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Background 68Ga-satoreotide trizoxetan is a novel somatostatin receptor antagonist exhibiting higher tumour-to-background ratios and sensitivity compared to 68Ga-DOTATOC. This randomised, 2 × 3 factorial, phase II study aimed to confirm the optimal peptide mass and radioactivity ranges for 68Ga-satoreotide trizoxetan, using binary visual reading. To that end, 24 patients with metastatic gastroenteropancreatic neuroendocrine tumours received 5–20 µg of 68Ga-satoreotide trizoxetan on day 1 of the study and 30–45 µg on day 16–22, with one of three gallium-68 radioactivity ranges (40–80, 100–140, or 160–200 MBq) per visit. Two 68Ga-satoreotide trizoxetan PET/CT scans were acquired from each patient post-injection, and were scored by experienced independent blinded readers using a binary system (0 for non-optimal image quality and 1 for optimal image quality). For each patient pair of 68Ga-satoreotide trizoxetan scans, one or both images could score 1. Results Total image quality score for 68Ga-satoreotide trizoxetan PET scans was lower in the 40–80 MBq radioactivity range (56.3%) compared to 100–140 MBq (90.6%) and 160–200 MBq (81.3%). Both qualitative and semi-quantitative analysis showed that peptide mass (5–20 or 30–45 µg) did not influence 68Ga-satoreotide trizoxetan imaging. There was only one reading where readers diverged on scoring; one reader preferred one image because of higher lesion conspicuity, and the other reader preferred the alternative image because of the ability to identify more lesions. Conclusions Binary visual reading, which was associated with a low inter-reader variability, has further supported that the optimal administered radioactivity of 68Ga-satoreotide trizoxetan was 100–200 MBq with a peptide mass up to 50 µg. Trial registration ClinicalTrials.gov, NCT03220217. Registered 18 July 2017, https://clinicaltrials.gov/ct2/show/NCT03220217

68Ga-satoreotide trizoxetan is a novel somatostatin receptor antagonist associated with high sensitivity and reproducibility in neuroendocrine tumour (NET) detection and localisation. However, the optimal peptide mass and radioactivity ranges for 68Ga-satoreotide trizoxetan have not yet been established. We therefore aimed to determine its optimal dosing regimen in patients with metastatic gastroenteropancreatic NETs in a prospective, randomised, 2×3 factorial, multicentre, phase II study. Methods: Patients received 68Ga-satoreotide trizoxetan at a peptide mass of 5-20 µg on day 1 of the study and of 30-45 µg on day 16-22, at one of three gallium-68 radioactivity ranges (40-80, 100-140, or 160-200 MBq). Whole-body PET/CT imaging was performed 50-70 minutes after each injection. The primary endpoint was the detection rate of NET lesions imaged by 68Ga-satoreotide trizoxetan relative to contrast-enhanced CT (CECT) (for each of the six peptide mass/radioactivity range combinations). Results: Twenty-four patients were evaluated in the per-protocol analysis. The median number of lesions detected by 68Ga-satoreotide trizoxetan PET/CT or PET only was at least twice as high as the number of lesions detected by CECT across the six studied peptide mass dose/radioactivity range combinations. There were no differences between the two peptide mass ranges and between the three radioactivity ranges in the number of identified lesions. However, a trend towards a lower relative lesion count was noted in the liver for the 40-80 MBq range. No relationship was observed between the radioactivity range per patient's body weight (MBq/kg) and the number of lesions detected by 68Ga-satoreotide trizoxetan. Median diagnostic sensitivity of 68Ga-satoreotide trizoxetan PET/CT, based on the number of lesions per patient, ranged from 85% to 87% across the different peptide mass and radioactivity ranges. Almost all reported adverse events were mild and self-limiting. Conclusion: A radioactivity of 100-200 MBq with a peptide mass up to 50 μg were confirmed as the optimal dosing regimen for 68Ga-satoreotide trizoxetan to be used in future phase III studies.

Thioredoxin reductase-1 (TrxR1)-, glutathione reductase (Gsr)-, and Nrf2 transcription factor-driven antioxidant systems form an integrated network that combats potentially carcinogenic oxidative damage yet also protects cancer cells from oxidative death. Here we show that although unchallenged wild-type (WT), TrxR1-null, or Gsr-null mouse livers exhibited similarly low DNA damage indices, these were 100-fold higher in unchallenged TrxR1/Gsr–double-null livers. Notwithstanding, spontaneous cancer rates remained surprisingly low in TrxR1/Gsr-null livers. All genotypes, including TrxR1/Gsr-null, were susceptible to N -diethylnitrosamine (DEN)-induced liver cancer, indicating that loss of these antioxidant systems did not prevent cancer cell survival. Interestingly, however, following DEN treatment, TrxR1-null livers developed threefold fewer tumors compared with WT livers. Disruption of TrxR1 in a marked subset of DEN-initiated cancer cells had no effect on their subsequent contributions to tumors, suggesting that TrxR1-disruption does not affect cancer progression under normal care, but does decrease the frequency of DEN-induced cancer initiation. Consistent with this idea, TrxR1-null livers showed altered basal and DEN-exposed metabolomic profiles compared with WT livers. To examine how oxidative stress influenced cancer progression, we compared DEN-induced cancer malignancy under chronically low oxidative stress (TrxR1-null, standard care) vs. elevated oxidative stress (TrxR1/Gsr-null livers, standard care or phenobarbital-exposed TrxR1-null livers). In both cases, elevated oxidative stress was correlated with significantly increased malignancy. Finally, although TrxR1-null and TrxR1/Gsr-null livers showed strong Nrf2 activity in noncancerous hepatocytes, there was no correlation between malignancy and Nrf2 expression within tumors across genotypes. We conclude that TrxR1, Gsr, Nrf2, and oxidative stress are major determinants of liver cancer but in a complex, context-dependent manner.

