Independent Adjudication Committee Research Articles

Abstract CT167: Pooled analysis of drug-related interstitial lung disease (ILD) in 8 single-arm trastuzumab deruxtecan (T-DXd) studies

Abstract Introduction: T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload. In patients (pts) with HER2-expressing or -mutated solid tumors, T-DXd has demonstrated strong antitumor activity with a manageable safety profile and is approved for treatment (tx) of pts with HER2+ metastatic breast cancer (BC) that has progressed on ≥2 anti-HER2 therapies (US) or after chemotherapy (Japan); ILD is an important identified risk. We further characterize ILD in a pooled analysis of 8 single arm phase 1 and 2 T-DXd monotherapy studies. Methods: Pts who received ≥1 dose of T-DXd monotherapy 5.4 mg/kg or higher across 8 single-arm studies were included (between Aug 28, 2015 and the data cutoff June 08, 2020). Potential ILD cases had imaging and clinical data (baseline through the time of ILD case) retrospectively reviewed by an independent adjudication committee to assess whether the reported ILD event was study drug related; events adjudicated as study drug related are reported. Results: 879 pts were included; 510 with BC, 148 with lung cancer, 107 with colorectal cancer, 78 with gastric cancer, and 34 with other cancers (2 had missing tumor type). Median tx duration was 6.9 mo (range, 0.7-50.1 mo); 139 pts (15.8%) experienced an adjudicated ILD event, most were grade (G) 1/2 (G1/2=108 [12.3%]; G3=9 [1.0%]; G4=1 [0.1%]; G5=21 [2.4%]). Among pts treated with T-DXd 5.4 mg/kg (n=315), 48 (15.2%) experienced an ILD event (G1/2=39 [12.4%]; G3=2 [0.6%]; G4=1 [0.3%]; G5=6 [1.9%]). Additional details on ILD events by dose and tumor type will be presented. Among adjudicated ILD events (any grade), the onset date as assessed by investigator was delayed compared with the adjudication committee-assessed date in 71 cases (median difference in onset date, 49 d [range, 1-288 d]). The majority of ILD events occurred in the initial 12 mo of tx. After 12 mo the risk of new onset of ILD decreased with a conditional probability of developing ILD of 7.0% in pts treated to month 12 without ILD and 1.4% in pts treated to month 18 without ILD, which was likely driven by pts with longer tx duration in the BC cohort; however, additional follow-up is required to confirm these observations. Data on the use of steroids to manage ILD will be presented. Conclusion: Pooled analysis showed that most ILD events were low grade (78% of pts with ILD had G1/2 events) and occurred in the first 12 mo of tx, with lowered risk for pts on tx > 12 mo. The adjudication committee identified ILD earlier than investigators in 48% of cases suggesting opportunity for early detection and intervention. Close monitoring, prompt recognition, and proactive management of ILD using current management guidelines may help to improve ILD outcomes. Citation Format: Charles A. Powell, Shanu Modi, Hiroji Iwata, Shunji Takahashi, Egbert F. Smit, Salvatore Siena, Dwan-Ying Chang, Charles S. Fuchs, Kun Nie, Amy Qin, Jasmeet Singh, Corina Taitt, Sunil Verma, D. Ross Camidge. Pooled analysis of drug-related interstitial lung disease (ILD) in 8 single-arm trastuzumab deruxtecan (T-DXd) studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT167.

YM150, an Oral Direct Factor Xa Inhibitor, as Prophylaxis for Venous Thromboembolism in Patients with Elective Primary Hip Replacement Surgery. A Dose Escalation Study.

