Leading beyond regulatory approval: Opportunities for statisticians to optimize evidence generation and impact clinical practice.

The role and value of statistical contributions in drug development up to the point of health authority approval are well understood. But health authority approval is only a true 'win' if the evidence enables access and adoption into clinical practice. In today's complex and evolving healthcare environment, there is additional strategic evidence generation, communication, and decision support that can benefit from statistical contributions. In this article, we describe the history of medical affairs in the context of drug development, the factors driving post-approval evidence generation needs, and the opportunities for statisticians to optimize evidence generation for stakeholders beyond health authorities in order to ensure that new medicines reach appropriate patients.

Development and validation of the Methotrexate Experience Questionnaire, a new methotrexate oral treatment adherence tool in rheumatoid arthritis.

OBJECTIVE: Despite the development of new biologic therapies, methotrexate (MTX) remains the preferred initial disease-modifying anti-rheumatic drug to treat rheumatoid arthritis (RA). Adherence to disease-modifying anti-rheumatic drugs is suspected to be highly variable potentially leading to reduced treatment effectiveness. This work aimed to develop and validate the Methotrexate Experience Questionnaire (MEQ), a tool to identify and characterize non-adherence to oral MTX. METHODS: MEQ development included a literature review and qualitative interviews with RA patients and physicians in the United States. A retrospective, cross-sectional study using data from Optimum Patient Care Research Database, a large primary care database of electronic medical records in the United Kingdom, was conducted to finalize the MEQ and evaluate its psychometric properties. RESULTS: Three hundred seven e-consented subjects (66% women, mean age of 65 years) completed the MEQ remotely, and were included in this analysis. Item-convergent and divergent validity were generally supportive of the construct validity of the MEQ and Cronbach's alpha of 0.87 supported its reliability. The MEQ Total score presented statistically significant correlations of small to medium size with all selected concurrent scales, as expected; the highest correlation was obtained between the general acceptance score of ACCEPT and the MEQ Total score (0.55, p < 0.001). Known-groups validity was demonstrated as a logical pattern of higher MEQ scores was obtained for patients considered adherent with both the 6- and 12-month Proportion of Days Covered (mean MEQ total score 82.7 for 12-month PDC ≥ 80% against 76.3 for 12-month PDC < 80%, p< 0.0001). Additionally, a pattern of lower MEQ scores was obtained for patients with more severe disease assessed with Routine Assessment of Patient Index Data 3. CONCLUSION: The 24-item MEQ is a reliable and valid instrument to assess the adherence of RA patients taking MTX, potentially improving over historical refill rate metrics by providing insights into the individual reasons for lack of adherence. This information should facilitate clinician-patient discussions and help inform treatment decisions.

Effect of disease duration and other characteristics on efficacy outcomes in clinical trials of tocilizumab for rheumatoid arthritis.

OBJECTIVE: To determine the extent to which disease duration, alone or in combination with other baseline clinical and non-clinical factors, explains variations in outcome of tocilizumab initiated in biologic-naïve patients with established RA. METHODS: In this pooled analysis of phase 3 and 4 clinical trials conducted by the sponsor, predictors of response, including demographics, disease characteristics at baseline (start of tocilizumab dosing) and study characteristics (e.g. patient inclusion criteria, tocilizumab dosing regimen) were evaluated. Response was measured as change from baseline to week 24 in Clinical Disease Activity Index (CDAI) and HAQ-Disability Index (HAQ-DI) scores and as the proportions of patients who experienced ≥50% improvement based on ACR criteria (ACR50) and CDAI remission (≤2.8) rates at week 24. RESULTS: Improvements in all outcomes investigated were observed in patients receiving tocilizumab. Although disease duration was statistically significant in the models, it accounted for <2% of variation in CDAI and HAQ-DI score changes from baseline to week 24; baseline CDAI and HAQ-DI values accounted for 32% and 15% of variations, respectively. Doubling of disease duration reduced the odds of achieving an ACR50 response by only 9%, and each additional 5-year period of disease duration decreased the odds of achieving CDAI remission by only 15%. CONCLUSION: RA duration, alone or in combination with other baseline characteristics, had a statistically significant but clinically small effect on the outcomes of tocilizumab initiated in biologic-naïve patients with established RA.

