Investigator-reported Adverse Events Research Articles

Oral 5-aminolevulinic Acid for Patients With Localized Prostate Cancer Undergoing Low-dose-rate Brachytherapy: AMBER Trial.

Radiotherapy is one of the most frequently used options for prostate cancer (PCa). However, adverse effects related to irradiation of surrounding normal organs are significant clinical concerns. Specifically, genitourinary toxicity can dramatically reduce the quality of life. This clinical trial investigated the efficacy of oral 5-aminolevulinic acid phosphate combined with sodium ferrous citrate (ALA-SFC) in patients treated with low-dose-rate brachytherapy (LDR-BT) using an iodine-125 seed source. The AMBER study was a prospective single-center trial involving patients with localized PCa who underwent LDR-BT without external-beam radiotherapy (jRCTs051190077). Fifty patients were included and instructed to take capsules of ALA-SFC twice a day (200 mg phosphate salt and 229.42 mg per day) for six months from the day of seed implantation (prescribed radiation dose of 160 Gy). Patient data were collected before implantation, during ALA-SFC treatment, and at 1, 3, 6, 9, and 12 months post-LDR-BT. The primary endpoint of this trial was urinary frequency at three months. Other patient-reported outcomes, investigator-reported adverse events, and oncological outcomes were secondary endpoints. Of 50 enrolled cases (45 in the per-protocol analysis, 49 in the safety analysis), urinary frequency and its increase from baseline did not differ from 141 historical controls at any time point, including at three months post-LDR-BT. Propensity score matched analysis confirmed no time-course differences in frequency, volume, or urinary symptom scores between groups. Biochemical failure-free and metastasis-free survival also remained similar. Oral supplementation of ALA-SFC to LDR-BT did not alleviate radiation-induced toxicity or improve oncological outcomes.

P147 EFFICACY AND SAFETY OF SACUBITRIL/VALSARTAN VERSUS AMLODIPINE IN JAPANESE PATIENTS WITH ESSENTIAL HYPERTENSION: A RANDOMIZED, OPEN-LABEL, MULTICENTER STUDY (PARASOL STUDY)

Background and Objective: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, is shown to be superior to renin-angiotensin system inhibitors in terms of blood pressure (BP) lowering effect in several clinical trials. However, there is limited evidence on the BP-lowering effect of sacubitril/valsartan in comparison with amlodipine, a widely used calcium channel blocker (CCB), and potent BP-lowering effect. This study is to investigate the efficacy and safety of sacubitril/valsartan monotherapy compared with amlodipine monotherapy in Japanese patients with essential hypertension. (jRCTs051220165) Methods: This was a multicenter, randomized, open-label, parallel-group, and active-controlled study conducted in Japan. Male or female Japanese patients aged 18 to 79 with either treated or untreated mild to moderate essential hypertension were eligible for this study and randomly assigned to the sacubitril/valsartan 200 mg group or amlodipine 5 mg group. Each study drugs were administered once daily for eight weeks. The primary endpoint was to demonstrate the non-inferiority of sacubitril/valsartan versus amlodipine in mean change from baseline for 24-h systolic blood pressure (SBP) after eight weeks of treatment. Results: A total of 359 patients were randomized in this study (sacubitril/valsartan group n=182, amlodipine group n=177; mean age was 58.3 and 58.1 years, 75.3% and 74.0% were male, baseline BPs were described in Table). At week 8, mean reductions from baseline for mean 24-h SBP in sacubitril/valsartan were non-inferior to that in amlodipine (between-treatment difference: −0.6 mmHg [95% CI: −3.2 to 2.0; P=0.003 for non-inferiority, independent t-test]). In addition, other BP parameters in sacubitril/valsartan were comparable to those in amlodipine (Table). For the investigator-reported adverse events, seven hypotension-related events (3.8%) were observed in sacubitril/valsartan and three events (1.7%) in amlodipine. Conclusions: In Japanese patients with essential hypertension, the BP-lowering effect of sacubitril/valsartan was non-inferior to that of amlodipine, and no marked differences in tolerability were observed. Early initiation of sacubitril/valsartan in hypertensive patients is expected to achieve good BP control, similar to the widely used CCB.

Repetitive LevosimenDan infusions fOR patients with advanced chronic heart failure in the vulnerable post-discharge period: the multinational randomized LeoDOR trial