Activated factor X (FXa) is a pivotal blood coagulation factor positioned at the crossroads of the extrinsic and intrinsic coagulation cascade. Inhibitors of FXa are anticoagulants that could be used in the prevention and treatment of thrombosis and venous thromboembolism (VTE). YM150 is a once daily, orally active FXa inhibitor. A randomized, enoxaparin-controlled, dose escalation study was performed in 174 patients undergoing elective primary hip replacement surgery to assess safety and efficacy of 7–10 days treatment with oral doses of YM150 (3, 10, 30 or 60 mg once daily starting 6–10 h after surgery) or s.c. enoxaparin (40 mg once daily starting 12 h before surgery). Safety is defined as major and/or clinically relevant non-major bleeding, and efficacy as venous thromboembolism detected by mandatory bilateral venography on the last treatment day and/or symptomatic VTE. The study was open-label with blinded evaluation of all outcomes by an independent Adjudication Committee. There were no major bleeds. Three clinically relevant non-major bleeds were reported, 1 (2.9%; 95% CI: 0–16%) in the 3 mg and 2 (5.7%; 1–19%) in the 10 mg YM150 dose groups. No trend was observed in the incidence of minor bleeds with dose of YM150 in the range 10 mg to 60 mg daily. The proportion of patients with minor bleeding events in the enoxaparin group (22%; 95% CI: 10–39%) was similar to that in the YM150, 60 mg daily group (24%; 11–41%). 147 patients (84%) were considered to have an evaluable venogram. The incidences of VTE were 52% (95% CI: 31–72%), 39% (22–57%), 23% (9–40%), and 19% (7–37%) for the respective 3, 10, 30 and 60 mg YM150 once daily dose groups in comparison with 39% (22–57%) for enoxaparin. Logistic regression analysis revealed a statistically significant dose-related trend (p=0.006) for patients reaching the VTE endpoint during YM150 treatment. No trend in any of the measured safety parameters was observed with study treatment (YM150 or enoxaparin) or dose of YM150. Oral, once daily doses of YM150, 10 mg to 60 mg administered 6 to 10 h after primary hip replacement, were shown to be safe, well tolerated and effective in this study.

P334 Tofacitinib for the treatment of Ulcerative Colitis: Analysis of malignancy rates from the Ulcerative Colitis clinical programme

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated analysis of adjudicated malignancies in the tofacitinib UC clinical programme, including final data from the open-label, long-term extension (OLE) study (as of 24 Aug 2020). Methods Malignancies were evaluated from 3 randomised, placebo-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951]; 1 P3 maintenance study [NCT01458574]) and an OLE study (NCT01470612). Three cohorts were analysed: Induction (P3 induction studies), Maintenance (P3 maintenance study) and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P3 or OLE studies; data from the previous data cut [May 2019] are also reported for comparison). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose <15 mg or ≥15 mg, respectively (82.1% of patients received PD 10 mg BID). An independent adjudication committee reviewed potential malignancies. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) were evaluated for malignancies (excluding non-melanoma skin cancer [NMSC]) and NMSC. Results 1124 patients were evaluated for malignancies (2809.4 patient-years of tofacitinib exposure; up to 7.8 years of treatment; median duration of 685.5 days). No malignancies (excluding NMSC) occurred in Induction Cohort patients. Malignancies (excluding NMSC) occurred in 1 Maintenance Cohort patient (who was receiving placebo) and in 25 Overall Cohort patients (IR 0.86 [95% confidence interval (CI) 0.56, 1.27]: PD tofacitinib 5 mg BID n=5, IR 0.63 [95% CI 0.20, 1.47]; PD tofacitinib 10 mg BID n=20, IR 0.95 [95% CI 0.58, 1.46]); 5 new cases since May 2019 (Table).1 NMSC events in the Induction and Maintenance Cohorts were previously reported (Table).1 NMSC events occurred in 21 Overall Cohort patients (IR 0.73 [95% CI 0.45, 1.12]): PD tofacitinib 5 mg BID n=5, IR 0.63 (95% CI 0.21, 1.48); PD tofacitinib 10 mg BID n=16, IR 0.77 (95% CI 0.44, 1.25); 2 new cases since May 2019 (Table).1 Conclusion There was no apparent clustering of types of malignancy, excluding NMSC. Malignancies (excluding NMSC) and NMSC IRs remained stable over time, being comparable to those previously reported in the tofacitinib UC clinical programme.1 In this analysis, malignancies (excluding NMSC) and NMSC IRs were similar to those in patients with UC treated with tumour necrosis factor inhibitors, as reported from claims data (IRs of 0.63 and 1.69, respectively).2 References