Comprehensive exploratory autoantibody profiling in patients with early rheumatoid arthritis treated with methotrexate or tocilizumab.

BACKGROUND: We sought to identify immunoglobin G autoantibodies predictive of early treatment response to methotrexate, the recommended first-line therapy for patients with newly diagnosed rheumatoid arthritis, and to the interleukin-6 receptor inhibitor biologic tocilizumab, initiated as the first disease-modifying anti-rheumatic drug. MATERIALS AND METHODS: In baseline sera of a subset of patients with newly diagnosed rheumatoid arthritis in the U-Act-Early study, selected based on specific responder/non-responder criteria using the Disease Activity Score assessing 28 joints (DAS28) within the first 20 weeks, we measured immunoglobin G antibody reactivity against 463 protein antigens and performed supervised cluster analysis to identify predictive autoantibodies for treatment response. The analysis subset comprised 56 patients in the methotrexate arm (22 responders, 34 non-responders) and 50 patients in the tocilizumab arm (34 responders, 16 non-responders). For comparison, these analyses were also performed in 50 age- and gender-matched healthy controls. RESULTS: Increased reactivity in responders versus non-responders was found in the methotrexate arm against two antigens-DOT1-like histone lysine methyltransferase (p = 0.009) and tropomyosin (p = 0.003)-and in the tocilizumab arm against one antigen-neuro-oncological ventral antigen 2 (p = 0.039). Decreased reactivity was detected against two antigens in the methotrexate arm-G1 to S phase transition 2 (p = 0.023) and the zinc finger protein ZPR1 (p = 0.021). Reactivity against the identified antigens was not statistically significant in either treatment arm for patients with rheumatoid factor-positive versus-negative or anti-cyclic citrullinated test-positive versus test-negative rheumatoid arthritis (p ≥ 0.06). CONCLUSIONS: Comprehensive profiling of baseline sera revealed several novel immunoglobin G autoantibodies associated with early treatment response to methotrexate and to tocilizumab in disease-modifying anti-rheumatic drug-naive patients with rheumatoid arthritis. These findings could eventually yield clinically relevant predictive markers, if corroborated in different patient cohorts, and may facilitate future benefit in personalised healthcare.

A noninterventional, multinational study to assess PD-L1 expression in cytological and histological lung cancer specimens.

BACKGROUND: The diagnosis of advanced lung cancer is made with minimally invasive procedures. This often results in the availability of cytological material only for subtype determination and companion diagnostic testing, with the latter being technically and clinically validated on histological material only. Thus, the primary objective of the MO29978 clinical study was to assess programmed death ligand 1 (PD-L1) protein expression on cytology samples as surrogates for histology samples in patients with lung cancer. METHODS: Formalin-fixed, paraffin-embedded histological samples and cytological cell blocks from 190 patients were analyzed with immunohistochemical assays using the rabbit monoclonal anti-PD-L1 antibody clones SP142 and SP263. PD-L1 expression was quantified on both tumor cells (TC) and tumor-infiltrating immune cells (IC). Overall concordance, sensitivity, specificity, and accuracy, with a 1% cutoff used for both assays, were assessed for PD-L1 expression on TC and IC. RESULTS: In non-small cell lung cancer histology and cytology samples measured with the PD-L1 (SP142) antibody (n = 173), the intraclass correlation coefficients were 0.40 and 0.06 on TC and IC, respectively. With SP142 and SP263, accuracies of 74.1% for TC and 51.9% for IC and accuracies of 75.2% for TC and 61.2% for IC, respectively, were reported. CONCLUSIONS: Overall, this study has demonstrated that PD-L1 analysis on TC is feasible in cytological material, but quantification is challenging. Tumor tissue should be preferred over cell block cytology for PD-L1 immunohistochemical analysis unless laboratories have validated their cytology preanalytical approaches and demonstrated the comparability of histology and cytology for TC PD-L1 results.

Effect on efficacy and safety trial outcomes of also enrolling patients on ongoing glucocorticoid therapy in rheumatoid arthritis clinical trials of tocilizumab or adalimumab or methotrexate monotherapy.

