genentech, Inc, Employee of: Corrona, LLC

Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial

Importance More than half of patients with acute ischemic stroke have minor neurologic deficits (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) at presentation. Although prior major trials of alteplase included patients with low NIHSS scores, few without clearly disabling deficits were enrolled. Objective To evaluate the efficacy and safety of alteplase in patients with NIHSS scores of 0 to 5 whose deficits are not clearly disabling. Design, Setting, and Participants The PRISMS trial was designed as a 948-patient, phase 3b, double-blind, double-placebo, multicenter randomized clinical trial of alteplase compared with aspirin for emergent stroke at 75 stroke hospital networks in the United States. Patients with acute ischemic stroke whose deficits were scored as 0 to 5 on the NIHSS and judged not clearly disabling and in whom study treatment could be initiated within 3 hours of onset were eligible and enrolled from May 30, 2014, to December 20, 2016, with final follow-up on March 22, 2017. Interventions Participants were randomized to receive intravenous alteplase at the standard dose (0.9 mg/kg) with oral placebo (n = 156) or oral aspirin, 325 mg, with intravenous placebo (n = 157). Main Outcomes and Measures The primary outcome was the difference in favorable functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days via Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from onset to treatment. Because of early termination of the trial, prior to unblinding or interim analyses, the plan was revised to examine the risk difference of the primary outcome by a linear model adjusted for the same factors. The primary safety end point was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous study treatment. Results Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years; 144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1-3]; median time to treatment, 2.7 hours [IQR, 2.1-2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients (78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable outcome (adjusted risk difference, −1.1%; 95% CI, −9.4% to 7.3%). Five alteplase-treated patients (3.2%) vs 0 aspirin-treated patients had sICH (risk difference, 3.3%; 95% CI, 0.8%-7.4%). Conclusions and Relevance Among patients with minor nondisabling acute ischemic stroke, treatment with alteplase vs aspirin did not increase the likelihood of favorable functional outcome at 90 days. However, the very early study termination precludes any definitive conclusions, and additional research may be warranted. Trial Registration ClinicalTrials.gov Identifier: NCT02072226

FRI0248 Long-term efficacy and safety of tocilizumab (TCZ) monotherapy in patients (PTS) with rheumatoid arthritis (RA) previously methotrexate (MTX) naive or mtx free for 6 months prior to study start

Background TCZ monotherapy has been studied in 3 global randomised clinical trials: AMBITION,1 ACT-RAY2 and ADACTA.3 The AMBITION trial demonstrated statistically significant superiority of a biologic monotherapy over MTX monotherapy; in pts who were MTX naive or MTX free for 6 mos prior to study start, TCZ 8 mg/kg monotherapy resulted in statistically greater ACR20/50/70 responses at 24 wks compared with MTX. Objectives In this post hoc exploratory analysis, efficacy and safety were evaluated in pts from AMBITION who remained on TCZ monotherapy in the long-term extension (LTE) study up to 240 wks. Methods Pts randomised to TCZ 8 mg/kg monotherapy in AMBITION (n=286) who entered the LTE (n=243) were included. During the LTE, MTX/other allowable disease-modifying anti-rheumatic drug (DMARD) could be added for pts who did not achieve a 50% reduction in number of tender and swollen joints from baseline of the core study. The rate, timing and nature of added DMARDs were characterised. Efficacy and adverse events (AEs) were also assessed up to 240 wks. Results Of 243 pts who entered the LTE, 57.2% (n=139) remained on monotherapy until withdrawal or data cut, 9.9% (n=24) added a DMARD before LTE entry and 32.9% (n=80) added a DMARD after LTE entry (18.5% [n=45] ≤3 wks post-entry; 14.4% [n=35] >3 wks post-entry). Added DMARDs included MTX (93% [97/104]), hydroxychloroquine (3% [3/104]), leflunomide (2% [2/104]) and parenteral gold (2% [2/104]). Of the 139 pts who remained on TCZ monotherapy, 102 (73%) reached 240 wks of treatment and 37 (27%) withdrew. Mean SJC, TJC and DAS28 (data not shown) decreased sharply during the first 24 wks and continued to decrease or were maintained thereafter (Table). Similar trends in improved disease state were observed; 40.1% and 16.7% of pts achieved DAS28 <2.6 and clinical disease activity index (CDAI) remission, respectively, by wk 24; rates increased or were maintained thereafter; absolute numbers achieving these endpoints increased to wks 192 and 120 (Table). Absolute numbers achieving DAS28 ≤3.2 and CDAI low disease activity increased to wks 120 and 96 (data not shown for wk 96), respectively. AEs for all pts in this analysis (n=243) were consistent with the known safety profile of TCZ. Image/graph Conclusions For pts who stayed on monotherapy during the trial, TCZ treatment provided durable efficacy over time, as demonstrated by increasing proportions and/or numbers achieving low disease activity and remission thresholds. AEs reported were consistent with the known safety profile of TCZ; no new safety signals were detected. References Ann Rheum Dis 2010;69:88; Ann Rheum Dis 2013;72:43; Ann Rheum Dis 2012;71(Suppl3):152 Disclosure of Interest: G. Jones Grant/research support from: Abbott, Roche, Novartis, Amgen, MSD, Auxilium, UCB, Consultant for: Abbott, Roche, Novartis, Amgen, MSD, UCB, Janssen, Genzyme, Speakers bureau: Abbott, Roche, Novartis, Amgen, MSD, UCB, Janssen, A. Sebba Consultant for: Genentech, Lilly, Novartis, Merck, Speakers bureau: Genentech, Novartis, A. Anisfeld Employee of: Genentech, a member of the Roche group, J. Devenport Employee of: Genentech, a member of the Roche group, C. Bernasconi Consultant for: Roche, D. Smart Employee of: Roche, D. Galindez Employee of: Genentech, a member of the Roche group, C. Mpofu Employee of: Roche, J. Gomez-Reino Grant/research support from: MSD, UCB, Consultant for: BMS, GSK, MSD, Pfizer, Roche, UCB, Speakers bureau: Abbott, BMS, GSK, MSD, Pfizer, Roche, UCB

Alteplase for the treatment of acute ischemic stroke in patients with low National Institutes of Health Stroke Scale and not clearly disabling deficits (Potential of rtPA for Ischemic Strokes with Mild Symptoms PRISMS): Rationale and design:

Rationale Over half of acute ischemic stroke patients have a low National Institutes of Health Stroke Scale of 0–5 and up to two-thirds may not appear clearly disabled at presentation. The efficacy of intravenous alteplase for the latter group is not known. Aim Potential of rtPA for Ischemic Strokes with Mild Symptoms (PRISMS) was designed to evaluate the safety and efficacy of intravenous alteplase for the treatment of acute ischemic stroke with National Institutes of Health Stroke Scale 0–5 and without clearly disabling deficits. Sample size estimates A maximum of 948 subjects were required to test the superiority hypothesis with 80% power, according to a one-sided 0.025 level of significance. Methods and design PRISMS was a multicenter, randomized, double-blind, placebo-controlled phase 3b clinical trial. Patients were randomized to the active arm (intravenous alteplase standard dose of 0.9 mg/kg, up to a maximum of 90 mg, plus oral aspirin placebo) or the control arm (intravenous alteplase placebo plus active oral aspirin dose of 325 mg). Study outcome The primary efficacy endpoint was favorable functional outcome, defined as a modified Rankin Scale score 0 or 1 assessed at 90-day postrandomization.