Abstract Background Studies of the repetitive use of intravenous levosimendan suggested a beneficial effect in patients with advanced heart failure (HF). It was the aim of the LeoDOR trial to test the efficacy and safety of intermittent levosimendan therapy in the vulnerable phase following a hospitalization for acute HF. Methods In this multicenter, double-blind, three-armed trial with an enrolment period from 3-2018 to 6-2021, patients with advanced HF were randomized 2:1 at the end of an index hospitalization for acute HF to intermittent levosimendan therapy or placebo for a period of 12 weeks. Levosimendan was administered according to center preference either as 6-hour infusion at a rate of 0.2 mcg/kg/min every 2 weeks, or as 24-hour infusion at a rate of 0.1 mcg/kg/min every 3 weeks. The primary efficacy assessment after 14 weeks was based on a global rank endpoint consisting of three hierarchical groups: Tier 1 = time to death or urgent heart transplantation or implantation of a ventricular assist device; Tier 2 = time to non-fatal HF requiring i.v. vasoactive therapy; Tier 3 = time-averaged proportional change in NTproBNP from baseline to week 14. Results Due to a forced interim interruption of the study as a result of the COVID-19 pandemic, the planned number of patients could not be recruited. The final modified intention-to-treat (mITT) analysis included 145 patients (93 in the combined levosimendan arm, 52 in the placebo arm). Patient characteristics were well balanced between treatment and placebo arms (mean age 69.3±9.7 vs 67.9±10.1, proportion of women 22.6% vs 21.2%, HF-hospitalizations in previous 12 months 1.9±1.4 vs. 1.7±1.1, NTproBNP at baseline 4740 ng/L (IQR 2235 – 9016) vs 5380 ng/L (IQR 2287 – 8204). There were no marked differences regarding HF medication and implanted devices. Compared with placebo, intermittent levosimendan had no significant effect on the primary endpoint (mean rank score 71.8 for the levosimendan group vs 75.1 for the placebo group; p = 0.65). However, there was a strong signal towards a higher incidence of the individual clinical components of the primary endpoint (tier 1 plus tier 2) in the levosimendan group vs the placebo group both after 14 weeks (HR 2.94, 95%CI 1.13–7.70; p = 0.028) and 26 weeks (HR 1.65 95%CI 0.87 – 3.12; p = 0.123). The number of investigator-reported adverse events during and immediately after drug application was 12.4% in the levosimendan group vs 11.8% in the placebo group (p = 0.905). Conclusion Our findings do not support the use of intermittent levosimendan to improve post-hospitalization clinical stability in patients who were recently hospitalized with HF and reduced LVEF. Further studies are warranted to find the correct use of levosimendan in advanced heart failure patients.

THU032 Osilodrostat Is Effective And Well Tolerated In Patients Of Asian And Non-Asian Origin With Cushing's Disease: A Pooled Analysis From LINC 3 And LINC 4

Abstract Disclosure: P.J. Snyder: Consulting Fee; Self; Teva Pharmaceutical Industries Ltd. B.M. Biller: Consulting Fee; Self; HRA Pharmaceuticals, Recordati, Sparrow, Xeris Pharmaceuticals (Strongbridge). M. Fleseriu: Consulting Fee; Self; Recordati, Sparrow, Xeris Pharmaceuticals (Strongbridge), HRA Pharmaceuticals. Grant Recipient; Self; Recordati, Sparrow, Xeris Pharmaceuticals (Strongbridge). R. Pivonello: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Pfizer, Inc., Bresmed Health Solutions, Damor Farmaceutici, S&R Farmaceutici, Organon Italia, Siunergos Pharma, Biohealth Italia. Research Investigator; Self; Novartis Pharmaceuticals, Recordati, Xeris Pharmaceuticals (Strongbridge), Corcept Therapeutics, Takeda, Neurocrine Biosciences, Camurus AB, Pfizer, Inc., Merck Serono, IBSA. E.J. Lee: None. R. Leelawattana: None. J.H. Kim: None. R. Walia: None. Y. Yu: None. Z. Liao: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. A. Shimatsu: Consulting Fee; Self; Recordati. Speaker; Self; Recordati. Introduction: Osilodrostat, a potent oral 11β-hydroxylase inhibitor, has demonstrated rapid and sustained normalization of cortisol in two Phase III studies (LINC 3, NCT02180217; LINC 4, NCT02697734) in patients (pts) with Cushing’s disease (CD). Relative osilodrostat bioavailability is estimated to be 20% higher in pts of Asian origin than other ethnicities, and body weight is not a major determinant of this difference. This analysis of the LINC 3 and LINC 4 studies evaluated the efficacy and safety of osilodrostat in pts of Asian and non-Asian origin with CD. Methods: Data were pooled from the LINC 3 and LINC 4 Phase III studies. LINC 3 comprised a 48-week (W) core phase, including an 8W randomized withdrawal for eligible pts. LINC 4 included a 12W, double-blind, placebo-controlled period and 36W of open-label osilodrostat. Both studies had an optional extension. Efficacy and safety outcomes were evaluated separately in pts of Asian and non-Asian origin. Periods where pts received placebo were excluded. Results: In total, 56/210 (27%) pts were of Asian origin, enrolled in China (n=16), South Korea (n=14), Japan (n=9), Thailand (n=9), India (n=7) and USA (n=1). Most non-Asian pts were Caucasian (n=138/154, 90%). Median (min−max) osilodrostat dose was 3.8 (1−25) and 7.3 mg/day (1−47) in pts of Asian and non-Asian origin, respectively. mUFC control was achieved at W48 and W72 in 64.3% and 68.1% of Asian pts and in 68.2% and 75.8% of non-Asian pts, respectively. Improvements from baseline in most cardiovascular and metabolic-related parameters and in physical manifestations of hypercortisolism were similar across both groups during osilodrostat treatment. Osilodrostat was well tolerated; the most common investigator-reported adverse events (AEs) in Asian pts were adrenal insufficiency (44.6%), nausea (33.9%) and decreased appetite (26.8%), and in non-Asian pts, nausea (45.5%), fatigue (40.9%) and headache (39.0%). The most common serious AE in Asian and non-Asian pts was adrenal insufficiency (5.4% and 5.2%, respectively). Hypocortisolism-related AEs occurred in 58.9% of Asian pts and 40.3% of non-Asian pts, most commonly reported by the investigator as adrenal insufficiency (44.6% and 22.1%). AEs related to pituitary tumor enlargement occurred in 21.4% of Asian and 9.1% of non-Asian pts. AEs related to arrhythmogenic potential and QT prolongation were infrequent in all pts. Conclusions: Osilodrostat demonstrated similar beneficial effects in Asian and non-Asian pts in terms of mUFC control and improvements in cardiovascular and metabolic-related parameters and physical manifestations of hypercortisolism. The mean dose to achieve beneficial effects was lower in pts of Asian than non-Asian origin. Osilodrostat was generally well tolerated in Asian and non-Asian pts; AEs related to hypocortisolism and pituitary enlargement were reported more frequently in Asian than non-Asian pts. Presentation: Thursday, June 15, 2023

Interim analysis: Open-label extension study of leniolisib for patients with APDS

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P= .004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. gov identifier: NCT02859727.