Quantitative computed tomography (QCT) measurements have been used extensively to ascertain information about bone quality and density due to the 3-dimensional information provided and the ability to segment out trabecular and cortical bones. QCT imaging helps to improve our understanding of the role that each bone compartment plays in the pathogenesis and prognosis of fracture. This study was conducted to explore longitudinal changes in femoral neck (FN) cortical bone structure using both volumetric bone mineral density (vBMD) and cortical shell thickness assessments via QCT in a double-blind, randomized, multicenter clinical trial in postmenopausal women with type 2 diabetes mellitus. This study also examined whether treatment-associated changes in the cortical bone vBMD and thickness in femoral neck quadrants could be evaluated. Subjects were randomized to rosiglitazone (RSG) or metformin (MET) for 52 wk followed by 24 wk of open-label MET. A subset of 87 subjects underwent QCT scans of the hip at baseline, after 52 wk of double-blind treatment, and after 24 wk of treatment with MET using standard full-body computed tomography scanners. All scans were evaluated and analyzed centrally. Cortical vBMD at the FN was precisely segmented from trabecular bone and used to assess a possible therapeutic effect on this bone compartment. QCT analysis showed reductions in adjusted mean percentage change in vBMD and in absolute cortical thickness occurred with RSG treatment from baseline to week 52, whereas changes with MET were generally minimal. The reductions observed during RSG treatment for 1 yr appeared to partially reverse during the open-label MET phase from weeks 52 to 76. The femoral neck quadrant may provide utility as a potential endpoint in clinical trials for the understanding of the therapeutic effect of new entities on cortical bone vs trabecular bone; however, further clinical validation is needed. Trial registration: The protocol (GSK study number AVD111179) was registered on ClinicalTrials.gov as NCT00679939.

New densitometer installation requires cross-calibration for accurate longitudinal assessment. When replacing a unit with the same model, the International Society for Clinical Densitometry recommends cross-calibrating by scanning phantoms 10 times on each instrument and states that spine bone mineral density (BMD) should be within 1%, whereas total body lean, fat, and %fat mass should be within 2% of the prior instrument. However, there is limited validation that these recommendations provide adequate total body cross-calibration. Here, we report a total body cross-calibration experience with phantoms and humans. Cross-calibration between an existing and new Lunar iDXA was performed using 3 encapsulated spine phantoms (GE [GE Lunar, Madison, WI], BioClinica [BioClinica Inc, Princeton, NJ], and Hologic [Hologic Inc, Bedford, MA]), 1 total body composition phantom (BioClinica), and 30 human volunteers. Thirty scans of each phantom and a total body scan of human volunteers were obtained on each instrument. All spine phantom BMD means were similar (within 1%

SummarySignificant advances have occurred in our understanding of the pathogenesis of knee osteoarthritis (OA) and some recent trials have demonstrated the potential for modification of the disease course. The purpose of this expert opinion, consensus driven exercise is to provide detail on how one might use and apply knee imaging in knee OA trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, sequences artifacts); quality assurance (QA)/control procedures; measurement methods; measurement performance (reliability, responsiveness, validity); recommendations for trials; and research recommendations.

Automated assessment of hepatic fat-fraction is clinically important. A robust and precise segmentation would enable accurate, objective and consistent measurement of hepatic fat-fraction for disease quantification, therapy monitoring and drug development. However, segmenting the liver in clinical trials is a challenging task due to the variability of liver anatomy as well as the diverse sources the images were acquired from. In this paper, we propose an automated and robust framework for liver segmentation and assessment. It uses single statistical atlas registration to initialize a robust deformable model to obtain fine segmentation. Fat-fraction map is computed by using chemical shift based method in the delineated region of liver. This proposed method is validated on 14 abdominal magnetic resonance (MR) volumetric scans. The qualitative and quantitative comparisons show that our proposed method can achieve better segmentation accuracy with less variance comparing with two other atlas-based methods. Experimental results demonstrate the promises of our assessment framework.

Objective Nerve growth factor antibodies (NGF-ab) have shown promising analgesic efficacy. Aim was to describe reader training efforts and present reliability data focusing on radiographic eligibility in the tanezumab program. Methods A multi-step process was used for reader calibration and reliability testing. First, a reference standard set of cases was created and diagnostic performance was evaluated. A second exercise focused on agreement of ordinal assessment (Kellgren–Lawrence grading) of radiographic osteoarthritis. Subsequently, 11 readers were trained and read a test set of 100 cases focused on eligibility assessments. Additional reliability testing and calibration of five core readers assessing eligibility of 30 cases was performed 3 and 6 months after study start. Results Sensitivity for the reference standard readings ranged from 0.50 to 0.90 and specificity from 0.40 to 0.83. Overall agreement for Kellgren–Lawrence grading ranged from 71.4% to 82.9%. For the 11 reader exercise, in 76% of cases at least 8 of 11 readers agreed on eligibility status. For the reliability testing 3 months after study start, in 80.0% of cases at least 4 of 5 readers agreed on eligibility with a κ = 0.43 (95% CI: 0.32–0.54). For the reliability testing after 6 months, in 83.3% of cases at least 4 of 5 readers agreed on eligibility with a κ = 0.52 (95% CI: 0.41–0.63). Conclusions After intense efforts spent in the development of an imaging program for an NGF-ab clinical program, the achieved reliability for eligibility assessment is substantial but not perfect. Ongoing efforts of calibration prior to including additional readers to the program and during study conduct between current readers will be needed to ensure agreement on potential adverse events and radiographic disease severity.

