Metroplex Clinical Research Center

Dallas, TX, United States

Metroplex Clinical Research Center

Dallas, TX, United States
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Isaacs J.D.,Northumbria University | Cohen S.B.,Metroplex Clinical Research Center | Emery P.,Leeds General Infirmary | Tak P.P.,University of Amsterdam | And 6 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Background: Studies examining the relationship between serological status (rheumatoid factor and/or anticitrullinated antibody) and rituximab treatment outcome in rheumatoid arthritis (RA) have been hampered by limited numbers of seronegative patients. Objective: To carry out a meta-analysis of trials from the rituximab RA clinical programme to investigate this relationship further. Methods: This was a meta-analysis of four placebo-controlled, phase II or III clinical trials. The efficacy end point in all analyses was change from baseline in Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at 24 weeks. Assay of serotype and missing data imputation methods were consistent across all studies. Results: The population analysed comprised 2177 patients (rituximab, n=1416; placebo, n=761). Demographics and baseline disease characteristics were well balanced. When a fixed-effects meta-analysis approach was used, the overall-effect model indicated evidence of additional treatment benefit with rituximab in seropositive patients: reduction in DAS28-ESR at week 24 was on average 0.35 units (95% CI 0.12 to 0.84; n=1394) greater than in seronegative patients; this effect was not seen in placebo patients. Heterogeneity indices indicated significant uncertainty in the overall-effect model (Q=8.8, I=0.77; p=0.03 (Χ2 test)). Baseline Health Assessment Questionnaire score, pain visual analogue scale, swollen joint counts of 28 joints and race were significant contributors to this heterogeneity, with additional analysis indicating that these effects may predominate in early RA (methotrexate-naïve) populations. A dominant effect was seen in patients for whom one or more tumour necrosis factor inhibitors had failed. Conclusion Although the difference was modest, the overall-effect model indicates that seropositive patients respond better to rituximab than seronegative patients.


Gladman D.,Western Research Institute | Fleischmann R.,Metroplex Clinical Research Center | Coteur G.,UCB Pharma | Woltering F.,UCB Pharma | Mease P.J.,Swedish Medical Center
Arthritis Care and Research | Year: 2014

Objective To examine the effect of certolizumab pegol (CZP) on patient-reported outcomes (PROs) in psoriatic arthritis (PsA) patients with and without prior tumor necrosis factor (TNF) inhibitor exposure. Methods The ongoing phase III RAPID-PsA trial was double blind and placebo controlled to week 24. Patients were randomized 1:1:1 to placebo every 2 weeks or CZP 400 mg at weeks 0, 2, and 4, followed by either CZP 200 mg every 2 weeks or CZP 400 mg every 4 weeks. PRO measures evaluated were the Health Assessment Questionnaire (HAQ) disability index (DI), health status (measured by the Short Form 36 [SF-36] health survey), Psoriatic Arthritis Quality of Life (PsAQOL), Fatigue Assessment Scale, patient assessment of pain (visual analog scale), and Dermatology Life Quality Index (DLQI). Post hoc analyses of PROs in patients with and without prior TNF inhibitor exposure were conducted. Change from baseline for all PROs was analyzed for the randomized population using analysis of covariance with last observation carried forward imputation. Results A total of 409 patients were randomized. Twenty percent had received a prior TNF inhibitor. Baseline demographics were similar between the treatment groups. At week 24, clinically meaningful differences in HAQ DI, SF-36, PsAQOL, fatigue, pain, and DLQI were observed in both CZP arms versus placebo (P < 0.001), irrespective of prior TNF inhibitor exposure. More CZP-treated patients reached SF-36 general population norms than placebo-treated patients. Conclusion Both CZP dosing schedules provided rapid improvements in PROs across multiple disease aspects in patients with PsA. The benefits of CZP treatment for health-related quality of life were seen across generic, PsA-specific, and dermatology-specific measures and were observed in patients regardless of prior TNF inhibitor exposure. © 2014 The Authors. Arthritis Care & Research is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.


Lee E.B.,Seoul National University | Fleischmann R.,Metroplex Clinical Research Center | Hall S.,Monash University | Wilkinson B.,Pfizer | And 8 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Methotrexate is the most frequently used first-line antirheumatic drug. We report the findings of a phase 3 study of monotherapy with tofacitinib, an oral Janus kinase inhibitor, as compared with methotrexate monotherapy in patients with rheumatoid arthritis who had not previously received methotrexate or therapeutic doses of methotrexate. METHODS: We randomly assigned 958 patients to receive 5 mg or 10 mg of tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the patient's assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician). RESULTS: Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg tofacitinib group and <0.1 point in the 10-mg tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels. CONCLUSIONS: In patients who had not previously received methotrexate or therapeutic doses of methotrexate, tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of tofacitinib need to be considered in the context of the risks of adverse events. Copyright © 2014 Massachusetts Medical Society.