Finerenone in Mild to Severe Chronic Kidney Disease and Type 2 Diabetes: A Fidelity Subgroup Analysis in Patients with Heart Failure

Patients with chronic kidney disease (CKD), type 2 diabetes (T2D), and heart failure (HF) have a very high risk of adverse cardiorenal events. FIDELITY (prespecified pooled analysis of FIDELIO-DKD [NCT02540993] and FIGARO-DKD [NCT02545049]) evaluated finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist in patients with CKD and T2D. This FIDELITY substudy analyzed the effects of finerenone in patients with and without a history of HF at baseline. Eligible patients had T2D and either a urine albumin-to-creatinine ratio (UACR [mg/g])≥30–<300 and estimated glomerular filtration rate (eGFR [mL/min/1.73m2])≥25–≤90, or UACR≥300–≤5000 and eGFR≥25, and received optimized renin–angiotensin system blockade. Key exclusion criteria included symptomatic chronic HF with reduced ejection fraction or recent HF hospitalization (HHF). Patients were randomized to finerenone or placebo. Outcomes included a cardiovascular outcome (time to cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or HHF) and a kidney outcome (kidney failure, sustained eGFR decrease≥57%, or kidney death). Investigator-reported adverse events were assessed. 1007/13,026 eligible patients had a history of HF at baseline. Primary results of the FIDELITY analysis were presented at the European Cardiology Society Congress 2021. This abstract will present detailed HF outcomes, including new onset and recurrent HF events in the total population and cardiovascular and kidney efficacy and safety results by history of HF at baseline. In FIDELITY, finerenone improved CV and kidney outcomes in patients with CKD and T2D versus placebo. The proposed analysis will provide further insights into the effects of finerenone on HF outcomes across a broad spectrum of CKD severity.

Finerenone and Cardiorenal Outcomes by History of Cardiovascular Disease in Patients with Type 2 Diabetes: Fidelity Analyses

Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) are at risk of cardiovascular complications. FIDELITY (prespecified pooled analysis of FIDELIO-DKD [NCT02540993] and FIGARO-DKD [NCT02545049]) evaluated finerenone (a selective, nonsteroidal mineralocorticoid receptor antagonist) in patients with CKD and T2D. Cardiovascular and kidney outcomes were compared in primary and secondary prevention populations. Patients with T2D, and either urine albumin-to-creatinine ratio (UACR [mg/g])≥30–<300 and estimated glomerular filtration rate (eGFR [mL/min/1.73m2])≥25–≤90, or UACR≥300–≤5,000 and eGFR≥25, treated with optimized renin–angiotensin system blockade, were randomized to finerenone or placebo. Cardiovascular outcomes (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or heart failure hospitalization) and kidney outcomes (kidney failure, sustained eGFR decrease≥57% or kidney death) were categorized by prior atherosclerotic cardiovascular disease (CVD). Investigator-reported adverse events (AEs) were assessed. 5,935/13,026 of eligible patients had a history of CVD. Finerenone lowered the risk of the cardiovascular outcome vs placebo (HR=0.86; 95%CI=0.78-0.95; 3.0-year median follow-up), with no treatment modification by CVD history (HR=0.83 [95%CI=0.74-0.94] in patients with CVD; HR=0.91 [95%CI=0.78-1.06] in patients without CVD; Pinteraction=0.375). The effect of finerenone on the kidney outcome (HR=0.77; 95%CI=0.67-0.88) was not modified by CVD (HR=0.71 [95%CI=0.57-0.88] and HR=0.81 [95%CI=0.68-0.97] in patients with and without CVD history, respectively; Pinteraction=0.325). AEs did not differ between CVD subgroups, with a low incidence of hyperkalemia-related treatment discontinuation that was more frequent in the finerenone group but similar between CVD subgroups. Finerenone reduced the risk of cardiovascular and kidney outcomes in patients with CKD and T2D vs placebo, irrespective of CVD history.

Empagliflozin and incidence of events consistent with acute kidney injury: Pooled safety analysis in more than 15 000 individuals.

Empagliflozin and incidence of events consistent with acute kidney injury: Pooled safety analysis in more than 15 000 individuals.

Nephrotic-range proteinuria in type 2 diabetes: Effects of empagliflozin on kidney disease progression and clinical outcomes.