SummaryImaging in clinical trials is used to evaluate subject eligibility, and/or efficacy of intervention, supporting decision making in drug development by ascertaining treatment effects on joint structure. This review focusses on imaging of bone and cartilage in clinical trials of (knee) osteoarthritis. We narratively review the full-text literature on imaging of bone and cartilage, adding primary experience in the implementation of imaging methods in clinical trials. Aims and constraints of applying imaging in clinical trials are outlined. The specific uses of semi-quantitative and quantitative imaging biomarkers of bone and cartilage in osteoarthritis trials are summarized, focusing on radiography and magnetic resonance imaging (MRI). Studies having compared both imaging methodologies directly and those having established a relationship between imaging biomarkers and clinical outcomes are highlighted. To make this review of practical use, recommendations are provided as to which imaging protocols are ideal for capturing specific aspects of bone and cartilage tissue, and pitfalls in their usage are highlighted. Further, the longitudinal sensitivity to change, of different imaging methods is reported for various patient strata. From these power calculations can be accomplished, provided the strength of the treatment effect is known. In conclusion, current imaging methodologies provide powerful tools for scoring and measuring morphological and compositional aspects of most articular tissues, capturing longitudinal change with reasonable to excellent sensitivity. When employed properly, imaging has tremendous potential for ascertaining treatment effects on various joint structures, potentially over shorter time scales than required for demonstrating effects on clinical outcomes.

Using placebo data from a recently completed disease-modifying osteoarthritis (OA) drug trial, we seek to inform study design of future radiographic studies.Eligible patients aged ≥40 years, with body mass index (BMI) 25-40kg/m(2) and symptomatic knee OA diagnosed by modified Kellgren and Lawrence grade (KLG) 2 or 3 and pain/stiffness and/or use of medication for knee pain in the past year, were assessed by radiography using a modified Lyon-schuss (mL/S) protocol for joint space narrowing (JSN) (primary outcome variable) at baseline and weeks 48 and 96. Multifaceted quality control was conducted throughout. Repeat images were requested when the medial tibial plateau (MTP) was not aligned (inter-margin distance [IMD]1.5mm) or for other quality issues. Data are given mean ± standard deviation.Patients (74.9% female; 61.3 ± 9.1 years) had BMI 31.6 ± 4.1kg/m(2) at baseline; 222 (173 females) had KLG2, 264 (191 female) KLG3. A significant loss in joint space width (JSW) from baseline to week 48 (-0.13 ± 0.36mm) and to week 96 (-0.22 ± 0.45mm) was observed for all randomised placebo patients (p0.001 for both), and at both time points when stratified by KLG2 or KLG3. Standard deviations were small relative to mean changes, providing standardised response means for all placebo patients of 0.35 (week 48) and 0.48 (week 96).Using a tightly controlled radiographic technique, JSN is a viable outcome variable for determining disease progression in mild-to-moderate knee OA. The mL/S protocol is a sensitive and feasible method for OA studies aiming to assess rate of JSN in the knee.

Quantitative imaging biomarkers could speed the development of new treatments for unmet medical needs and improve routine clinical care. However, it is not clear how the various regulatory and nonregulatory (eg, reimbursement) processes (often referred to as pathways) relate, nor is it clear which data need to be collected to support these different pathways most efficiently, given the time- and cost-intensive nature of doing so. The purpose of this article is to describe current thinking regarding these pathways emerging from diverse stakeholders interested and active in the definition, validation, and qualification of quantitative imaging biomarkers and to propose processes to facilitate the development and use of quantitative imaging biomarkers. A flexible framework is described that may be adapted for each imaging application, providing mechanisms that can be used to develop, assess, and evaluate relevant biomarkers. From this framework, processes can be mapped that would be applicable to both imaging product development and to quantitative imaging biomarker development aimed at increasing the effectiveness and availability of quantitative imaging.http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100800/-/DC1.RSNA, 2011

