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The aim of this project was to perform an empirical evaluation of the impact of on site source data verification (SDV) on the data quality in a clinical trial database to guide an informed decision on selection of the monitoring approach.We used data from three randomized phase III trials monitored with a combination of complete SDV or partial SDV. After database lock, individual subject data were extracted from the clinical database and subjected to post hoc complete SDV. Error rates were calculated with focus on the degree of on study monitoring and relevance and analyzed for potential impact on end points.Data from a total of 2566 subjects including more than 3 million data fields were 100% source data verified post hoc. An overall error rate of 0.45% was found. No sites had 0% errors. 100% SDV yielded an error rate of 0.27% as compared with partial SDV having an error rate of 0.53% (P0.0001). Comparing partly and fully monitored subjects, minor differences were identified between variables of major importance to efficacy or safety.The findings challenge the notion that a 0% error rate is obtainable with on site monitoring. Data indicate consistently low error rates across the three trials analyzed. The use of complete vs. partial SDV offers a marginal absolute error rate reduction of 0.26%, i.e. a need to perform complete SDV of about 370 data points to avoid one unspecified error and does not support complete SDV as a means of providing meaningful improvements in data accuracy.

Skibstransport er fortsat den mest økonomiske og miljøvenlige transportform med et meget lille vægtspecifikt CO2-udslip. En yderligere forøgelse af denne effektivitet vil forårsage en højere intern motortemperatur. For at tillade dette uden at kompromittere pålideligheden af motoren, er det nødvendigt med nye højtemperaturlegeringer til brug på en specifik motorkomponent, udstødningsventilspindlen.To legeringer bruges til en udstødningsventilspindel; en legering til spindelbunden, og en til spindelsædet. Da spindlen er placeret i udstødsgasstrømmen, kondenserer forbrændingsprodukter såsom V2O5 og Na2SO4 på overfladen, hvor de forårsager en aggressiv form for højtemperaturkorrosion. De nuværende industristandarder kan modstå servicetemperaturer op til 500°C for spindelsædet og 700°C for spindelbunden. Dette projekt havde til opgave at hæve disse grænser med hver 50°C.Litteratursøgning og en in-situ korrosiontest viste at den mest korrosionsbestandige legering i dette miljø er Legering 657 (Ni-baseret, 49% Cr, 1.5% Nb). Denne legering kan opfylde kravet om en driftstemperatur på 750°C for spindelbunden, men er uegnet til spindelsædet, da den er for svag.Termodynamiske beregninger antydede at det var muligt at modificere sammensætningen af den nuværende spindelsædelegering, Legering 718 (Ni-baseret, 19% Cr, 18% Fe, 5.1% Nb, 3% Mo, 1% Ti og 0.6% Al), og derved at opnå en mere korrosionsbestandig legering. For at validere beregningerne blev 16 Ni-baserede legeringer med 40% Cr, og et varierende indhold af Nb, Ta og Ti, produceret ved eksperimentiel lasercladding. Varmebehandlinger viste at disse legeringer var udskilningshærdbare, og at enkelte af dem opnåede høje hårdheder. Baseret på resultaterne blev fem Ni-baserede legeringer med 35-45% Cr og 4-6% Nb bestilt for at identificere brugbare legeringssammensætninger. Omfattende mikrostrukturkvantificering af legeringerne fastslog en generel overeenstemmelse mellem de termodynamiske beregninger og den faktiske fasesammensætning.Resultaterne fra varmebehandlingerne viste en sammenhæng mellem den opløsningsglødede mikrostruktur og de mekaniske egenskaber. Dette ledte til design af Ni40Cr3.5Nb, som er Ni-baseret med 40% Cr og 3.5% Nb. Denne legering er udskilningshærdbar til samme hårdhed som Legering 718, og laboratorieforsøg tyder på at den er egnet til anvendelse ved en servicetemperatur på 550°C. Transport by ship remains the most economical and environmentally friendly mode of transport with a very low weight specific CO2 footprint. Further increase of the fuel efficiency of large ships will results in a higher internal engine temperature. To allow this without compromising the reliability of the engine, new high temperature alloys are required for a specific engine component, the exhaust valve spindle.Two alloys are used for an exhaust valve spindle; one for the bottom of the spindle, and one for the spindle seat. Being placed in the exhaust gas stream, combustion products such as V2O5 and Na2SO4 condense on the spindle, causing hot corrosion. Current industry standards can withstand service temperatures of up to 500°C for the spindle seat and 700°C for the spindle bottom. This project was tasked with increasing these temperatures 50°C each.Literature review as well as an in-situ corrosion test revealed that the most resistant alloy in such an environment is Alloy 657 (Ni-based, 49 wt% Cr, 1.5 wt% Nb). This alloy is suitable for the spindle bottom, but not for the spindle seat, as it is too weak.Thermodynamic calculations suggested that it was possible to modify the chemistry of the current valve seat alloy, Alloy 718 (Ni-based, 19 wt% Cr, 18 wt% Fe, 5.1 wt% Nb, 3 wt% Mo, 1 wt% Ti and 0.6 wt% Al), and thereby to obtain a more hot corrosion resistant alloy. To validate these calculations, 16 Ni-based alloys, containing 40 wt% Cr and Nb, Ta and Ti in varying levels, were produced by experimental laser cladding. Heat treatments proved that these alloys were precipitation hardenable, and that some of them reached high levels of hardness. Based on these results, five Ni-based alloys containing 35-45 wt% Cr and 4-6 wt% Nb were ordered, to narrow down the feasible alloy compositions. During the alloy development work, extensive microstructure quantification was performed, the results of which validated the predictive thermodynamical calculations.The heat treatment results showed that a relation exists between the solution treated microstructure and the mechanical properties. This lead to the design of the alloy Ni40Cr3.5Nb (Ni-based, 3.5 wt% Nb and 0.5 wt% Ti). This alloy is precipitation hardenable to the same level of hardness as Alloy 718, and laboratory testing suggests that it is suitable for application at service temperatures of 550°C.