SummaryBackgroundDiabetic kidney disease with nephrotic-range proteinuria (NRP) is commonly associated with rapid kidney function loss, increased cardiovascular risk, and premature mortality. We explored the effect of empagliflozin in patients with type 2 diabetes and cardiovascular disease, complicated by presence of this major risk factor for progressive kidney disease, in a post-hoc analysis of data from the EMPA-REG OUTCOME trial (NCT01131676).MethodsCox proportional hazards models were used to investigate the risk of cardiovascular and kidney outcomes in participants with and without NRP, defined by urine albumin-to-creatinine ratio (UACR) ≥2200 mg/g at baseline. Annual loss of eGFR during chronic treatment (eGFR slopes) and hypothetical time to projected end-stage kidney disease (ESKD), conditioning upon linearity of eGFR change over time if a patient did not decease before projected ESKD, were calculated using a random-intercept random-coefficient model. Safety was described based on investigator-reported adverse events.Findings112 participants (pooled empagliflozin, n = 70; placebo, n = 42; median on-treatment follow-up of 1·9 years on placebo compared with 2·3 years on empagliflozin) presented with NRP at baseline; eGFR and UACR were balanced between treatments. Empagliflozin benefits on cardiovascular death, hospitalisation for heart failure, or kidney outcomes, were consistent in participants with and without NRP (pinteraction >0·1). Treatment effects of empagliflozin on adjusted annual mean eGFR slope were more pronounced in participants with NRP versus those without (pinteraction 0·005). Empagliflozin was estimated to double the median hypothetical time to projected ESKD in participants with NRP. The overall safety profile of empagliflozin was comparable between participants with and without NRP at baseline.InterpretationOur data suggests that empagliflozin might slow kidney function loss and delay the estimated onset of projected ESKD in patients with type 2 diabetes and cardiovascular disease complicated by NRP.

Kidney Function After Initiation And Discontinuation Of Empagliflozin (EMPA) In Heart Failure (HF) Patients (Pts) With And Without Type 2 Diabetes (T2D): Insights From The Emperial Trials

Introduction EMPA induces an initial decline in estimated glomerular filtration rate (eGFR) in T2D pts. Although considered hemodynamic and reversible, it may raise concerns in clinical practice. This phenomenon needs to be better understood in pts with HF, beyond T2D. Hypothesis To assess eGFR after starting/stopping EMPA in HF pts with/without T2D in the EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and heart failure symptoms In patients with chronic heArt faiLure)-Reduced and -Preserved trials. Methods Pts with HF (NYHA class II-IV, diagnosed ≥3 months prior), baseline eGFR >20 mL/min/1.73 m2, elevated NT-proBNP, and LVEF ≤40% in EMPERIAL-Reduced and >40% in -Preserved, received placebo (PBO) or EMPA 10mg. Overall and across subgroups by baseline T2D status, eGFR changes were analyzed for pooled EMPA (both EMPERIAL trials) vs PBO using a mixed model repeated measures analysis. Acute renal failure (ARF) incidence was assessed by investigator-reported adverse events (AEs) coded according to the narrow standardized MedDRA query. Results EMPERIAL-Reduced and -Preserved included 312 (156 EMPA, 156 PBO) and 315 pts (157 EMPA, 158 PBO), respectively. At baseline in the pooled data set, 55.6% had T2D. Overall, mean baseline eGFR±SD was 57.6±19.3 mL/min/1.73 m2. PBO-adjusted mean eGFR±SE change from baseline with pooled EMPA was -2.3±0.7 and -3.3±0.8 at Weeks 6 and 12, respectively (Figure A). Change in eGFR±SE from last value on treatment to follow-up was -0.3±0.5 in PBO and +3.9±0.5 in EMPA groups (Figure A). These findings were consistent across subgroups by baseline T2D status (Figure B). Incidence rates of ARF were similar in PBO and EMPA groups (n=9 and n=8; 11.8 and 10.7 per 100pt-years, respectively), and also consistent across subgroups by baseline T2D status. Serious ARF occurred in 4 PBO pts and 1 EMPA pt. Conclusions In HF pts with baseline eGFR down to 20 mL/min/1.73 m2, eGFR dynamics after starting/stopping EMPA and kidney AEs were similar to EMPA's known eGFR change on and off treatment, and kidney safety profile, regardless of T2D status.

Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial

The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial. EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 [SD 17·36] vs 72·96 [17·82]; p=0·00011) and after induction (76·48 [17·52] vs 72·32 [18·60]; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 [SD 17·05] for placebo vs 18·17 [28·35] for ipilimumab) and insomnia (15·17 [22·53] vs 25·60 [29·19]). Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events. Bristol-Myers Squibb.

A pharmacokinetic study of lipegfilgrastim in children with Ewing family of tumors or rhabdomyosarcoma

PurposeNeutropenia is a common complication from chemotherapy, limiting optimal dosing and treatment. Lipegfilgrastim is a long-acting granulocyte colony-stimulating factor developed for the management of chemotherapy-induced neutropenia. The objectives of this phase 1, multinational, open-label, single-arm study were to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a single body weight-adjusted dose of lipegfilgrastim and to evaluate the efficacy, safety, and tolerability of the drug in children with Ewing family of tumors or rhabdomyosarcoma treated with myelosuppressive chemotherapy.MethodsEnrolled patients received lipegfilgrastim (100 µg/kg) 24 h after the last chemotherapy treatment in week 1. Patients were stratified into three age groups: 2 to <6, 6 to <12, and 12 to <18 years. Blood samples for PK analyses were obtained at baseline and at 3, 8, 24, 30, 48, 72, 96, 144, and 240 h postdose for the two oldest groups and up to 144 h in the youngest group.ResultsTwenty-one patients were enrolled and received lipegfilgrastim, seven in each age group. Lipegfilgrastim exposure levels were comparable across age groups, with concentrations maintained over a prolonged period after a single injection. Differences in PD were mainly associated with chemotherapy type. Most investigator-reported adverse events were attributed to chemotherapy and not to lipegfilgrastim. Severe adverse events were noted in 57% of patients; febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia were more frequent among the oldest patients.ConclusionsResults support the use of a body weight-adjusted dose to achieve equivalent initial peak exposure levels of lipegfilgrastim in children of various ages.