P260 An analysis of non-melanoma skin cancer rates in the tofacitinib Ulcerative Colitis clinical programme

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated analysis of non-melanoma skin cancer (NMSC) events in the tofacitinib UC clinical programme, including final data from the open-label, long-term extension (OLE) study (as of 24 Aug 2020). Methods NMSC events were evaluated from 3 randomised, placebo (PBO)-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951]; 1 P3 maintenance study [NCT01458574]) and an OLE study (NCT01470612), as 3 cohorts: Induction (P3 induction studies [patients (pts) receiving tofacitinib 10 mg twice daily (BID) or PBO]); Maintenance (P3 maintenance study [pts receiving tofacitinib 5 or 10 mg BID or PBO]); Overall (pts receiving tofacitinib 5 or 10 mg BID in P3 or OLE studies). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose <15 or ≥15 mg, respectively (82% of pts received PD 10 mg BID). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique pts with events per 100 pt-years of exposure) were evaluated for NMSC. A Cox proportional hazards model was used for risk factor analysis. Results 1124 pts were evaluated for NMSC (2809.4 pt-years of tofacitinib exposure; up to 7.8 years of treatment; median duration 685.5 days). NMSC events in Induction and Maintenance were previously reported (Table 1).1 In Overall, NMSC occurred in 21 pts (IR 0.73 [95% confidence interval (CI) 0.45, 1.12]): PD tofacitinib 5 mg BID n=5, IR 0.63 (0.21, 1.48); PD tofacitinib 10 mg BID n=16, IR 0.77 (0.44, 1.25) (Table 1); 2 new cases since May 2019.1 Eleven pts had squamous cell carcinoma and 15 pts had basal cell carcinoma; 5 pts had both. No NMSC was metastatic or led to discontinuation. IRs by time interval and subgroup are reported (Table 2). Prior NMSC (hazard ratio [HR] 12.08 [95% CI 4.20, 34.76]) and age (per 10-year increase, HR 2.01 [1.38, 2.93]) were significant risk factors for NMSC in the multivariable analysis. Prior immunosuppressant use was not a significant risk factor in either the multivariable or univariate analyses. Conclusion In this analysis, NMSC IRs for tofacitinib were similar to those in pts with UC treated with biologics2 and those previously reported in the tofacitinib UC clinical programme.1 NMSC events were more likely to occur in pts with recognised NMSC risk factors: prior NMSC and increasing age.3 Dose dependency of NMSC IR could not be concluded here, as dose changes were permitted. NMSC IRs remained stable over time, up to 7.8 years of exposure. References

TROPION-PanTumor01: Dose analysis of the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd, DS-1062) for the treatment (Tx) of advanced or metastatic non-small cell lung cancer (NSCLC).