STUDY DESIGN: Image analysis model development.OBJECTIVE: The objective of this study was to develop a novel clinical workflow tool that uses model-based shape recognition technology to allow efficient, semiautomated detailed annotation of each vertebra between T4 and L4 on plain lateral radiographs.SUMMARY OF BACKGROUND DATA: Identification of prevalent vertebral fractures, especially when not symptomatic, has been problematic despite their importance. There is a recognized need to increase the opportunities to detect vertebral fractures so that clinically beneficial therapeutic interventions can be initiated.METHODS: Radiographs obtained from 165 subjects in the Canadian Multicenter Osteoporosis Study (CaMos) were used to construct a vertebral shape model of the vertebral column from T4 to L4 using a statistical learning technique, as well as to estimate the accuracy and precision of this automated software tool for vertebral shape analysis. Radiographs showing scoliosis greater than 15 degrees were excluded.RESULTS: Vertebral contours defined by 95 points per vertebra, represented by 79,895 points in total, were assessed on 841 individual vertebrae. The mean absolute accuracy error calculated over each vertebra in each test image was 1.06 +/- 1.2 mm. This value corresponded to an average 3.4% of vertebral height. The mean precision error, reflecting interobserver variability, per vertebra of the resulting annotations was 0.61 +/- 0.73 mm. This value corresponded to an average 2.3% of vertebral height. Accuracy and precision error estimates did not differ notably by vertebral level.CONCLUSION: The results of the current study indicate that statistical modeling can provide a robust tool for the accurate and precise semiautomated annotation of vertebral body shape from T4 to L4 in patients who do not have scoliosis greater than 15 degrees . This method may prove useful as a clinical workflow tool to aid the physician in vertebral fracture assessment and might contribute to decision-making about pharmacologic treatment of osteoporosis.

The thigh inter-muscular adipose tissue (IMAT) quantification plays a critical role in various medical analysis tasks, e.g., the analysis of physical performance or the diagnose of knee osteoarthritis. In recent years, several techniques have been proposed to perform automated thigh tissues quantification. However, nobody has provided effective methods to track fascia lata, which is an important anatomic trail to distinguish between subcutaneous adipose tissue (SAT) and I-MAT in thigh. As a result, the estimation of IMAT may not be accurate for subjects with pathological conditions. On the other hand, tissue prior information, e.g., intensity, orientation and scale, becomes critical to infer and refine the fascia lata boundary from image appearance cues. In this paper, we propose a novel data-driven and sparsity-constrained de-formable model to obtain accurate fascia lata labeling. The model deformation is driven by the target points on fascia lata detected by a local discriminative classifier in a narrowband fashion. By using a sparsity-constrained optimization, the deformation is solved with errors and outliers suppression. The proposed approach has been evaluated on a set of 3D MR thigh volumes. In a comparison with another state-of-art framework, our approach produces superior performance.

The tissue quantification in the thigh (e.g. cross-sectional areas of adipose tissue and muscle) is important, since their quantities reflect adverse metabolic effects and muscle function. Traditional manual analysis is time-consuming and operator-dependent, especially in the case of multi-slices or 3D datasets. In clinical trials, there are a large amount of datasets acquired from magnetic resonance imaging (MRI) or X-ray computed tomography (CT) that requires automatic labeling of individual tissues. Since most segmentation algorithms are not suited for different modalities, we present an automatic and robust framework for the quantitative assessment of muscle and fat tissues on 3D MR or CT data. In our framework, a variational Bayesian Gaussian mixture model is used to cluster regions of interest in images into adipose tissues (fat and marrow), muscle, bone and background. The identification of each cluster is based on marrow detection. Furthermore, we use a combination of parametric and geodesic active contour models to distinguish different adipose tissues in 3D images. To validate our proposed framework, we have conducted preliminary experiments on five volumetric mid-thigh axial datasets of MR and CT images from clinical trials.

Automated assessment of hepatic fat fraction is clinically important. A robust and precise segmentation would enable accurate, objective and consistent measurement of liver fat fraction for disease quantification, therapy monitoring and drug development. However, segmenting the liver in clinical trials is a challenging task due to the variability of liver anatomy as well as the diverse sources the images were acquired from. In this paper, we propose an automated and robust framework for liver segmentation and assessment. It uses single statistical atlas registration to initialize a robust deformable model to get fine segmentation. Fat fraction map is computed by using chemical shift based method in the delineated region of liver. This proposed method is validated on 14 abdominal magnetic resonance (MR) volumetric scans. The qualitative and quantitative comparisons show that our proposed method can achieve better segmentation accuracy with less variance comparing with an automatic graph cut method. Experimental results demonstrate the promises of our assessment framework.

Objectives To evaluate if the mean smallest detectable change (SDC) of multiple time intervals using the Bland & Altman (B&A) levels of agreement (LoA) method is an appropriate surrogate for the generalisability analysis method for estimating the overall SDC of radiological progression in rheumatoid arthritis (RA) trials. Secondly, to compare the SDC based on 95% LoA with the SDC based on 80% LoA, and to investigate the association between SDC and baseline damage and progression. Methods Fifteen datasets from randomised controlled trials in RA were scored by 13 experienced readers as pairs according to the modified Sharp/van der Heijde method. The SDC using the 95% and 80% LoA and the generalisability methods was calculated. Results 21 295 radiographic time points from 7643 patients were included. The mean (range) SDC for the LoA and the generalisability methods was 3.1 (2.3–4.3) and 3.2 (2.3–4.6) units, respectively. The mean±SD difference between the two methods was −0.13±0.28. The mean SDC including all intervals (n=31) was 3.0±0.7 for 95% LoA and 2.0±0.4 for 80% LoA. No relationship was observed between baseline damage and the SDC, whereas the SDC increased with increasing radiological progression. Conclusions The mean of the interval SDCs obtained by the simple LoA method is a valid surrogate for the SDC obtained by complex generalisability methods. The SDC depends on the level of radiographic progression rather than on the level of absolute damage. In addition, the use of an SDC based on 80% rather than on 95% LoA is proposed.