BACKGROUND: In rheumatoid arthritis (RA) trials, inclusion of patients on background treatment with glucocorticoids (GCs) might impact efficacy and safety outcomes. OBJECTIVES: To determine if inclusion of patients on background GC use influenced efficacy and safety outcomes of RA randomised clinical trials on initiation of tocilizumab (TCZ) or adalimumab (ADA) or methotrexate (MTX) monotherapy. METHODS: Data of four double-blind RA randomised controlled trials (AMBITION, ACT-RAY, ADACTA and FUNCTION) with in total four TCZ, one ADA and two MTX monotherapy arms were analysed. Analyses of covariance of changes from baseline to week 24 in efficacy endpoints and radiographic progression up to week 104 were performed, correcting for relevant covariates. Incidence rates of serious adverse events (SAEs) were assessed. RESULTS: No statistically significant differences were found in efficacy parameters between background GC users and non-GC users, except for less radiographic progression associated with GC usage in one MTX arm. SAE rates were not statistically significantly different between GC users and non-GC users in the treatment arms. CONCLUSION: No effect of including patients on background GC treatment on efficacy and safety trial outcomes was found, with the exception of reduced radiological joint damage in one MTX arm.

Long-term safety and effectiveness of tocilizumab in patients with rheumatoid arthritis and inadequate responses to csDMARDs and/or TNF inhibitors: an open-label study close to clinical practice.

OBJECTIVE: To assess the long-term safety, tolerability, and effectiveness of tocilizumab (TCZ) as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in clinical practice in patients with moderate to severe rheumatoid arthritis (RA). METHODS: Patients in the 24-week, open-label ACT-SURE study who had at least a moderate EULAR response by week 24 and were from a participating country were eligible for this long-term extension (LTE); the patients continued to receive TCZ 8 mg/kg intravenously every 4 weeks as monotherapy or in combination with ≥ 1 csDMARD for up to an additional 108 weeks. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs). Effectiveness endpoints included Disease Activity Score in 28 joints (DAS28) responses, American College of Rheumatology (ACR) responses, and patient-reported outcomes (PROs). RESULTS: Of the 1102 patients who completed the core 24-week study, 934 participated in the LTE; the median exposure to TCZ was 64.3 weeks. From baseline to the end of the LTE, AEs and SAEs occurred in 90% and 9% of patients, respectively. The overall event rates (95% CI) of AEs and SAEs were 406.5 per 100 patient-years (PY) (395.5, 417.8) and 8.8 per 100 PY (7.3, 10.6), respectively. Mean (SD) improvement in DAS28 was 4.12 (1.18), P < 0.0001. The DAS28 remission rates, ACR response rates, and PRO scores were maintained during the LTE study. CONCLUSION: In clinical practice, TCZ as monotherapy or in combination with csDMARDs was safe, well tolerated, and efficacious in patients with moderate to severe RA.

Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis.

OBJECTIVES: This post hoc analysis of the TOZURA study programme evaluated the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) as monotherapy or with concomitant conventional synthetic DMARDs (csDMARDs) in patients with RA categorized by baseline glucocorticoid (GC) use. METHODS: TOZURA was a multinational, open-label, single-arm, common-framework study programme (11 protocols, 22 countries) in patients with moderate to severe RA in whom csDMARDs or biologic therapies had failed or who were MTX naïve. Patients received once-weekly TCZ-SC 162 mg for ⩾24 weeks as monotherapy or in combination with csDMARDs and/or oral GC use (⩽10 mg/day prednisone or equivalent), which was to be continued unchanged for 24 weeks. Treatment subgroups were defined by baseline GC use and analysed for efficacy and safety. RESULTS: Of 1804 patients who received TCZ-SC, 145 received monotherapy + GC, 208 received monotherapy without GC, 730 received combination therapy + GC and 721 received combination therapy without GC. The median GC dose in both GC subgroups was 5 mg/day. The proportion of patients who achieved clinical remission, defined as DAS in 28 joints using ESR <2.6, increased similarly from baseline to week 24 in all subgroups. Improvements in patient-reported outcomes were similar in all subgroups. Overall adverse event profiles were generally similar between subgroups, with some slight numerical differences between GC and non-GC subgroups. CONCLUSION: The incremental efficacy benefits of TCZ-SC as monotherapy and in combination with csDMARDs were similar between patients with and without previous and continued oral GC treatment, with generally similar safety profiles. TRIAL REGISTRATION: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT01941940, NCT01941095, NCT01951170, NCT01987479, NCT01988012, NCT01995201, NCT02001987, NCT02011334, NCT02031471, NCT02046603, NCT02046616.