Background Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Trials of new analgesics for OA pain is impaired by substantial placebo-response (PR), and data describing characteristics and pain sub-types particularly associated with placebo-response is needed. Objectives The purpose of this post-hoc analysis was to investigate clinical characteristics and pain subtypes associated with PR as measured by the five pain questions of the Western Ontario and McMasters Arthritis (WOMAC) Index of the target (T)- and the non-target (NT) knees in the pooled data of two phase III randomized clinical trials of an oral treatment in OA. Methods Pooled data from the placebo-groups of two phase III randomized clinical trials (NCT00486434 and NCT00704847) in patients with knee OA followed for two years were analyzed. Main inclusion criteria for T knees were a Kellgren-Lawrence grade of 2 or 3, Joint-Space Width (JSW) of minimum of 2.0 mm at the medial tibio-femoral joint, and WOMAC pain ≥150 out of 500 mm. All analyses were performed on data from the T knees (N=771) and a sub-group of NT knees matching the pain inclusion criteria of the T knees (N=256). All subjects in the analysis belonged to the Per-Protocol population. Pain of the T and NT knees was measured using the WOMAC pain sub-index, five questions: Q1; during walking on a flat surface, Q2; using stairs, Q3 at night while in bed, Q4; sitting or lying and Q5; while standing. Changes in percent from baseline pain were calculated at months 1, 6, 12 and 24, and differences between individual questions were assessed using a repeated measures ANOVA. Pain by category (“under load”; WOMAC questions 1, 2 and 5 and “idle”; WOMAC questions 3 and 4) were similarly analyzed for change over time, and compared in a repeated measures ANOVA. Selected patient baseline characteristics; pain by WOMAC question, Joint-space width (JSW), age, and BMI were assessed for association with PR defined as change in percent from baseline to year two using Spearman9s correlation. Results Baseline pain was significantly higher in WOMAC Q2, compared to other pain questions (p The level of PR was significantly higher in questions related to pain while under load (Q1, Q2, Q5) compared to pain while idle (Q3, Q4), and this was statistically significant in the T knee (p Baseline BMI, age and JSW was not associated with PR. This indicates while no common clinical characteristics were associated with PR, other, perhaps psychological, factors may affect the susceptibility to PR. Conclusions These results indicate that the level of PR is significantly different between pain subtypes, as pain under load is significantly more susceptible to lead to PR than pain while idle. Disclosure of Interest A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, A.-C. Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, C. Christiansen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, J. Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, H. Guhring: None declared, C. Ladel: None declared, M. Michaelis: None declared, B. Riis Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Valter: None declared

Presenting laboratory test data, along with anecdotal field information on DISA Air Group's recently developed dust control cartridge filter, Klaus Bihlet, DISA Danmark A/S, Denmark, explains why the UniClean promises to be a major step forward in industrial air filtration.