Fleischmann R.,Metroplex Clinical Research Center | Kremer J.,Albany Medical College | Cush J.,Baylor Research Institute | Schulze-Koops H.,Ludwig Maximilians University of Munich | And 6 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. METHODS: In this phase 3, double-blind, placebo-controlled, parallel-group, 6-month study, 611 patients were randomly assigned, in a 4:4:1:1 ratio, to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, placebo for 3 months followed by 5 mg of tofacitinib twice daily, or placebo for 3 months followed by 10 mg of tofacitinib twice daily. The primary end points, assessed at month 3, were the percentage of patients with at least a 20% improvement in the American College of Rheumatology scale (ACR 20), the change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores (which range from 0 to 3, with higher scores indicating greater disability), and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating more disease activity). RESULTS: At month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8% in the 5-mg tofacitinib group and 65.7% in the 10-mg tofacitinib group vs. 26.7% in the combined placebo groups, P<0.001 for both comparisons). The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (-0.50 and -0.57 points, respectively, vs. -0.19 points; P<0.001). The percentage of patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6% and 8.7% in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4% with placebo; P = 0.62 and P = 0.10 for the two comparisons). Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts. CONCLUSIONS: In patients with active rheumatoid arthritis, tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function. (Funded by Pfizer; ORAL Solo ClinicalTrials.gov number, NCT00814307.) Copyright © 2012 Massachusetts Medical Society.


Van Vollenhoven R.F.,Karolinska Institutet | Fleischmann R.,Metroplex Clinical Research Center | Cohen S.,Metroplex Clinical Research Center | Lee E.B.,Seoul National University | And 11 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis. METHODS: In this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion. The three primary outcome measures were a 20% improvement at month 6 in the American College of Rheumatology scale (ACR 20); the change from baseline to month 3 in the score on the Health Assessment Questionnaire-Disability Index (HAQ-DI) (which ranges from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity). RESULTS: At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P<0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts. CONCLUSIONS: In patients with rheumatoid arthritis receiving background methotrexate, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy. (Funded by Pfizer; ORAL Standard ClinicalTrials.gov number, NCT00853385.) Copyright © 2012 Massachusetts Medical Society.


Fleischmann R.,University of Texas Southwestern Medical Center | Fleischmann R.,Metroplex Clinical Research Center
Current Opinion in Rheumatology | Year: 2012

Purpose of Review: Since the introduction of biologic therapies into the treatment paradigm of rheumatoid arthritis (RA), there has been hope that oral small molecule immune modulators would be developed that would have a risk:benefit profile at least similar to biologic therapies, be more convenient for the patient and, hopefully, be less expensive. This article reviews the progress made in the development of these compounds over the past year. Recent Finding: Additional information has become available in the past year on five oral compounds including kinase inhibitors (tofacitinib, fostamatinib, VX-509), an S1P lyase inhibitor (LX 3305) and a chemokine receptor-1 antagonist (CCX354-C). Efficacy has been shown in phase III with tofacitinib and in phase II with fostamatinib and VX-509; safety was the primary endpoint of the trials of CCX354-C and LX3305. Regarding side effects, liver test elevation and neutropenia occurred with tofacitinib, VX-509 and fostamatinib; lipid elevation with tofacitinib and VX-509; creatinine elevation and anemia with tofacitinib, and hypertension and diarrhea with fostamatinib. Summary: Compounds that inhibit tyrosine kinase pathways involved in cellular signalling have been shown to be effective in the treatment of RA with a reasonable risk:benefit ratio. It is too early to tell about inhibitors of other pathways. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Fleischmann R.,Metroplex Clinical Research Center
Expert Opinion on Biological Therapy | Year: 2010

Importance of the field: The treatment of rheumatoid arthritis has changed dramatically over the past 25 years, first with the introduction of methotrexate and then the introduction of biologic therapy. These agents have provided patients with multiple treatment options to try to achieve disease remission. Unfortunately, no one single agent is fully effective in every patient; different patients respond to different therapies, even those with the same mechanism of action, in different ways. Another medication, such as certolizumab pegol, is a welcome addition to our treatment armamentarium of rheumatoid arthritis. Areas covered in this review: The basis of this review is all the peer-reviewed manuscripts found in PubMed and Medline searches from 1990 to 2009 and abstracts on certolizumab pegol presented at the American College of Rheumatology and European League Against Rheumatism within the past 5 years. What the reader will gain: This review should enable the reader to fully understand the benefit:risk ratio of certolizumab pegol in the treatment of rheumatoid arthritis. Take home message: Certolizumab pegol is an effective agent either in combination with methotrexate or as monotherapy in the treatment of rheumatoid arthritis with a safety profile similar to other approved TNF inhibitors. © 2010 Informa UK Ltd.


