Sixty-one patients with active RA participated in a double-blind, parallel group, randomized, multicenter methodology study receiving infliximab or placebo through 14 weeks. This is an open access article distributed under the terms of the Creative Commons Wrist joint Licensewhich permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The data are owned by Merck and Co. The data were accessed by the authors within regulated and controlled databases, either that of Merck or temporarily at the imaging companies, VirtualScopics and Spire Sciences, during the period of analysis.
Final results are transferred to Merck. Interested researchers would make a request to EngageZone, a website controlled by Merck data management, which facilitates distribution of clinical data to credentialed researchers.
Requests articulațiile rănite din dulciuri access to the study data can be submitted through the EngageZone Web site or via email to dataaccess merck. All authors, including Merck employees, participated in interpretation of data, writing or review of the manuscript, as well as the decision to submit the manuscript for publication.
Spire Sciences, Inc. Competing interests: C. Beals, R. Baumgartner, A. Cheng, D. Feng, M. Vallee, and B. Peterfy and J. DiCarlo are employees of Spire Sciences, Inc.
Ashton is an employee of VirtualScopics, employed by Merck to analyze study results; A. Balanescu, G. Mirea, A. Harabagiu, and S. Popa claim no conflicts of interest. There are no additional declarations from the authors relevant to this research relating to employment, consultancy, products in development, patents, or revenues from marketed products to declare.
Requests for data access can be submitted to: dataaccess merck.
Introduction Wrist joint arthritis RA treatment options have expanded markedly over the past wrist joint.
However, as these therapies have become available, the acceptable duration for placebo control has also shortened, with rescue therapy typically offered within 14—16 weeks. The need to demonstrate both symptomatic and structure-modifying efficacy in randomized placebo wrist joint clinical trials RCT within this short time frame, along with growing difficulties recruiting RA patients into such studies, has made the use of radiography in RCTs impractical[ 1 ].
MRI has been shown to wrist joint more sensitive than radiography for detecting joint destruction in RA, and uniquely able to evaluate the up-stream inflammatory drivers of bone erosion and articular cartilage loss, namely osteitis and synovitis. One of the challenges of DCE-MRI is achieving sufficient imaging speed to capture the change in T1 signal within inflamed synovium, while maintaining sufficient spatial resolution and anatomical coverage to delimit the entire synovial tissue from adjacent joint fluid accurately.
The compromise of restricting enhancement measurements to small regions of interest ROIs within synovial tissue is confounded by the spatial heterogeneity of inflammation in RA. In this study, we overcame these challenges by devising a DCE-MRI technique suitable for multicenter clinical trials that imaged the entire wrist and MCP joints simultaneously and with sufficient speed to measure kinetic synovial enhancement parameters accurately.
The baseline characteristics and inflammatory imaging endpoints from this study were previously used to derive a whole blood wrist joint transcript signature that predicted a subsequent reduction in Ktrans with infliximab[ 11 ].
Both imaging methods similarly discriminated infliximab treatment from placebo on measures related to synovial inflammation, yet remained stable during placebo treatment. Appropriate MRI techniques, along with clinical measures of RA activity, should improve the characterization dureri articulare trittiko drug effects on inflammation and structural damage in RA.
Materials and methods This was a week, randomized, double-blind, placebo-controlled, methodology study Study Protocol PO; S1 File conducted from April 6, to March 29, in 3 clinical centers in Europe.
The study was conducted in accordance with principles of Good Clinical Practice and was approved by the appropriate institutional review boards, the Comisia Nationala de Etica pentru Studiul Clinic al Wrist joint, Bucharest Romania and Comitetul National de Etica studiu clinic al medicamentelor si metodelor noi de tratament, Chisinau, Moldova. All subjects provided written informed consent.
Key elements of the clinical protocol are available in supporting information S1 File. Patients had no contraindications to infliximab or MRI. Study medication was prepared by an unblinded trained person using the randomization code and without other involvement in study procedures, assessments, or data recording.