Assessment of Adverse Events in Protocols, Clinical Study Reports, and Published Papers of Trials of Orlistat: A Document Analysis.

BackgroundLittle is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials.Methods and FindingsWe received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report.None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were “bothersome,” a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that “all adverse events were recorded.”For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student’s t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper.Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs.ConclusionsIn the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.

Pancreatitis in tigecycline Phase 3 and 4 clinical studies

ObjectivesTo examine the incidence of pancreatitis among subjects enrolled in the tigecycline clinical trial programme, summarize cases and examine concomitant use of other pancreatitis-causing medications.MethodsSubject data from Phase 3 and 4 comparative tigecycline studies were included in the analysis; investigator-reported adverse events of ‘pancreatitis’, ‘necrotizing pancreatitis’ or ‘pancreas disorder’ were reviewed. Data were summarized and cases were reported. No statistical comparisons were made. The incidence of overall pancreatitis with 95% CIs was calculated. The Wilson score method was used to calculate CIs.ResultsNineteen subjects with investigator-determined pancreatitis were identified from the programme database, which included 3788 subjects treated with tigecycline and 3646 subjects treated with a comparator. There were 9 cases identified among the tigecycline-treated subjects [9 of 3788 (0.24%; 95% CI, 0.11–0.45)] and 10 cases among the comparator-treated subjects [10 of 3646 (0.27%; 95% CI, 0.13–0.50)]. The demographic characteristics of the subjects with pancreatitis were similar between treatment groups. The median duration of tigecycline therapy was 8.0 days compared with 11.0 days of comparator treatment. Concomitant or prior exposure to a Badalov class I medication was evident in the majority of subjects who developed pancreatitis. A numerically higher number of tigecycline-treated subjects were exposed to furosemide prior to the onset of pancreatitis than comparator-treated subjects.ConclusionsPancreatitis was uncommon in subjects treated with tigecycline, with an occurrence of <1%. Concomitant medications known to cause pancreatitis should be considered when prescribing tigecycline, but may not identify those at risk of developing pancreatitis.

Adverse events in HEAAL: when to hold and when to fold

This editorial refers to ‘Predicting adverse events during angiotensin receptor blocker treatment in heart failure: results from the HEAAL trial’, by M.S. Kiernan et al., published in this issue on pages 1401–1409. In 2009, the HEAAL investigators 1 reported that losartan 150 mg/ day reduced the rate of death and admissions for heart failure with reduced ejection fraction (HFREF) compared with patients receiving losartan 50 mg/day, the dose previously recommended and evaluated in ELITE II 2 to compare losartan with captopril. This important contribution pointed out the necessity to determine the effective dose of a drug in patients with HFREF rather than relying upon the dose used to lower blood pressure in patients with essential hypertension. In this issue of the journal, the HEAAL investigators 3 report that investigator-reported adverse events (AEs), including kidney impairment, hyperkalaemia, and hypotension, were associated with an increased risk of death compared with those patients who did not experience them, and that these AEs were more frequent in the losartan 150 mg than the losartan 50 mg group. The median serum creatinine on the day of their investigator-reported AE was 1.8 mg/dL, potassium 5.8 mmol/L, and systolic and diastolic blood pressures were 86 and 60 mmHg, respectively. Independent of the dose of losartan, these AEs were more frequent in older patients, those receiving an aldosterone blocker, and in those who reported the incident AE as the reason for intolerance to angiotensin-converting enzyme inhibitor therapy, one of the criteria for treatment with losartan. Baseline levels of serum creatinine were predictive of subsequent renal impairment, while entry levels of serum potassium predicted the occurrence of hyperkalaemia, and baseline systolic blood pressure predicted subsequent hypotension. Diabetes mellitus, baseline haemoglobin, and diuretic use were also predictive of subsequent kidney impairment and hyperkalaemia. However, while these factors were predictive of subsequent AEs, the association between investigator-reported kidney impairment, hyperkalaemia, and hypotension and the excess risk of subsequent death and first hospitalization for HF was independent of these baseline factors. Also of note was the finding that the frequency of these AEs continued to increase over time and was not limited to the period surrounding initiation of therapy with losartan. On the basis of these findings, the HEAAL investigators 3 suggest close monitoring in patients with the baseline risk factors they identified and in patients treated with losartan 150 mg/day. The finding that these AEs were associated with an increase in mortality, while not surprising, is nevertheless of importance and raises the issue of how we can avoid these AEs and how we should respond once they occur. It is important to emphasize that while there were significantly more AEs associated with the use of losartan 150 than 50 mg/day the strategy of losartan 150 mg significantly reduced cardiovascular events in comparison with 50 mg 1 and that the same AEs were associated with an increase in mortality when they occurred in patients on losartan 50 mg. While avoiding these AEs that were associated with an increase in mortality is desirable, it should be pointed out that these AEs are often difficult to predict in an individual patient and may be the cost of some strategies shown to be effective in reducing total mortality in patients with HFREF. One might conclude given the dictum ‘primun non nocere’ that since losartan 150 mg/day is associated with an increase in the incidence of AEs that resulted in an increase in mortality, it is better to avoid this strategy, especially in individuals at high risk for the development of these AEs with losartan such as those with chronic kidney disease, diabetes mellitus, or low haemoglobin, the very old, and those on an aldosterone blocker. These are, however, the very individuals who are at greatest risk and most in need of effective therapy to reduce their cardiovascular risk. Many clinicians have used this reasoning and have, for example, avoided the use of indicated aldosterone blockers in patients with HFREF 4 due to the fear of inducing hyperkalaemia, despite the evidence that aldosterone blockers reduce cardiovascular events even in these high-risk individuals. 5 While close monitoring should be instituted when prescribing losartan or similar agents to patients with the baseline risk factors identified by the HEAAL investigators, 3 the failure to attempt initiation may place the patient at greater risk than that associated with the development of these AEs. A more difficult question is what should one do once these AEs occur in a patient with HFREF. Our initial impulse might be to withhold or reduce the dose of the drug thought to be responsible for

