A predictive standardized bleeding questionnaire (Vicenza score), previously validated for identifying individuals with type 1 von Willebrand's disease (VWD), has never been prospectively validated in tertiary care paediatric settings. The aim of this study was to assess the Vicenza score's predictive power in identifying type 1 VWD, low von Willebrand factor (VWF) and platelet function defects (PFD) in a prospective cohort of patients, 0-17 years old, referred to a paediatric haematology clinic for evaluation of a bleeding disorder. Before the initial visit, caregivers consented to answer the questionnaire via telephone. Patients' medical records were reviewed after haematological evaluation. VWF:Ag or VWF:RCo<30 IU dL(-1) were labelled 'definite type 1 VWD' while 30-50 IU dL(-1) were labelled 'Low VWF'. PFA-100 screening followed by abnormal electron microscopy and/or platelet aggregation studies diagnosed a PFD. At least one haemorrhagic symptom was present in 99 of the 104 children who completed the study (mean number of symptoms 2.87, mean Vicenza score 3.24). Eight met criteria for 'definite type 1 VWD', 23 for 'low VWF' and 13 for 'PFD'. The sensitivity, specificity, and positive and negative predictive value (NPV) of the Vicenza score demonstrated poor diagnostic utility with the exception of high specificity in ruling out 'definite type 1 VWD'. The NPV was comparably high with qualitative (>2 bleeding symptoms) and quantitative (Vicenza score ≥ 2) criteria. The Vicenza score has limited predictive value in paediatric tertiary care settings. While the NPV of excluding 'definite type 1 VWD' is high, simpler qualitative criteria is similarly predictive.

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BackgroundDespite the availability of several treatment options some patients with Rheumatoid Arthritis (RA) fail to benefit and for those who do response rates are similar across therapeutic classes. Thus there remains a need for new therapies with novel mechanisms of action. MBS2320 is a selective modulator of immune metabolism that shows anatomically appropriate osteoid layering and a broader spectrum of osteoprotective efficacy compared to TNFα inhibition in preclinical models.ObjectivesTo investigate the safety, tolerability and pharmacokinetics of MBS2320 in healthy volunteers and patients with Rheumatoid Arthritis (RA) receiving a stable dose of methotrexate (MTX).MethodsCohorts of healthy volunteers (randomised 6:2 drug:placebo) received single or multiple oral doses of MBS2320 for 14 days. Single Ascending Dose (SAD) cohorts comprised 2, 10, 25, 50, 75, 125, 250, 375 mg (PO) and Multiple Ascending Dose (MAD) cohorts 75, 100, 160 mg/d. Patients with RA received 75 mg/d for 14 days in addition to their existing weekly MTX treatment. Safety and tolerability were assessed throughout. Plasma MBS2320 (SAD, MAD and patients with RA) and MTX (patients with RA only) were measured using LC-MS/MS. In patients with RA, C-reactive protein (CRP) and biomarkers of bone turnover were assessed on Day 14.ResultsA total of 96 healthy subjects and 9 patients with RA entered the Study and were randomised to the drug or matching placebo.MBS2320 was well tolerated by healthy subjects at single oral doses of 2 to 375 mg. There were no serious adverse events (SAEs). Nausea was the most commonly reported adverse event (AE) and occurred most frequently at the high doses but was mild and resolved without treatment. Daily doses of 75 to 160 mg QD MBS2320 for 14 days were generally well tolerated by healthy subjects. The most common drug-related treatment emergent adverse events (TEAEs) were gastrointestinal disorders, particularly nausea. There were no significant effects on clinical laboratory tests, vital signs, ECG or physical examination.Multiple doses of MBS2320 (75 mg) were also generally well tolerated by subjects with RA when co-administered with MTX. There were no clinically significant findings or trends in the laboratory tests, vital signs or ECG data, and no clinically significant findings on physical examination. No SAEs were reported. The majority of TEAEs were mild in severity with diarrhoea and nausea reported most frequently.In healthy subjects, MBS2320 was steadily absorbed following doses of 50 to 375 mg MBS2320. Systemic exposure (AUC) increased in a dose-proportional manner across all doses and was unaffected by food. In RA patients there was no indication of a PK interaction between MTX and MBS2320 in either direction.In patients with RA, serum CTX-1, P1NP and osteocalcin increased following 14 days of treatment, while TRAP5b was decreased or unchanged. Median CRP was decreased relative to baseline in after 7 days’ treatment with MBS2320, and remained low on Day 14.ConclusionMBS2320 was well tolerated for up to ...