SummaryMonoclonal antibodies that bind and inhibit nerve growth factor (NGF) have demonstrated both, good analgesic efficacy and improvement in function in patients with osteoarthritis (OA). Despite initial promising data, trials in OA had been suspended by the Federal Food and Drug Administration (FDA) due to concerns over accelerated rates of OA progression. Imaging will play a crucial role in future clinical trials to define eligibility of potential participants and to monitor safety during the course of these studies. This will require baseline and frequent follow-up radiographs of both, the index joints and other large weight bearing joints to identify subjects at risk prior inclusion and on study so treatment can be discontinued.This imaging overview in the form of an atlas describes and illustrates potential exclusionary joint imaging findings at eligibility and potential adverse joint events on radiography and magnetic resonance imaging (MRI) in studies investigating a-NGF compounds. The overarching goal of this atlas is to facilitate trial design and to promote a common language and understanding between potential expert readers. This first section of the atlas will focus on knee joint specific findings that are relevant to a-NGF studies.

s / Osteoarthritis and Cartilage 23 (2015) A82eA416 A360 eligibility and safety findings relevant for aNGF clinical trials. More than 400 images were reviewed to define the most relevant and characteristic imaging findings. Diagnoses of exclusion for eligibility due to potentially increased risk of RPOA are subchondral insufficiency fractures (SIF), atrophic OA and severe malalignment of the knee in the medial-lateral direction. Diagnoses relevant for safety after enrolment (i.e. joint safety findings), i.e. RPOA, SIF, osteonecrosis and pathologic fractures will also be discussed. Several of these diagnoses have non-specific findings on the radiograph or cannot be detected radiographically in early stages. Thus, in cases of inconclusive or suspicious radiography, an additional MRI examination may be acquired to rule out or confirm some of these diagnoses. Results: Early and late signs of diagnoses relevant for eligibility will be presented. Fig 3A. Radiograph of the hip joint shows superior JSN (arrows) without relevant osteophytes present. Fig 3B. Follow up image 12 months later shows near-complete destruction of the femoral head (arrows) and subsequent migration of the femur superiorly consistent with RPOA. Conclusions: Expert readers in aNGF programs need to be aware of relevant imaging findings. These include early signs of diagnoses relevant for RPOA on radiography, and other potential X-ray and MRI diagnoses relevant for eligibility and safety during aNGF studies. 591 PROLONGED JOINT RESIDENCY OF TRIAMCINOLONE ACETONIDE AFTER AN INTRA-ARTICULAR INJECTION OF FX006, A SUSTAINED RELEASE FORMULATION FOR THE TREATMENT OF OSTEOARTHRITIS N. Bodick y, J. Lufkin y, C. Willwerth y, J. Hauben y, A. Kumar y, P. Boen y, J. Bolognese z, C. Schoonmaker z, M. Clayman y. y Flexion Therapeutics, Burlington, MA, USA; zCytel Inc, Cambridge, MA, USA Purpose: Although available intra-articular (IA) corticosteroids are well established in the treatment of painful osteoarthritis (OA), limitations include short duration of pain relief (1-4 weeks), an effect consistent with the transient residency of these compounds in the joint and high plasma corticosteroid concentrations immediately following injection. FX006 is a novel IA sustained-release injectable formulation of 25% triamcinolone acetonide (TCA) in poly(lactic-co-glycolic acid) microspheres intended to prolong therapeutic concentrations of TCA in the joint and limit systemic exposure. In a previously described 6-week long clinical study, FX006 at 40 mg demonstrated maintenance of synovial concentrations of TCA consistent with pharmacologic activity for a period of at least 6 weeks, when levels of TCA produced by an equivalent dose of TCA IR were below the limit of quantitation. The current study extended these data on joint residency by measuring synovial fluid levels of TCA at later time points. Methods: In this multi-center, open-label study, patients with OA of the knee received a single IA injection of FX006 containing 10 or 40mg TCA, or 40mg of a standard, immediate-release suspension of TCA (TCA IR). A total of 50 patients were enrolled (FX006 10 mg: 10 patients, FX006 40 mg: 30 patients, TCA IR: 10 patients). Synovial fluid and plasma samples were obtained at baseline (pre-dose) and at the planned Final Visit at either Week 12, 16, or 20, depending on cohort assignment and availability of fluid in the knee. Concentrations of TCA were measured in plasma or in filtered synovial fluid samples using High Performance Liquid Chromatographic methods with Tandem Mass Spectrometry Detection and Automated Extraction, validated for the determination of TCA in human plasma and synovial fluid respectively. The quantitation limits of both assays were 50 to 50000 pg/mL. Results: In the FX006 10 mg group, 8 patients had synovial fluid available for analysis at Week 12. In the FX006 40 mg group, 6 patients had synovial fluid available for analysis at Week 12, 8 patients at Week 16 and 11 patients at Week 20. In the TCA IR group, 5 patients had synovial fluid available for analysis at Week 12. The concentrations of TCA achieved by 40mg FX006 in the synovial fluid atWeek 12 were 924 pg/mL, at Week 16, the IA concentrations of TCAwere 224 pg/mL and by Week 20 they were below the lower limit of quantitation (Figure; geometric means from the earlier 6-week study and the current study are merged). The IA concentration of TCA in patients receiving 40 mg of TCA IR at Week 12 was below the lower limit of quantitation. FX006 maintained a gradient between synovial and systemic plasma concentrations of TCA for 16 weeks.