9058 Background: Datopotamab deruxtecan (Dato-DXd; DS-1062) is an ADC composed of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a topoisomerase I inhibitor via a tetrapeptide-based cleavable linker. Methods: TROPION-PanTumor01 (NCT03401385) is a multicenter dose-escalation/expansion study evaluating Dato-DXd administered Q3W in patients (pts) with advanced NSCLC (since expanded to other tumor types, excluded from this analysis). Efficacy and safety were evaluated in 175 pts for dose analysis. Pharmacometric analyses (population pharmacokinetics [popPK] and exposure-response modeling) were conducted across doses to inform dose selection for further development. Results: At data cutoff (Sept 4, 2020), median follow-up was 7.4 mo (range, 0.10-21.7 mo). Select all-grade TEAEs were 1.5- to 2-fold higher in the 8 mg/kg vs 4 and 6 mg/kg cohorts: vomiting (34% vs 12% and 18%), anemia (28% vs 4% and 16%), diarrhea (20% vs 6% and 11%), and mucositis (29% vs 6% and 13%). Rates of grade ≥3 drug-related TEAEs and serious drug-related TEAEs were ≥2-fold higher with the 8 mg/kg dose (n = 80; 34% and 20%) relative to the 4 mg/kg (n = 50; 10% and 8%) and 6 mg/kg (n = 45; 16% and 9%) doses. Rates of drug-related interstitial lung disease (ILD), as determined by an independent adjudication committee, were higher in the 8 mg/kg cohort (15% vs 2% and 2% in the 4 and 6 mg/kg cohorts); 3 pts in the 8 mg/kg cohort experienced grade 5 ILD. Dose interruptions and reductions due to TEAEs increased with dose (4 mg/kg: 4% and 2%; 6 mg/kg: 20% and 9%; 8 mg/kg: 20% and 31%). More pts in the 8 mg/kg cohort discontinued Tx early due to AEs (15%) compared with those in the 4 mg/kg (4%) and 6 mg/kg (7%) cohorts. ORRs determined by blinded independent central review were similar: 8 mg/kg, 25% (20/80); 6 mg/kg, 21% (8/39); and 4 mg/kg, 23% (9/40). Preliminary median PFS (95% CI) was 5.4 mo (4.1-7.1 mo) in the 8 mg/kg cohort, 8.2 mo (1.5-11.8 mo) in the 6 mg/kg cohort, and 4.3 mo (2.0 mo-NE) in the 4 mg/kg cohort. PFS was limited by early censoring due to immature duration of follow-up, with the majority of pts having ≤3 mo of follow-up in the 4 (66%) and 6 mg/kg (67%) cohorts vs 8 mg/kg (46%) cohort. In pharmacometric analyses, tumor-size change from baseline and probability of complete response/partial response positively correlated with exposure (AUC) of Dato-DXd. Incidences of dose reduction and grade ≥2 stomatitis/mucositis were also positively correlated with exposure; projected probabilities in a virtual population bootstrapped from pts with NSCLC in the popPK data confirmed these trends. Updated results will be presented. Conclusions: A Dato-DXd dose of 6 mg/kg was selected for the randomized, phase 3, TROPION-Lung01 trial (NCT04656652) based on better tolerance and improved efficacy, including a trend toward increased PFS. Clinical trial information: NCT03401385.

Efficacy and safety of suvratoxumab for prevention of Staphylococcus aureus ventilator-associated pneumonia (SAATELLITE): a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial