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.

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.

Long-Term Safety and Efficacy of Subcutaneously Administered Tocilizumab for Adult Rheumatoid Arthritis: A Multicenter Phase 3b Long-term Extension Study.

INTRODUCTION: To assess the long-term safety and efficacy of subcutaneous tocilizumab (TCZ-SC) in US patients with rheumatoid arthritis (RA) who rolled over from the two global phase 3 studies, SUMMACTA (NCT01194414) and BREVACTA (NCT1232569), into this open-label, single-arm, phase 3b study. METHODS: Patients continued to receive TCZ-SC 162 mg weekly or every other week or switched from intravenous TCZ to TCZ-SC 162 mg qw for up to 84 weeks. The primary endpoint was the proportion of patients with serious adverse events (SAEs). Secondary endpoints included clinical efficacy, laboratory abnormalities, and immunogenicity. RESULTS: Of the 217 patients treated, 76.5% were female, and the mean age was 58.4 years. A total of 23 patients (10.6%) had ≥1 SAE. The most common SAEs were infections (3.7%). Alanine aminotransferase elevations (38.2%) were not associated with hepatic injury. Grade 3/4 neutropenia (3%) was transient and not associated with serious infections. Immunogenicity was low (<1%) and not associated with SAEs. No anaphylaxis or deaths occurred. Thirteen patients (6.0%) withdrew due to safety reasons. Mean Clinical Disease Activity Index and Disease Activity Score in 28 joints remained stable throughout the trial. CONCLUSIONS: The long-term safety of TCZ-SC during the long-term extension period was consistent with the safety profiles from SUMMACTA and BREVACTA, with no new safety signals. Efficacy improvements observed from baseline remained stable over time. These results demonstrated the durability of the safety and efficacy responses, and low immunogenicity, with long-term exposure to TCZ-SC in patients with RA. FUNDING: F. Hoffmann-La Roche, Ltd. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier, NCT01662063.

Correction of: Exploring Concordance of Patient-Reported Information on PatientsLikeMe and Medical Claims Data at the Patient Level.

[This corrects the article DOI: 10.2196/jmir.5130.].

Exploring Concordance of Patient-Reported Information on PatientsLikeMe and Medical Claims Data at the Patient Level.

BACKGROUND: With the emergence of data generated by patient-powered research networks, it is informative to characterize their correspondence with health care system-generated data. OBJECTIVES: This study explored the linking of 2 disparate sources of real-world data: patient-reported data from a patient-powered research network (PatientsLikeMe) and insurance claims. METHODS: Active patients within the PatientsLikeMe community, residing in the United States, aged 18 years or older, with a self-reported diagnosis of multiple sclerosis or Parkinson's disease (PD) were invited to participate during a 2-week period in December 2014. Patient-reported data were anonymously matched and compared to IMS Health medical and pharmacy claims data with dates of service between December 2009 and December 2014. Patient-level match (identity), diagnosis, and usage of disease-modifying therapies (DMTs) were compared between data sources. RESULTS: Among 603 consenting patients, 94% had at least 1 record in the IMS Health dataset; of these, there was 93% agreement rate for multiple sclerosis diagnosis. Concordance on the use of any treatment was 59%, and agreement on reports of specific treatment usage (within an imputed 5-year period) ranged from 73.5% to 100%. CONCLUSIONS: It is possible to match patient identities between the 2 data sources, and the high concordance at multiple levels suggests that the matching process was accurate. Likewise, the high degree of concordance suggests that these patients were able to accurately self-report their diagnosis and, to a lesser degree, their treatment usage. Further studies of linked data types are warranted to evaluate the use of enriched datasets to generate novel insights.