Characterization of the wear of piston rings and cylinder liner is an important aspect of large two stroke diesel engine design. Two major wear mechanisms exist; corrosive wear and mechanical wear. This paper deals with the most aggressive form of the latter, which is known as scuffing. Different material combinations for piston rings and cylinder liners are examined using a block-on-ring test rig. An accelerated wear test run without lubricant is used. Results show that the morphology of cast iron is an important parameter affecting the wear resistance of the material. It is also demonstrated that ceramic coating on the piston ring decreases the dry wear rate of both piston ring and liner, while the coefficient of friction is increased.

Background Cartilage and synovium are two central tissues remodeled in osteoarthritis (OA). Recent data has shown that type II collagen degradation (CTX-II) is a biomarker of cartilage and subchondral turnover. CRPM and C3M are biomarkers of synovial inflammation and turnover. Objectives To identify different subtypes of OA related to progression by measuring biomarkers of cartilage degradation and synovial inflammation. Methods Fasting serum (n=767) and urine (n=620) samples from knee OA patients, of the placebo arms of two phase III RCTs (NCT00486434 and NCT00704847) were analyzed for Serum C3M, CRPM, (type III collagen and C-reactive protein neo-epitope) and creatinine-corrected urinary CTX-II (type II collagen C-terminal telopeptide). The relationship between the biomarkers and the 5 baseline-reported WOMAC pain subscale questions, using the sum of target and non-target knee, were analyzed: A; during walking on a flat surface, B; using stairs (up or down), C; at night while in bed, D; sitting or lying and E; while standing. Joint space width was analyzed at baseline and at 24 months. Log-transformed data were analyzed by Spearman9s rho and by multiple regression analysis, where WOMAC or radiographic scores were the dependent variable and biomarkers, age, gender and BMI as covariates. Cut-offs was based on reference value and difference between the high/low groups was analyzed by Mann-Whitney. Results CTX-II was significantly correlated with WOMAC with all 5 sub-questions (p Conclusions CTX-II was associated with all types of pain, especially with pain associated with walking on a flat surface, indicating that CTX-II is related to pain from continuous skeletal load, supported by the strong correlation with JSW. C3M, from the synovium, was weakly correlated pain by using stairs and standing still. C3M was correlated to progression indicating that patients with certain levels of C3M had a higher likelihood for progression. We found that the two inflammatory markers could facilitate patient segregation. These biomarkers may assist in identification of the inflammation driven OA phenotype, which needs to be treated different than non-inflammatory OA. Acknowledgements The CSMC021C2301/2 investigators Disclosure of Interest A. Bay-Jensen Shareholder of: Nordic Bioscience, Grant/research support from: EC FP7 programs, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, K. Musa Employee of: Nordic Bioscience, A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, P. Alexandersen: None declared, J. Andersen: None declared, B. Riis: None declared, C. Christiansen Shareholder of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Grant/research support from: EC FP7 programs, Employee of: Nordic Bioscience