Interim Safety and Effectiveness Results From a 5-Year Observational Study of Deferasirox in Pediatric Patients Aged 2–

AbstractAbstract 2125 Background:Young children typically receive more blood transfusions per kg body weight compared with adults, increasing the risk of iron overload. Iron overload may lead to endocrine abnormalities that can affect growth and development. Data from clinical trials of the iron chelator deferasirox (Exjade®) have demonstrated tolerability and efficacy in transfused patients with a range of underlying anemias. The registration clinical trials included 52 patients aged 2–<6 years who were randomized to receive deferasirox. A 5-year multinational observational registry was initiated to gather further safety and effectiveness data of deferasirox in transfusion-dependent pediatric patients with chronic iron overload. Methods:Patients aged 2–<6 years at enrollment received deferasirox according to local (country-specific) prescribing information. The initial recommended deferasirox dose (ranging from 10–30 mg/kg/day) was based on country-specific prescribing information and adjusted according to serum ferritin levels, therapeutic goals, tolerability and patient weight change. The objectives of this interim analysis were to collect information on renal and hepatic safety; monitoring of serum ferritin levels and investigator-reported adverse events (AEs) was also conducted. Biochemistry analysis, including serum ferritin levels, was based on the full analysis set, and comprised all patients who received ≥1 dose of deferasirox during the registry. The population used for safety analyses comprised all patients who received ≥1 dose of deferasirox and had at least one post-baseline safety assessment. Enrollment is now complete, and study completion is expected June 2015. Results:As of October 31, 2011, 247 patients (mean age 3.1 years; 1.2% <2 years; 84.2% ≥2–≤4 years; 14.6% >4–≤6 years) with β-thalassemia (n=160, 64.8%), sickle cell disease (n=48, 19.4%), Diamond–Blackfan anemia (DBA; n=11, 4.5%) and other anemias (n=28, 11.3%) were enrolled and received ≥1 deferasirox dose. Patients received deferasirox for a mean ± SD of 30.0 ± 15.2 months. Mean dose was 25.4 ± 6.9 mg/kg/day; 169/243 (69.5%) of these patients had no dose adjustments for a period of ≥1 year, despite a mean percentage weight change of +16.6 ± 12.0% (range −8.9 to 59.1%) during that time. 63/243 (25.9%) had no dose adjustments for a period of ≥2 years and percentage weight increased by +22.5 ± 16.1% (range −1.2 to 72.4%) during that time. At baseline (n=214), median serum ferritin was 1757 ng/mL (range 334–9577), decreasing to 1489 ng/mL (range 156–5102) in patients reaching the 30-month evaluation point (n=57). Mean iron intake was high and remained stable throughout (∼0.6 mg/kg/day).5/247 patients (2.0%) had SCr increases >age-adjusted ULN and >33% increase from baseline on two consecutive measurements (baseline range 20–39 μmol/L); none of these five patients discontinued. Increased ALT >5 × ULN was confirmed in 11/247 patients (4.5%); most abnormalities were transient, five of these patients discontinued (increased ALT [n=3], protocol deviation [n=1] and vomiting [n=1]). The most common (≥4 patients) investigator-reported drug-related AEs were investigations and GI disorders; these are shown in the Table as investigator-reported preferred terms. The majority of investigations were mild-to-moderate in severity. [Display omitted] Overall, 178/247 patients (72.1%) are continuing the study. Main reasons for discontinuation were protocol deviation (n=12, 4.9%) and AEs (n=7, 2.8%: increased ALT; proteinuria; hepatic AE [increased ALT/AST for second time after drug administration]; abdominal pain/vomiting/hypokalemia/transaminase elevation; vomiting; reversible increase of ALT of 239 U/L reported as hepatic cytolysis; transaminase elevation/lack of efficacy; all n=1). One patient with DBA died (severe pancytopenia and sepsis following bone marrow transplantation). Conclusions:The safety profile of deferasirox in very young pediatric patients was consistent with the available evidence in adult patients, including the rate of creatinine and liver enzyme changes which did not appear to be progressive. Many patients did not have appropriate dose adjustments during the study, despite substantial increases in weight. In addition to safety and efficacy parameters, weight change in pediatric patients should be considered during dose adjustments to optimize efficacy and safety. Disclosures:Vichinsky:Novartis: Consultancy, Research Funding; ApoPharma: Consultancy, Research Funding; ARUP Research lab: Research Funding. Bernaudin:Novartis: Research Funding. El-Ali:Novartis: Employment. Arrowsmith:Novartis: Employment. Martin:Novartis: Employment.