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

OBJECTIVE: 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. METHODS: In a pooled, post hoc analysis of 5 pivotal trials of TCZ, we examined the distributions of baseline serum concentrations of IL-6 and CRP, stratified by randomized treatment group, and week 24 Disease Activity Score in 28 joints (DAS28) status (DAS28 <2.6 versus DAS28 ≥2.6). Relationships between early biomarker changes and later changes in DAS28 scores were evaluated using Spearman's correlations and scatterplots. Finally, percentage changes from baseline in IL-6 and CRP levels were evaluated. RESULTS: Distributions of baseline IL-6 and CRP levels were similar for patients who achieved DAS28 scores <2.6 within 6 months of TCZ initiation and those who did not. Correlations between early changes in these 2 biomarkers and change in DAS28 scores were low (rho < 0.3 for all). Mean percentage increases from baseline in IL-6 concentrations were observed in all treatment groups (highest in the 8 mg/kg dose group); mean percentage decreases in CRP concentrations were greater at week 2 and at all visits for the 8 mg/kg dose group. CONCLUSION: Baseline serum concentrations of IL-6 and CRP may not be predictive of clinical outcomes after TCZ treatment. Data demonstrate the efficacy of TCZ in patients across a broad range of baseline serum IL-6 and CRP concentrations. Similarly, changes in these biomarkers after TCZ dosing are expected and may or may not correspond to changes in other clinical signs and symptoms. These results complement previous reports describing the complex interactions among biomarker changes, other therapeutic mechanisms of action, and clinical outcomes.

Interpreting the multi-biomarker disease activity score in the context of tocilizumab treatment for patients with rheumatoid arthritis.

The multi-biomarker disease activity (MBDA) score measures 12 proteins involved in the pathophysiology of rheumatoid arthritis (RA) to assess disease activity (DA). Previous studies demonstrated correlations between MBDA and clinical DA scores with some RA therapies. In this analysis, the relationship between DA and MBDA scores and changes in MBDA component biomarkers were evaluated in tocilizumab (TCZ)-treated patients. Patients from the ACT-RAY study were included in this analysis if they had DA measures and serum collected at pre-specified time points with sufficient serum for MBDA testing at ≥1 visit. Descriptive statistics, associations between outcomes, and percentage agreement between DA categories were calculated. Seventy-eight patients were included and were similar to the ACT-RAY population. Correlations between MBDA score and DAS28-CRP were ρ = 0.50 at baseline and ρ = 0.26 at week 24. Agreement between low/moderate/high categories of MBDA score and DAS28-CRP was observed for 77.1 % of patients at baseline and 23.7 % at week 24. Mean changes from baseline to weeks 4, 12, and 24 were proportionately smaller for MBDA score than DAS28-CRP. Unlike some other MBDA biomarkers, interleukin-6 (IL-6) concentrations increased in most patients during TCZ treatment. Correlations and agreement between MBDA and DAS28-CRP or CDAI scores were lower at week 24 versus baseline. The proportionately smaller magnitude of response observed for MBDA score versus DAS28-CRP may be due to the influence of the increase in IL-6 concentrations on MBDA score. Thus, MBDA scores obtained during TCZ treatment should be interpreted cautiously and in the context of available clinical information.

The rheumatoid arthritis treat-to-target trial: a cluster randomized trial within the Corrona rheumatology network.

BACKGROUND: The treat-to-target (T2T) approach to the care of patients with rheumatoid arthritis involves using validated metrics to measure disease activity, 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. The study described is a newly launched cluster-randomized behavioral intervention to assess the feasibility and effectiveness of the T2T approach in US rheumatology practices. It is designed to identify patient and provider barriers to implementing T2T management. This initial paper focuses on the novel study design and methods created to provide these insights. METHODS/DESIGN: This trial cluster-randomizes rheumatology practices from the existing Corrona network of private and academic sites rather than patients within sites or individual investigators to provide either T2T or usual care (UC) for qualified patients who meet the 2010 revised American College of Rheumatology criteria for the diagnosis of rheumatoid arthritis and have moderate to high disease activity. Specific medication choices are left to the investigator and patient, rather than being specified in the protocol. Enrollment is expected to be completed by the end of 2013, with 30 practices randomized and enrolling a minimum of 530 patients. During the 12-month follow-up, visits are mandated as frequently as monthly in patients with active disease in the T2T group and every 3 months for the UC group. Safety data are collected at each visit. The coprimary endpoints include a comparison of the proportion of patients achieving low disease activity in the T2T and UC groups and assessment of the feasibility of implementing T2T in rheumatology practices, specifically assessment of the rates of treatment acceleration, frequency of visits, time to next visit conditional on disease activity, and probability of acceleration conditional on disease activity in the 2 groups. DISCUSSION: This cluster-randomized behavioral intervention study will provide valuable insights on the outcomes and feasibility of employing a T2T treatment approach in clinical practice in the United States. TRIAL REGISTRATION: NCT01407419.