Staphylococcus aureus remains a common cause of ventilator-associated pneumonia, with little change in incidence over the past 15 years. We aimed to evaluate the efficacy of suvratoxumab, a monoclonal antibody targeting the α toxin, in reducing the incidence of S aureus pneumonia in patients in the intensive care unit (ICU) who are on mechanical ventilation. We did a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial at 31 hospitals in Belgium, the Czech Republic, France, Germany, Greece, Hungary, Portugal, Spain, and Switzerland. Eligible patients were in the ICU, aged ≥18 years, were intubated and on mechanical ventilation, were positive for S aureus colonisation of the lower respiratory tract, as assessed by quantitative PCR (qPCR) analysis of endotracheal aspirate, and had not been diagnosed with new-onset pneumonia. Patients were excluded if they had confirmed or suspected acute ongoing staphylococcal disease; had received antibiotics for S aureus infection for more than 48 h within 72 h of randomisation; had a Clinical Pulmonary Infection Score of 6 or higher; had an acute physiology and chronic health evaluation II score of 25 or higher with a Glasgow coma scale (GCS) score of more than 5, or an acute physiology and chronic health evaluation II score of at least 30 with a GCS score of 5 or less; had a Sequential Organ Failure Assessment score of 9 or higher; or had active pulmonary disease that would impair the ability to diagnose pneumonia. Colonised patients were randomly assigned (1:1:1), by use of an interactive voice or web response system, to receive either a single intravenous infusion of suvratoxumab 2000 mg, suvratoxumab 5000 mg, or placebo. Randomisation was done in blocks of size four, stratified by country and by whether patients had received systemic antibiotics for S aureus infection. Patients, investigators, and study staff involved in the treatment or clinical evaluation of patients were masked to patient assignment. The primary efficacy endpoint was the incidence of S aureus pneumonia at 30 days, as determined by a masked independent endpoint adjudication committee, in all patients who received their assigned treatment (modified intention-to-treat [ITT] population). Primary safety endpoints were the incidence of treatment-emergent adverse events at 30 days, 90 days, and 190 days after treatment, and the incidence of treatment-emergent serious adverse events, adverse events of special interest, and new-onset chronic disease at 190 days after treatment. All primary safety endpoints were assessed in the modified ITT population. This trial is registered with ClinicalTrials.gov (NCT02296320) and the EudraCT database (2014-001097-34). Between Oct 10, 2014, and April 1, 2018, 767 patients were screened, of whom 213 patients with confirmed S aureus colonisation of the lower respiratory tract were randomly assigned to the suvratoxumab 2000 mg group (n=15), the suvratoxumab 5000 mg group (n=96), or the placebo group (n=102). Two patients in the placebo group did not receive treatment after randomisation because their clinical conditions changed and they no longer met the eligibility criteria for dosing. As adjudicated by the data monitoring committee at an interim analysis, the suvratoxumab 2000 mg group was discontinued on the basis of predefined pharmacokinetic criteria. At 30 days after treatment, 17 (18%) of 96 patients in the suvratoxumab 5000 mg group and 26 (26%) of 100 patients in the placebo group had developed S aureus pneumonia (relative risk reduction 31·9% [90% CI -7·5 to 56·8], p=0·17). The incidence of treatment-emergent adverse events at 30 days were similar between the suvratoxumab 5000 mg group (87 [91%]) and the placebo group (90 [90%]). The incidence of treatment-emergent serious adverse events at 30 days were also similar between the suvratoxumab 5000 mg group (36 [38%]) and the placebo group (32 [32%]). No significant difference in the incidence of treatment-emergent adverse events between the two groups at 90 days (89 [93%] in the suvratoxumab 5000 mg group vs 92 [92%] in the placebo group) and at 190 days (93 [94%] vs 93 [93%]) was observed. 40 (40%) patients in the placebo group and 50 (52%) in the suvratoxumab 5000 mg group had a serious adverse event at 190 days. In the suvratoxumab 5000 mg group, one (1%) patient reported at least one treatment-emergent serious adverse event related to treatment, two (2%) patients reported an adverse event of special interest, and two (2%) reported a new-onset chronic disease. In patients in the ICU receiving mechanical ventilation with qPCR-confirmed S aureus colonisation of the lower respiratory tract, the incidence of S aureus pneumonia at 30 days was not significantly lower following treatment with 5000 mg suvratoxumab than with placebo. Despite these negative results, monoclonal antibodies still represent one promising therapeutic option to reduce antibiotic consumption that require further exploration and studies. AstraZeneca, with support from the Innovative Medicines Initiative Joint Undertaking.

Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Nonmelanoma Skin Cancer Rates From the Ulcerative Colitis Clinical Program.

BackgroundTofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program.MethodsNonmelanoma skin cancer events were evaluated from 3 randomized, placebo-controlled studies: 2 identical, 8-week induction studies (NCT01465763, NCT01458951), a 52-week maintenance study (NCT01458574), and an open-label, long-term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis.ResultsNonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient-years of tofacitinib exposure; ≤6.8 years’ treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10-year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors.ConclusionsFor patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.