Dual Energy X-Ray Absorptiometry (DXA) has become the “gold standard” technique for the assessment of bone mineral density (BMD). More recently, this type of trial data has been handled by specialist quality assurance (QA) centers partly at the recommendation of regulatory agencies. The data are generally transmitted via paper and/or diskette from the site to the QA center. The aims of this study were to test the feasibility of transmitting these types of image files of about 80kBytes from the investigator site to the QA center directly via modem. One hundred sixty images and related data were transmitted transat-lantically, without error and at a lower cost than using conventional methodologies. The time from patient DXA scan to QA review was also significantly shortened thereby improving data quality further.

Medical instruments can be used for screening, diagnosis, prognosis, and monitoring natural history or therapeutic intervention. With the developing role of ultrasonometry it is important to assess how these instruments will effectively be used for each of these utilizations. No two types of ultrasonometers are the same: there are differences in anatomical sites, measurement variables and methodology in obtaining those variables. To determine optimal utilization the clinician has to evaluate each instrument. Eight factors have to be considered for each utilization comprising of discrimination, precision, reliability, relevance, acceptance by regulatory authorities, inexpensive, acceptability to the patient, and safety. This paper discusses these factors and presents an overview in relationship to the utilization of instruments using ultrasonometry.

There are four key uses for medical imaging: screening, diagnosis or prognosis, monitoring the natural history of the disease, and monitoring therapeutic intervention. There are eight key metrics when evaluating a biomarker or imaging technique which has to be put into context with the key use of the system. This chapter will describe these key metrics in this context with particular emphasis of the use in clinical trials.

Medical imaging is now utilized extensively in clinical trials for eligibility, efficacy, and safety evaluations. The uses of imaging span from a qualitative assessment of disease findings to quantitative assessments, each resting on diagnosis of the condition or change in the severity of the condition. This introductory chapter is designed for the novice with a limited or no background in radiological techniques and aims to briefly review the different imaging techniques, technology, terminology, and optimal imaging uses.

Postmenopausal status and type 2 diabetes mellitus (T2DM) are independent risk factors for fractures. An increased fracture risk has been observed with rosiglitazone (RSG), a thiazolidinedione, in patients with T2DM.This was a randomized, double-blind study in postmenopausal women with T2DM. A 52-week double-blind phase (RSG or metformin [MET]) was followed by a 24-week open-label phase, during which time all patients received MET.The primary endpoint was to assess the mean percentage change in bone mineral density (BMD) at the femoral neck (FN) by dual-energy x-ray absorptiometry from baseline to week 52 in the RSG treatment group. Key secondary objectives included assessment of changes in BMD at the total hip, trochanter, and lumbar spine and to evaluate RSG effects on bone turnover markers.From baseline to week 52, RSG was associated with a reduction in FN BMD by dual-energy x-ray absorptiometry (-1.47%). During the open-label phase (weeks 52-76), no further loss in FN BMD was observed. A decrease in BMD occurred at the total hip during RSG or MET treatment at 52 weeks (-1.62 and -0.72%, respectively). Total hip BMD loss by RSG was attenuated after switching to MET and was similar between treatment groups at the end of the open-label phase. From baseline to week 52, bone turnover markers significantly increased with RSG compared with MET, but decreased significantly during the open-label phase.RSG for 52 weeks in postmenopausal women with T2DM was associated with small reductions in FN, total hip, and lumbar spine BMD and increased bone turnover markers. These effects are attenuated after cessation of RSG treatment.

Objective The aim of this study is to provide data on the adjudication rate for a predetermined threshold of difference in change score between two readers in randomized controlled trials (RCTs). Methods Fifteen datasets from RCTs in RA were scored by 13 experienced readers as pairs according to the modified Sharp-van der Heijde method. The theoretical adjudication rates for thresholds of between 3 and 20 units were calculated. We investigated the influence of the number of time points within the same session, the length of the interval and disease duration on the adjudication rates. Results A total of 21,295 time points from 7643 patients from 15 databases were included in the analysis. The adjudication rate was inversely related to the threshold. Higher adjudication rates were observed with a higher number of time points, longer time intervals and in early versus established RA. The adjudication rates ranged from 0% to 22% depending on the scenario. Conclusion With trained and experienced readers, the adjudication rate in RA RCTs is low even with very conservative adjudication thresholds.