Background Osteoarthritis (OA) is recognized as a heterogeneous disorder, with several possible drivers of disease progression, including involvement of bone, cartilage and synovium. The degree of joint pain has been shown to be both diagnostic and prognostic for OA, but meaningful clinical characteristics to identify the group of patients at risk of rapid progression are still needed. Objectives The aim of this analysis was to identify key pain characteristics (WOMAC 5 pain questions) associated with risk of structural progression, and notable changes in reported pain over time. Methods A combined post-hoc analysis of two phase III RCTs (NCT00486434 and NCT00704847), evaluating the efficacy and safety of oral salmon calcitonin in patients with painful knee OA (N=2,206) was performed. Analysis of structural progression was made based on data from the placebo group only, stratifying patients into quintiles of baseline (BL)-reported WOMAC pain level and further investigating the 5 WOMAC pain subscale questions: Q1; during walking on a flat surface, Q2; using stairs (up or down), Q3 at night while in bed, Q4; sitting or lying and Q5; while standing. The association between joint space narrowing (JSN) and WOMAC pain was assessed in a mixed model with JSN as dependent variable and other relevant BL variables as fixed effects. Results Spearman correlation coefficients indicates that each WOMAC pain sub-score expresses individually different information, as rho coefficients ranged from a minimum of 0.40 between Q2 and Q3, and maximally 0.67 for Q3 and Q4 (p The relative change in overall WOMAC pain-score at year 2 was not significantly influenced by level of BL pain score. For each of the sub-score questions, a trend towards higher BL pain level being associated with higher relative and absolute pain relief was observed at year two, with some differences among the individual sub-score questions. Separate analysis of target and contralateral knees revealed interesting differences in association of BL pain level and structural progression. JSN of target knees appeared to be independent of BL levels of Q1-Q5, whereas in contra-lateral knees there was a tendency of higher BL levels of Q1, Q2 and Q5 being associated with higher JSN (Figure). These results highlight differences in perceived pain caused by osteoarthritis over time, and may be indicative of individual pain phenotypical characteristics. The results indicate that acute, likely nociceptive, pain associated with walking and standing was more associated with structural progression than what may be interpreted as a possibly different, perhaps centrally augmented pain experienced without direct mechanical loading of the joint. Conclusions These data from a large clinical trial dataset in OA describe significant associations between pain, pain subtypes and progression in OA, which may be related to different biochemical disease drivers. Acknowledgements We wish to sincerely thank all the participants and investigators of the CSMC021C2301/02 studies. Disclosure of Interest A. Bihlet: None declared, A.-C. Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, B. Riis Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, C. Christiansen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, J. Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, H. Guhring Employee of: Merck Serono, M. Michaelis Employee of: Merck Serono, C. Ladel Employee of: Merck Serono

Background Cartilage and bone are the central tissues affected by osteoarthritis (OA). Remodeling of these tissues can be measured by soluble biomarkers. Recent data has shown that urinary type II collagen C-terminal telopeptide (u-CTX-II) is a biomarker of cartilage and subchondral bone turnover. Bone resorption may be quantified by type I collagen cross-linked C-terminal degradation in serum (s-CTX-I). Objectives The purpose of this analysis was to investigate the association between cartilage and bone remodeling, measured by u-CTX-II and s-CTX-I, and clinically recorded knee pain and KL score, as well as the OA risk factor Body Mass Index (BMI). Methods Fasting serum (n=767) and urine (n=620) samples were collected at baseline from patients with painful knee OA participating in the placebo arms of two phase III RCTs (NCT00486434 and NCT00704847). Creatinine-corrected u-CTX-II (IDS PLC, United Kingdom]) and s-CTX-I (Roche, United Kingdom) were measured. The relationship between the biomarkers and baseline-reported WOMAC pain level of the target knee, radiographic OA score (KL) and BMI were analyzed by Spearman9s correlations on log-transformed biomarker data and by multiple regression analysis (OLS), where WOMAC, KL score or BMI were set as the dependent variable and biomarkers, BMI and age as covariates, adjusted for gender. Results Both CTX-I and CTX-II were significantly correlated to BMI (r=-0.26, p Conclusions This cross-sectional analysis of data from a large clinical trial dataset shows strong correlations between the biomarkers CTX-I, CTX-II and pain and obesity. These findings may be a reflection of high mechanical joint loading caused by overweight, contributing to pathological bone and cartilage wear which could lead to increased pain. Longitudinal data to support this hypothesis is needed. These data indicate that CTX-I and CTX-II may assist in identifying disease drivers of a specific, painful OA phenotype to be further investigated. Acknowledgements We wish to thank the participants and investigators of the CSMC021C2301/2 trials. Disclosure of Interest A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, A.-C. Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, B. Riis Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, C. Christiansen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, J. Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, K. Musa Employee of: Nordic Bioscience, P. Alexandersen Grant/research support from: Nordic Bioscience