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1293 Poster Board I-315 INTRODUCTION Type I von Willebrand disease (VWD) is the most common inherited bleeding disorder. Repetitive testing of von Willebrand factor (VWF) levels is necessary before the diagnosis can be safely ruled out, as VWF levels fluctuate in response to genetic and environmental factors. A predictive bleeding score (BS) could reveal individuals that may benefit from repetitive testing and those for whom repetitive testing is unlikely to be of benefit. While a standardized questionnaire (the Vicenza score) was developed to evaluate hemorrhagic symptoms, it was never prospectively validated for a pediatric population in a tertiary care setting. SUBJECTS The study targeted children, ages 0 to 17 years, referred to the Hemostasis and Thrombosis Center (HTC) of Nationwide Children's Hospital for a coagulation evaluation as a result of bleeding symptoms, family history of a bleeding disorder and/or abnormal coagulation labs found during pre-operative screening. Children were excluded if they had a previously diagnosed bleeding disorder, if their caregiver did not speak English or if the child did not undergo VWF:Ag and VWF:RCo testing. METHODS Prior to the diagnosis or exclusion of a bleeding disorder in the child, caregivers consented to answer the questionnaire over the telephone. Descriptions of the Vicenza score are available online (http://www.euvwd.group.shef.ac.uk/bleed_score.htm). LABORATORY TESTING A single VWF:Ag or VWF:RCo <30 IU/dL was classified as “Definite Type 1 VWD” while levels from 30-50 IU/dL were classified as “Low VWF” (http://www.nhlbi.nih.gov/guidelines/vwd). Platelet function analysis (PFA-100) screened for platelet function defects, with some patients undergoing follow-up platelet aggregation studies and/or platelet electron microscopy. Laboratory studies from other institutions were excluded from analysis. Patients' medical records were reviewed after hematologic evaluation, and the resultant data was analyzed with STATA 10.1 (Stata Corp., College Station, TX). RESULTS A total of 104 children (52 females and 52 males) with a mean age of 7.53 years (range 1 month to 17 years) were included. At least one hemorrhagic symptom was present in 99 of the 104 children (95%) with the mean number of symptoms being 2.87 (range 0 to 7). The mean Vicenza score was 3.24 (range -1 to 13). Of the 104 children, 8 met criteria for “Definite Type 1 VWD,” 23 met criteria for “Low VWF,” 14 were diagnosed with a “Platelet Function Defect,” and 2 children had bleeding secondary to Ehlers Danlos syndrome. Children with non-bleeding disorders (e.g. Factor XII deficiency) or no laboratory evidence of a bleeding disorder were classified as “No Bleeding Disorder.” In general, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and positive diagnostic likelihood ratio of the bleeding questionnaire demonstrated poor predictive value in our patient population with the exception of high specificity in ruling out “Definite Type 1 VWD” (Table). The NPV was comparably high with both qualitative (>2 bleeding symptoms) and quantitative (BS ≥2) criteria. CONCLUSIONS The Vicenza score, previously validated in adults and in a pediatric primary care setting, appears to have limited predictive value in a pediatric tertiary care setting when evaluating patients with platelet function defects or low VWF levels. While the Vicenza score has a high NPV to exclude “Definite Type 1 VWD,” the use of simpler qualitative criteria is similarly predictive. Disclosures No relevant conflicts of interest to declare.