Objective To determine if inhibition of inducible nitric oxide synthase (iNOS) with cindunistat hydrochloride maleate slows progression of osteoarthritis (OA) Methods This 2-year, multinational, double-blind, placebo-controlled trial enrolled patients with symptomatic knee OA (Kellgren and Lawrence Grade (KLG) 2 or 3). Standard OA therapies were permitted throughout. Patients were randomly assigned to cindunistat (50 or 200 mg/day) or placebo. Randomisation was stratified by KLG. Radiographs to assess joint space narrowing (JSN) were acquired using the modified Lyon-schuss protocol at baseline, week 48 and 96. Results Of 1457 patients (50 mg/day, n=485; 200 mg/day, n=486; placebo, n=486), 1048 (71.9%) completed the study. Patients were predominantly women; 56% had KLG3. The primary analysis did not demonstrate superiority of cindunistat versus placebo for rate of change in JSN. In KLG2 patients, JSN after 48 weeks was lower with cindunistat 50 mg/day versus placebo (p=0.032). Least-squares mean±SE JSN with cindunistat 50 mg/day ( −0.048±0.028 mm) and 200 mg/day (−0.062±0.028 mm) were 59.9% (95% CI 6.8% to 106.9%) and 48.7% (95% CI -8.4% to 93.9%) of placebo, improvement was not maintained at 96 weeks. No improvement was observed for KLG3 patients at either time-point. Cindunistat did not improve joint pain or function, but was generally well tolerated. Conclusions Cindunistat (50 or 200 mg/day) did not slow the rate of JSN versus placebo. After 48-weeks, KLG2 patients showed less JSN; however, the improvement was not sustained at 96-weeks. iNOS inhibition did not slow OA progression in KLG3 patients. Clinical trial listing NCT00565812

Objectives Post-hoc analyses have shown an increase incidence of fractures among type 2 diabetes (T2DM) patients treated with thiazolidinediones (TZDs). The mechanisms by which TZDs may be associated with increased fracture risk is not well understood. This article describes the study design and baseline characteristics for a prospective, randomized, double-blind, active-controlled trial to evaluate the effects of rosiglitazone on changes in measures of skeletal structure, surrogates of bone strength and metabolism. Methods Postmenopausal women without osteoporosis and diagnosed with T2DM were randomized in a double-blind design to either rosiglitazone or metformin for 52 weeks, then all subjects received open-label metformin for 24 weeks. Study endpoints included changes in bone mineral density (BMD), quantitative computed tomography (QCT), digitized hip radiography (HXR) and high resolution magnetic resonance imaging (hrMRI). Serum markers of bone metabolism and indices of glycemic control were assessed within and between treatment groups. Results A total of 226 subjects were randomized. Baseline characteristics included: age 63.8 ± 6.5 years; years postmenopausal 16.9 ± 8.4; duration of diabetes 3.5 (1.8–7.8) years; body mass index (BMI) 31.4 ± 5.9 kg/m2; and glycated hemoglobin (HbA1c) 6.4 ± 0.65%. At baseline, mean T-scores were −0.95 ± 0.91 at the femoral neck, −0.02 ± 0.97 at the total hip and −0.55 ± 1.25 at the total spine. Since there are no well recognized techniques to determine bone mass and structure at the distal limbs (cortical bone sites where fractures were reported in RSG subjects), using the femoral neck as a surrogate for these areas may be a potential limitation of the study. Conclusion This is the first randomized trial utilizing multiple techniques to evaluate bone mass, structure, serum markers of bone remodeling, and potential reversibility of changes after discontinuation of rosiglitazone. This study will provide information about RSG bone effects in a population of postmenopausal women at risk for bone loss and subsequent fracture. ClinicalTrials.gov number NCT00679939

The diagnosis and treatment of osteoporosis is still a relatively young science. Although Albright first described osteoporosis in 1947,1 it is only since the late 1980s and early 1990s that we have had the instruments available for the diagnosis and then treatment of this disease. As for any medical area in its infancy, we can, therefore, expect a significant number of changes in the coming years, as a result of more comprehensive understanding of bone physiology and elucidation of the genetic factors leading to increased risk factors.

When your clinical centre has been notified that you have been selected as a site for a new clinical trial in osteoporosis, you can be assured that the sponsor has made an assessment of the subject population and facilities available. It is now up to the investigator, site administrator, and staff to prove the sponsor made the right decision in placing the study at their site. Because delays in study start-up can cause a sponsor to lose millions of dollars, it is imperative to get the study up and running as soon as possible. During this process, the emphasis is on speed and accuracy. Always remember that there are many qualified sites able and willing to take on this project should your commitment falter. You can congratulate yourself that you have been chosen to participate, but the site must be organized to get to work on the project quickly!

Medical instruments can be used in one of four primary ways: for screening, diagnosis, prognosis, and monitoring the natural history of the disease or therapeutic intervention. Good quantitative endpoints in clinical trials are usually obtained from instruments measuring a physiological parameter that is relevant to the anticipated effect of the molecular entity under investigation, and nowhere is this more apparent than in the field of osteoporosis. The surrogate endpoint of choice, bone mineral density (BMD), is in fact a recognised diagnostic endpoint in its own right in that the World Health Organization (WHO) criterion for defining osteoporosis in an individual is a BMD that is >2.5 standard deviations (SD) below peak bone mass. However, in the arena of clinical trials the choice of endpoint is not as simple as this (see Section 2.3).

Study Design and the Pretrial Phase.- Study Design and Endpoints.- Ethical Considerations.- Standardization and Pretrial Quality Control.- Performing the Trial.- Organization of the Clinical Trial by the Sponsor.- Local Site Organization.- Clinical Trial Quality Assurance.- Laboratory and Instrument Quality Control.- Data Analysis and Presentation.- Data Analysis and Presentation: Writing a Paper for Publication.- Background.- Current Therapies for Osteoporosis.- The Ideal Drug for Treatment of Osteoporosis.- Instrument Measurements in Osteoporosis Clinical Trials: Evaluating the Endpoints.- Biochemical Markers of Bone Turnover.- Future Therapies and Clinical Trials.