Background Parathyroid hormone (PTH) controls serological calcium levels and is important for bone growth regulation. In addition, PTH may have important roles in articular cartilage homeostasis, which a number of in vitro and in vivo studies have indicated. It has been reported that articular cartilage exposed to PTH have both chondroprotective and chondrodestructive outcomes, so it remains unclear whether the direct effect of PTH on articular cartilage is anabolic and merely remodeling. Cartilage diseases such as osteoarthritis could have benefits of a systemic anabolic treatment. This hypothesis may be investigated by biochemical markers of cartilage turnover in clinical settings. Objectives In this study we investigated if PTH had cartilage anabolic capacities by a measuring the level type II collagen formation by the serological biomarker ProC2. Methods In an open labeled, randomized, repeat dose parallel group study of teriparatide (20ug SC) in female osteoporosis patients the serological level of ProC2 was assessed. There were 32 controls (mean age 65.8 years and BMI 25.23) and 32 cases (mean age 66.4years and BMI 24.79). ProC2 was quantified in fasting serum at baseline, week 4, 12 and 24. The ProC2 assay uses a monoclonal antibody to quantify the N-terminal fragment QDVRQPG of type II pro-collagen splice variant B. Two-way ANOVA with Bonferroni9s multiple comparisons test was used to investigate the difference between the ProC2 levels at the different time points and in the three groups; low, medium or high ProC2 level at baseline. Results There were no significant difference between the ProC2 level in cases and controls at any time point. When patients were divided at baseline into low, medium and high ProC2 level, cases with low ProC2 at baseline had significantly increased ProC2 levels at week 12 (P=0.031) and 24 (P=0.025). Furthermore, there was a tendency towards increased ProC2 levels already at week 4 in cases with low ProC2 baseline, though not significant. This relationship was not found in any of the other groups, either cases or controls. In addition, the ProC2 level was significantly increased in the cases with low ProC2 at baseline at week 12 compared to cases with higher ProC2 levels at baseline (P=0.035 and P=0.009). Conclusions Patients with low ProC2 level at baseline have significantly anabolic effects of PTH after 12 and 24 weeks of treatment. Patients with middle or high levels of ProC2 at baseline do not have anabolic effects of PTH at any time point. This indicates that a sub-population of patient will have anabolic effects of PTH treatment. However, this study cannot identify if the effect of PTH is purely anabolic or merely remodeling, as this study investigated formation of type II collagen and not collagen type II turnover. This means that PTH could be a systemic anabolic treatment for diseases such as osteoarthritis. Disclosure of Interest None declared

Background Osteoarthritis (OA) is a heterogeneous disorder, which has been described in several different population studies. However there is a significant difference between patient populations recruited in OA interventional clinical trials and epidemiological studies. While epidemiological studies focus on incidence, prevalence, risk and cause of OA, clinical trials aim at enrolling patients with certain characteristics based on defined guidelines on clinical outcome measures. There is therefore a need for in-depth, post-hoc analysis of clinical studies in OA. Objectives The aim of the analysis was to investigate the associations between JSW, KL-score, pain and JSN (joint space narrowing), as well as BMI (Body mass index), by combining data from two phase III studies (N=2,206). Methods This is a post-hoc analysis of two randomized, double-blind, multi-center, placebo-controlled trials (CSMC021C2301 and CSMC021C2302), evaluating the efficacy and safety of oral salmon calcitonin in subject with painful knee OA, enrolling 1,176 and 1,030 patients, respectively. The analysis includes baseline data on KL-score, pain and function metrics from the WOMAC questionnaire, as well as demographics. The main inclusion criteria for the target knee were: ACR OA criteria, KL-score 2 or 3 and JSW of ≥2.0 mm, and significant WOMAC pain. Both knees were analyzed. Moreover, analysis of the two-year data on JSN was included for the placebo arm Results The mean JSW was comparable in knees of KL-0 and -1 and significantly decreased with increasing KL-2, -3 and -4 (p Conclusions These data from potentially the largest clinical trial dataset in OA to date clearly describe significant associations between KL-score, JSW, pain and BMI in patients with symptomatic knee OA. Consequently, this dataset is ideally suited for identification of different phenotypes of OA, and biomarkers associated with those. Patients with symptomatic OA at baseline progressed significantly faster than patients with asymptomatic disease, however with important variations that need accounting for when designing clinical trials, such as relations to pain, BMI and JSN. These results suggest that disease phenotypes rather than disease status are responsible for disease progression and may act as background material for designing future clinical trials in OA. Disclosure of Interest M. Karsdal Employee of: Nordic Bioscience, A.-C. Bay-Jensen: None declared, A. Bihlet Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, P. Alexandersen Employee of: Nordic Bioscience, C. Christiansen Employee of: Nordic Bioscience DOI 10.1136/annrheumdis-2014-eular.4503