Concomitant Medications and Gastrointestinal Events in Thalassemia and MDS Patients Receiving Deferasirox for Transfusional Iron Overload: Data From the EPIC Study

AbstractAbstract 5182 Background:The 1-yr open-label, single-arm, multicenter EPIC (Evaluation of Patients’ Iron Chelation with Exjade®) trial assessed the efficacy and safety of deferasirox in patients with transfusion-dependent iron overload, including patients with thalassemia and with myelodysplastic syndromes (MDS). The most frequent adverse events (AEs) in the EPIC trial were gastrointestinal (GI) disturbances. Here, we qualitatively examine concomitant medication (con med) use in thalassemia and MDS patients with/without GI events to consider the impact of con med use on GI events. Methods:Thalassemia and MDS patients from the EPIC study were included. A GI event was defined as an investigator-reported AE with the system organ class ‘GI disorders' after start of treatment. Data are reported here for the most frequently received con meds of interest, by preferred term, which also had notable differences in their frequency among patients with/without GI events; con meds that may have been prescribed to treat GI events are excluded from interpretation: propulsives, antipropulsives, proton pump inhibitors, laxatives and electrolyte solutions. Results:Among thalassemia patients (n=1115; 48. 3% male; aged 18. 2 yrs [range 2–72]), 345 (30. 9%) patients experienced a GI event. Mean deferasirox dose was 23. 8 ± 5. 4 mg/kg/d in patients with a GI event and 24. 3 ± 5. 5 mg/kg/d in patients with no GI event; median serum ferritin (SF) at end of study (EOS) was 2734 ng/mL (391–23997) and 3223 ng/mL (259–17644), respectively. 28. 9% of thalassemia patients did not receive any con meds; 15. 7% received ≥7 different types of con meds. Thalassemia patients with a GI event received a mean of 6. 0 different types of con meds, vs 2. 1 in patients without a GI event. Con meds were received in 91. 9% of patients with a GI event vs 61. 8% of patients without a GI event. Anti-inflammatory, antibiotic or antifungal con meds were more frequent in thalassemia patients who experienced a GI event (Figure A). The con med with the largest relative difference in frequency among patients with vs without a GI event was paracetamol/codeine phosphate (7. 2 vs 0. 5%, respectively).Among MDS patients (n=341; 59. 8% male; aged 67. 9 yrs [11–89]), 248 (72. 7%) patients experienced a GI event. Deferasirox dose was 18. 8 ± 4. 9 mg/kg/d in patients with a GI event and 20. 4 ± 6. 4 mg/kg/d in patients with no GI event; SF at EOS was 1977 ng/mL (254–9835) and 2045 ng/mL (141–10155), respectively. 12. 3% of MDS patients did not receive any con meds; 37. 8% received ≥7 different types. Patients with a GI event received a mean of 9. 6 different types of con meds vs 4. 5 in patients without a GI event. Con meds were received in 89. 5% of patients with a GI event, vs 82. 8% of patients without a GI event. In patients with MDS, antibiotic, antifungal or opioid medications were more frequent in patients with GI events (Figure B). The con med with the largest relative difference in frequency among patients with vs without a GI event was tramadol hydrochloride (7. 7 vs 1. 1%, respectively).Most frequent con med in both populations was paracetamol (acetaminophen; Figure). In patients receiving paracetamol who had a GI event, the most frequent types of GI events in thalassemia patients were diarrhea, abdominal pain and nausea; in MDS patients these were diarrhea, constipation and abdominal pain. In patients receiving paracetamol, mean alanine aminotransferase level at EOS in thalassemia patients with a GI event was 49. 0 vs 46. 3 U/L in patients with no GI event; and 38. 9 vs 27. 2 U/L in MDS patients, respectively. Discussion:In both thalassemia and MDS patients, concomitant use of antifungal and antibiotic medications was more frequent in patients with GI events, although it should be considered that GI events are also the most frequent AEs of, for eg, amoxicillin/potassium clavulanate and ciprofloxacin. Paracetamol use was higher in patients who had GI events; types of GI events were typical of those observed during deferasirox treatment and did not appear related to liver toxicity. Anti-inflammatory medications were more frequent in thalassemia patients with GI events, as were opioid medications in MDS patients. Con meds may affect the frequency of GI AEs reported with deferasirox. Further investigation is needed to determine whether these observations result from a potential interaction of the metabolic pathways of con meds and deferasirox – eg, CYP450 metabolism of paracetamol – or the action of the con meds alone. [Display omitted] Disclosures:Cappellini:Novartis: Speakers Bureau. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kattamis:Novartis: Honoraria, Research Funding, Speakers Bureau. Louw:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Martin:Novartis: Employment. Gattermann:Novartis: Honoraria, Research Funding, Speakers Bureau.

Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma

An international, Phase II trial was conducted to assess two doses of ofatumumab, a human CD20 monoclonal antibody, combined with cyclophosphamide (750mg/m(2) ), doxorubicin (50mg/m(2) ), prednisone (100mg days 3-7) and vincristine (1·4mg/m(2) ) (O-CHOP), as frontline treatment for follicular lymphoma (FL). 59 patients with previously untreated FL were randomized to ofatumumab 500mg (n=29) or 1000mg (n=30) day 1, with CHOP on day 3 every 3weeks for six cycles. Median duration of FL was 0·1years for both dose groups; 34% and 38% of patients had high-risk Follicular Lymphoma International Prognostic Index (FLIPI) scores in the 500- and 1000-mg dose groups, respectively. Overall response rate was 90% for the 500-mg group and 100% for the 1000-mg group. 62% of patients achieved complete response (CR)/unconfirmed CR (CRu). 76% of patients with FLIPI score 3-5 attained CR/CRu. Longer follow-up time is needed for analysis of survival end points. The most common Common Terminology Criteria grade 3-4 investigator-reported adverse events were leucopenia (29%) and neutropenia (22%). No deaths have been reported. O-CHOP was safe and efficacious in patients with previously untreated FL, including high-risk FLIPI groups. This trial was registered at www.clinicaltrials.gov (NCT00494780).