Fleischmann R.,Metroplex Clinical Research Center | Fleischmann R.,Southwestern University
Expert Opinion on Biological Therapy | Year: 2010

Importance of the field: Twenty-five years ago, rheumatoid arthritis (RA) was a relentless disease, treated symptomatically because of the lack of effective, well tolerated medications which could halt disease in most patients. The introduction of methotrexate, sulfasalazine and leflunomide, and aggressive treatment, changed the prognosis of RA in the 1990s. Biologic therapies have dramatically changed the long-term prognosis of patients with rheumatoid and psoriatic arthritis and ankylosing spondylitis. Areas covered in this review: Unfortunately, no one single agent is fully effective in every patient. For this reason, another agent, golimumab (GLM), a TNF-α inhibitor (TNF-I) was developed. The basis of this review is all peer-reviewed manuscripts on GLM in the treatment of RA, psoriatic arthritis (PsA) and ankylosing spondylitis (AS) found in Pub Med. and Medline from 2000 to 2010 and abstracts presented at the major rheumatology congresses within the past five years. What the reader will gain: This review describes the efficacy and safety of GLM and should enable an understanding of the benefitrisk profile of GLM in the treatment of RA, PsA and AS. Take home message: GLM is effective and has a safety profile similar to other TNF-I in the treatment of RA, AS and PsA. © 2010 Informa UK Ltd.


Fleischmann R.,Metroplex Clinical Research Center | Baumgartner S.,Metroplex Clinical Research Center
Rheumatology (Oxford, England) | Year: 2014

OBJECTIVE: The aim of this study was to evaluate the pharmacodynamics (PDs), pharmacokinetics (PKs) and safety of lesinurad (selective uric acid reabsorption inhibitor) in combination with febuxostat (xanthine oxidase inhibitor) in patients with gout.METHODS: This study was a phase IB, multicentre, open-label, multiple-dose study of gout patients with serum uric acid (sUA) >8 mg/dl following washout of urate-lowering therapy with colchicine flare prophylaxis. Febuxostat 40 or 80 mg/day was administered on days 1-21, lesinurad 400 mg/day was added on days 8-14 and then lesinurad was increased to 600 mg/day on days 15-21. sUA, urine uric acid and PK profiles were evaluated at the end of each week. Safety was assessed by adverse events, laboratory tests and physical examinations.RESULTS: Initial treatment with febuxostat 40 or 80 mg/day monotherapy resulted in 67% and 56% of subjects, respectively, achieving a sUA level <6 mg/dl. Febuxostat 40 or 80 mg/day plus lesinurad 400 or 600 mg/day resulted in 100% of subjects achieving sUA <6 mg/dl and up to 100% achieving sUA <5 mg/dl. No clinically relevant changes in the PKs of either drug were noted. The combination was well tolerated.CONCLUSION: The clinically important targets of sUA <6 mg/dl and <5 mg/dl are achievable in 100% of patients when combining lesinurad and febuxostat. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.


Cohen S.B.,Metroplex Clinical Research Center
Best Practice and Research: Clinical Rheumatology | Year: 2010

There has been renewed interest in the B cell as a target for the treatment of rheumatoid arthritis (RA) over the past decade. Efficacy with rituximab has been demonstrated in randomised clinical trials (RCTs) resulting in regulatory approval for patients failing tumour necrosis factor (TNF) inhibitors. Although the actual mechanism of action has not been clearly delineated, several molecules are under development to modify B cell number/function in hope of superior efficacy/safety or ease of administration. The safety of rituximab over the intermediate time point has been comparable to that seen with other biologic disease-modifying anti-rheumatic drugs (DMARDs). The recent report of cases of progressive multifocal leukoencephalopathy in three patients receiving rituximab for RA is a concern and, for now, limits rituximab to salvage therapy for the treatment-resistant patient. How this impacts on other B-cell inhibitors under development is not yet clear. Development of biomarkers that will assist our therapeutic decisions to enhance the benefit/risk ratio for our patients are needed as we move forward with further selective targeted therapies. © 2009 Elsevier Ltd. All rights reserved.

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