WRIST JOINT - Definiția și sinonimele wrist joint în dicționarul Engleză
Treatment allocation was blinded to investigators, study staff, and subjects. After 14 weeks of double-blinded therapy, participants in consultation with their physician could elect 3 months of open label infliximab treatment following the labeled dosing recommendations based on their previous randomized treatment assignment. Joint counts were performed by examiners masked to treatment assignment who did not serve as study physicians.
MRI assessments MRI of the most clinically severe hand and wrist was acquired at baseline and weeks 2, 4, and 14 using a 1.
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An acrylic frame[ 10 ] was used to ensure fixed, reproducible positioning of the hand and wrist joints on serial MRI examinations. Two small tubes containing solutions of copper sulfate sufficient to provide T1 values of 90ms and ms were made in a single batch and distributed to all clinical sites. Tubes were placed alongside the index and fifth fingers to serve as standards to verify appropriate T1 wrist joint, which is related to Gd concentrations for DCE-MRI measurements[ 1415 ].
Small ROIs were placed manually over volumes of enhancing synovium or enhancing tissue synovitis and osteitis without knowledge of the treatment or the order in which examinations were acquired.
Software identified enhancing tissue by comparison of pre- and post-GBCA images.
A trained technologist removed enhancing tissue that represented blood vessels or skin, and the resulting enhancing tissue map underwent radiologist review. Care was wrist joint to ensure that identical locations were selected for each study visit of an individual subject.
Hand \u0026 wrist bones \u0026 muscles of the hand
The rate of GBCA synovial leakage was measured using a pharmacokinetic compartment wrist joint 16 ] that quantifies the exchange of contrast agent between the plasma and tissue extracellular space synovium. The model requires a measure of the rate of GBCA input into the plasma, and is derived using an automated method[ 1517 ] from T1 signal intensity in the radial artery over time. Outputs of the model include Ktrans sec-1a rate constant that reflects the flow and permeability surface area of enhancing synovium primary endpoint and volume of enhancing tissue synovitis and osteitis.
One scan-rescan assessment of Ktrans reproducibility in RA patients using this exact technique was consistent with that identified in tumors Ashton, personal communication and with published reliability using a similar approach[ 18 ].
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RAMRIS8 of synovitis, osteitis and bone erosion at the wrist and MCP were determined at baseline, 2, 4 and 14 weeks by two independent radiologists blinded to visit order and treatment assignments. Statistical methods Ktrans of wrist synovium was the primary endpoint of the study. The mean change wrist joint baseline to a given time point was estimated and tested from this model. Statistical significance of the dichotomous endpoints was determined using Fisher's exact test comparing placebo and treatment groups.
All analyses were conducted on the changes from baseline to Weeks 2, 4 and Interpretation of the p-values for each endpoint was conducted in stepwise fashion using a closed stepwise procedure with p-values interpreted starting with Week Inter-reader agreement was assessed at baseline in terms of intra-class correlation coefficient ICC.
The primary method of comparisons amongst endpoints was comparison of treatment effect size.
Sinonimele și antonimele wrist joint în dicționarul de sinonime Engleză
For continuous endpoints, treatment effects of infliximab compared wrist joint those of placebo were expressed in terms of effect size calculated from the cLDA model as difference between infliximab and placebo effects divided by the pooled standard deviation [ 22 ].
It was assumed wrist joint infliximab effect sizes for Ktrans would be at least as large as those for DAS28, if the method was likely to be useful. The study planned to enroll 30 patients per group to account for potential dropouts.
Results Sixty-one adults with moderate to severe RA were enrolled into the study over a period of nine months Fig 1.
One patient meeting clinical criteria did not have sufficient synovitis at baseline on centralized expert reading to qualify, but was randomized to treatment in error.
Since the patient was eligible on clinical grounds, the patient was not discontinued, and was included in all analyses. Ninety-one percent were positive for Rheumatoid Factor. Baseline characteristics are described in Table 1. Baseline MRI scores also were consistent with high disease activity. Clinical and MRI results are presented as the patients were randomized and treated.
All patients completed the study.