Background SDC is an important statistic in evaluating radiographic progression in clinical trials in Rheumatoid Arthritis (RA). Two methods to estimate the SDC are available: one is based on the standard deviation (SD) of the difference between change-scores obtained by two readers (according to Bland&Altman (B&A)) and the other is based on generalisability analysis (using ANOVA). ANOVA is required in the case of multiple time points and multiple readers, but is more complicated and time consuming. Objectives To evaluate if the average SDC of all available time intervals using the B&A method is a valid surrogate for the ANOVA method to estimate the SDC of radiological progression in RA studies including multiple time points. Methods Fifteen datasets from radiographic trials in RA comprised of 20,098 radiographic time points from 7,643 patients were scored by 13 readers as pairs. Scoring was performed by each reader independently according to the modified Sharp van der Heijde method (SHS)1 with the reader blinded to chronological sequence. The number of time points per study was 2 in 2 trials, 3 in 10 trials, and 4 in 3 trials. According to the B&A method, the datasets were evaluated to calculate the 95% limits of agreement SDC [(± 1.96*SDΔ (changescore))/($√ $2*$√ $K)], where K represents the number of readers, for all intervals between different time points per study and its average. Using the ANOVA method, calculations of the SDC per study were performed considering all time points. Statistical analysis was performed using SPSS software version 18.0. Results Median (range) baseline- and progression score was 32 (18-48) and 0.9 (0.5-1.8) units, respectively. Table 1 shows the results for all SDCs using both methods. The average SDC of all intervals calculated with the B&A method was very similar to SDC obtained by ANOVA. The mean difference between both methods was -0.13 (SD 0.28, range -0.48-0.25) units. Conclusions We propose to report the mean interval SDC as a good surrogate for the true SDC in trials with multiple time points. References van der Heijde DM. Lancet. 1989 May 13;1(8646):1036-8. Disclosure of Interest None Declared

Background For the evaluation of radiographic progression in RCTs, at least 2 readers should read all films in order to constrain measurement error. If differences in change scores between readers exceed a certain threshold, a third reader (adjudicator) can be used to obtain a more precise result. While the selection of a threshold that triggers this 3rd read is somewhat arbitrary (historically between 7 and 15 points), regulatory authorities suggest a cause for concern if 20% or more of the cases in a given clinical trial results in adjudication. Objectives To provide data on which percent of sets of radiographs need adjudication for a predetermined cut-off of difference in change score from baseline between two readers in RCTs in patients with early and established RA. Methods Fifteen datasets from radiographic trials in RA were scored by 13 readers as pairs according to the modified Sharp van der Heijde method (SHS). The reader was blinded to chronological sequence. The number of time points per study was 2 in 2 trials, 3 in 10 trials, and 4 in 3 trials. We calculated the theoretical adjudication rates if adjudication thresholds from 3 to 20 units were selected per study plus the weighted mean for all studies. We investigated the influence of the number of time points within the same session, the length of the interval, and mean disease duration (early (≤3 years) versus established RA) on the adjudication rates. Statistical analysis was performed using SPSS software version 18.0. Results 20.098 time points from 7.643 patients were included in the analysis. Median (range) sample size of the studies was 517 (103-901) patients, and the number of time points within one reading session was 2 for 1172 patients, 3 for 5296 patients and 4 for 1175 patients. Median (IQR) baseline radiological damage- and progression scores were 32 (18-48) and 1.05 (0.5-2.0) respectively. The percentage of adjudicated cases was inversely related to the threshold. The higher the number of time points within the same reading session, and the longer the time interval, the higher the adjudication rate. The adjudication rate was also higher in RCTs with early vs established RA, especially at lower thresholds. In all cases, the adjudication rate remained below 19%, even with a very conservative threshold selection of 3 units. Conclusions With trained and experienced readers, the adjudication rate in RCTs with patients with RA is low even with very conservative adjudication thresholds, which adds to the validity of the SHS scoring method as a precise and reliable outcome measure in RA. The adjudication rate is higher in RCTs with early- vs established RA. Disclosure of Interest None Declared

Vitamin-D deficiency is not as rare in Jamaica as previously believed. 9 children with vitamin-D deficiency rickets have been seen at the University Hospital of the West Indies during the past 5 years. All were over 3 years of age at time of presentation. Both dietary deficiency of vitamin D and lack of exposure to sunlight seem to be important causes. Children living in rural Jamaica seem to be more susceptible to the disease than those living in a city, due perhaps to more prolonged breast feeding and lack of fortified milk feeds on weaning.

SummaryImaging of hip in osteoarthritis (OA) has seen considerable progress in the past decade, with the introduction of new techniques that may be more sensitive to structural disease changes. The purpose of this expert opinion, consensus driven recommendation is to provide detail on how to apply hip imaging in disease modifying clinical trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, artifacts associated with various MRI sequences); quality assurance/control procedures; measurement methods; measurement performance (reliability, responsiveness, and validity); recommendations for trials; and research recommendations.

The clinical and laboratory findings in six Jamaican infants with the exomphalos-macroglossia-gigantism syndrome are described. The incidence was calculated as 1:13,700 births. There was no family history of similar disease in any case and no evidence of chromosomal abnormality, virus infection, or infantile hypoglycemia. Three infants died, and two showed typical histological features in the kidneys and adrenal glands.