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.

Continued benefit of tocilizumab plus disease-modifying antirheumatic drug therapy in patients with rheumatoid arthritis and inadequate clinical responses by week 8 of treatment.

OBJECTIVE: To evaluate whether patients with rheumatoid arthritis who did not respond sufficiently to tocilizumab (TCZ) plus disease-modifying antirheumatic drug (DMARD) treatment by Week 8 responded at later timepoints when continuing to take their original dose of TCZ. METHODS: In this posthoc analysis of data from phase III randomized controlled trials of inadequate responders (IR) to DMARD or tumor necrosis factor-α inhibitors (anti-TNF), percentages of patients meeting early response criteria were calculated by randomized treatment arm (TCZ 4 mg/kg, 8 mg/kg, or placebo in combination with DMARD). Percentages of patients achieving certain disease activity thresholds at later timepoints were calculated for patients who had/had not achieved response by Week 8. RESULTS: In DMARD-IR early nonresponders, 29.0%, 17.2%, and 3.7% of TCZ 8 mg/kg-randomized, TCZ 4 mg/kg-randomized, and placebo-randomized patients, respectively, achieved 28-joint Disease Activity Score (DAS28) ≤ 3.2 by Week 24. Among anti-TNF-IR patients without early response, 26.5%, 8.5%, and 1.9% of TCZ 8 mg/kg-randomized, TCZ 4 mg/kg-randomized, and placebo-randomized patients, respectively, achieved DAS28 ≤ 3.2 at Week 24. CONCLUSION: A substantial number of DMARD-IR patients taking TCZ 4 or 8 mg/kg and anti-TNF-IR patients taking TCZ 8 mg/kg who failed to respond by 8 weeks benefited from continued TCZ treatment in combination with DMARD. In contrast, the anti-TNF-IR patients without early responses who continued to take TCZ 4 mg/kg were unlikely to experience a cumulative benefit. ClinicalTrials.gov registration numbers: NCT00106548, NCT00106574, NCT00106535, NCT00106522.

Early effects of tocilizumab in the treatment of moderate to severe active rheumatoid arthritis: a one-week sub-study of a randomised controlled trial (Rapid Onset and Systemic Efficacy [ROSE] Study).

OBJECTIVES: Tocilizumab has demonstrated efficacy in managing rheumatoid arthritis (RA) from week 2 onward. This sub-study assessed effects of tocilizumab plus disease-modifying anti-rheumatic drugs (DMARDs) during the first week of therapy. METHODS: Rapid Onset and Systemic Efficacy was a 24-week, randomised, double-blind, placebo-controlled, parallel-group trial. Adults with moderate to severe active RA taking DMARDs received tocilizumab 8 mg/kg (or placebo) plus DMARDs every 4 weeks. Data were analysed from the first 62 patients at designated study sites who agreed to clinical evaluation and blood sampling at days 3 and 7 and had C-reactive protein levels ≥1 mg/dl. Outcomes included American College of Rheumatology core data set measures, disease activity score using 28 joints (DAS28) and routine assessment of patient index data 3 (RAPID3) scores. RESULTS: Baseline evaluations were similar between groups (tocilizumab, n=40; placebo, n=22). Patient global assessments of disease activity and pain improved significantly in favour of tocilizumab (mean change from baseline to day 7: -16.2 [tocilizumab], 0.8 [placebo] [p=0.005] and -12.2 [tocilizumab], 1.4 [placebo] [p=0.01], respectively). Physician global assessment of disease activity also improved more with tocilizumab (-15.4 [tocilizumab], -5.6 [placebo] [p=0.05]). Changes from baseline in tender/swollen joint counts, physical function and RAPID3 scores were not significantly different between groups. DAS28 significantly improved with tocilizumab versus placebo at day 7 (-1.16 [tocilizumab], -0.27 [placebo] [p=0.007]). CONCLUSIONS: Tocilizumab showed significant improvement in patient-reported disease activity, pain and DAS28 score as early as day 7 after first infusion, earlier than physician-reported measures, which may take longer to manifest.