A Multi‐Institutional Observational Study of Testosterone Levels after Testosterone Pellet (Testopel®) Insertion

Implantable testosterone pellets were approved by the Food and Drug Administration in 1972 for the treatment of testosterone deficiency syndrome (TDS). Clinical use of this testosterone delivery modality has been limited until its recent reintroduction (Testopel(®) , Slate Pharmaceuticals, Durham, NC, USA). Six academic institutions collaborated and combined their databases to more fully characterize serum testosterone levels after the pellet implantations. To assess the time-dependent serum testosterone levels after subcutaneous testosterone pellets in clinical practice for the treatment of TDS. Data were retrospectively pooled and analyzed from data in six academic institutions. Variables included patient age, total testosterone concentrations before and after implantation, the number of testosterone pellets implanted, and the time from implantation to measurement of serum testosterone concentrations. Three hundred eighty men undergoing 702 insertions were included for analysis using JMP (version 4.0.4; SAS Institute, Cary, NC, USA). Main outcome measures were postimplantation total testosterone levels and investigator-reported adverse events. Testosterone levels as a function of the number of pellets implanted and time from implantation were assessed. Implantation of six to ≥10 testosterone pellets (450 to ≥750 mg) increased total testosterone into the therapeutic range at 1 month postimplantation and sustained therapeutic levels (>300) for 4-6 months. Higher pellet numbers (10-12 pellets) were associated with higher, more consistent, and longer maintenance of testosterone levels within the therapeutic range. Four extrusions and three hematomas were reported early in our experience; other investigator-reported adverse events were generally mild to moderate in nature and transient in duration. No subjects required analgesics. Testosterone pellets (Testopel(®) , Slate Pharmaceuticals) provide sustained levels of testosterone for at least 4 months and up to 6 months in men with TDS. Implantation of ≥8 pellets achieved optimal results with respect to peak mean testosterone level and duration of effect. Testosterone pellets were generally well tolerated.

Evaluation of the Acute Coronary Syndrome Safety Profile of Dabigatran Etexilate in Patients Undergoing Major Orthopaedic Surgery: Findings From Four Phase III Trials

Abstract 2309 Introduction:We have previously investigated the incidence of acute coronary syndrome (ACS) events in patients treated with the new oral, reversible, direct thrombin inhibitor, dabigatran etexilate (DE) compared with enoxaparin in the treatment and post-treatment periods in patients undergoing major orthopaedic surgery in three phase III trials (RE-MODEL™, RE-NOVATE® and RE-MOBILIZE®). Whether identified through local investigator reporting or blinded central event adjudication, no significant differences in ACS event rates were detected among orthopaedic surgery patients treated with DE compared with enoxaparin during or after treatment. Overall event rates were low, consistent between investigator and centrally adjudicated assessments, and without evidence for a ‘rebound' effect for either agent in this post-surgical population. In a pooling with a fourth trial (RE-NOVATE® II), we have now conducted an analysis of investigator-reported adverse events possibly related to ACS from 10,148 treated patients. Methods:Patients in the RE-MODEL™, RE-NOVATE®, RE-NOVATE® II and RE-MOBILIZE® trials were randomized to receive oral DE 150 mg (n = 2737) or 220 mg (n = 3692) once daily, or subcutaneous enoxaparin (n = 3719) for 6–35 days, and were followed for 90 days post-surgery. Potential ACS events during treatment were identified based on investigator-reported adverse events classified using pre-specified Standard Medical Dictionary for Regulatory Authorities (MedDRA) Queries (SMQs). This list included terms relating to locally diagnosed ACS as well as broader MedDRA terms that could reflect undiagnosed ACS. Results:In all four trials, adverse events included in the SMQ ‘ischaemic heart disease' (sub-terms myocardial infarction [MI], acute MI, angina pectoris, myocardial ischaemia, ACS, unstable angina, coronary artery disease, coronary artery occlusion, cardiac enzymes increased, electrocardiogram ST segment depression, electrocardiogram T wave abnormal, ischaemic cardiomyopathy and troponin increased) were reported by the investigator in 16 (0.4%) and 32 (1.2%) patients in the DE 220 mg and DE 150 mg groups, respectively, compared to 25 (0.7%) in the enoxaparin group during treatment. The incidence of individual adverse event terms possibly related to ACS in the respective treatment groups (DE 220 mg, DE 150 mg and enoxaparin) was as follows: MI 3 (0.1%), 11 (0.4%) and 9 (0.2%); acute MI 1 (0.0%), 3 (0.1%) and 1 (0.0%); ACS 1 (0.0%), 0 (0.0%) and 0 (0.0%); unstable angina 1 (0.0%), 0 (0.0%) and 0 (0.0%). Conclusions:The analysis of > 10,000 patients showed no significant differences in investigator-reported ACS-related adverse event rates among orthopaedic surgery patients during treatment, comparing DE with enoxaparin. This is in agreement with, and supports previous findings of, investigator-related and centrally adjudicated ACS events from three trials. Disclosures:Eriksson:Bristol-Myers Squibb: Consultancy; Bayer: Consultancy; Astellas: Consultancy. Smith:Boehringer Ingelheim: Employment. Caprini:ESAI: Consultancy; Pfizer: Consultancy; GSK: Consultancy; Sanofi: Consultancy; Boehringer Ingelheim: Consultancy; Covidien: Consultancy. Hantel:Boehringer Ingelheim: Employment. Clemens:Boehringer Ingelheim: Employment. Feuring:Boehringer Ingelheim: Employment.