Causes of Cardiovascular Hospitalization and Death in Patients With Transthyretin Amyloid Cardiomyopathy (from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT

In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis aimed to assess the causes of CV-related death and hospitalization in ATTR-ACT to provide further insight into the progression of ATTR-CM and efficacy of tafamidis. ATTR-ACT was an international, double-blind, placebo-controlled, and randomized study. Patients with hereditary or wild-type ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. The independent Endpoint Adjudication Committee determined whether certain investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. Cause-specific reasons for CV-related deaths (heart failure [HF], arrhythmia, myocardial infarction, sudden death, stroke, and other CV causes) and hospitalizations (HF, arrhythmia, myocardial infarction, transient ischemic attack/stroke, and other CV causes) were assessed. Total CV-related deaths was 53 (20.1%) with tafamidis and 50 (28.2%) with placebo, with HF (15.5% tafamidis, 22.6% placebo), followed by sudden death (2.7% tafamidis, 5.1% placebo), the most common causes. The number of patients with a CV-related hospitalization was 138 (52.3%) with tafamidis and 107 (60.5%) with placebo; with HF the most common cause (43.2% tafamidis, 50.3% placebo). All predefined causes of CV-related death or hospitalization were less frequent with tafamidis than placebo. In conclusion, these data provide further insight into CV disease progression in patients with ATTR-CM, with HF the most common adjudicated cause of CV-related hospitalization or death in ATTR-ACT. Clinical trial registration ClinicalTrials.gov: NCT01994889.

Abstract P3: Andexanet Alfa for Acute Bleeding During Treatment With Edoxaban

Introduction: We previously reported results of a prospective cohort study evaluating andexanet alfa (andexanet) for anticoagulation reversal in patients with acute bleeding on a factor Xa inhibitor. Study enrollment continued to accumulate additional data on patients on edoxaban, which are presented here. Methods: Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a 400 or 800 mg bolus and a 480 or 960 mg 2-hour follow-on infusion of andexanet, depending on edoxaban dosage and time of last dose. The co-primary efficacy outcomes were change in anti-factor Xa activity and the rate of excellent or good hemostasis, 12 hours after andexanet treatment, as determined by an independent adjudication committee. Efficacy was analyzed in patients with confirmed major bleeding and baseline anti-factor Xa activity ≥75 ng/mL. Safety was analyzed in all patients. Results: A total of 36 patients (mean age 82 years, 61.1% male and 91.7% with atrial fibrillation) with acute major bleeding on edoxaban received andexanet. The primary site of bleeding was intracranial in 29 (80.6%) patients. In the efficacy population (n=20), median anti-factor Xa activity decreased from 160.5 (interquartile range [IQR] 106.2-222.2) ng/mL at baseline to 50.9 (IQR 19.9-119.4) ng/mL at the end of bolus (median decrease 69.2%, 95% confidence interval [CI] 25.5-80.2%). Excellent or good hemostasis at 12 hours was achieved in 75.0% (95% CI 50.9-91.3%) of patients overall and in 81.3% (95% CI 54.4-96.0%) of those with intracranial hemorrhage (ICH). Within 30 days, a total of 4 (11.1%) patients experienced at least one thrombotic event and 4 (11.1%) others died. Conclusions: In patients with acute bleeding on edoxaban, andexanet significantly decreased anti-factor Xa activity. Excellent or good hemostasis at 12 hours was observed in 75.0% of patients overall and 81.3% of those with ICH. Thrombotic events occurred at a rate expected in such patients.

Cervical ripening in prolonged pregnancies by silicone double balloon catheter versus vaginal dinoprostone slow release system: The MAGPOP randomised controlled trial.

Prolonged pregnancies are a frequent indication for induction of labour. When the cervix is unfavourable, cervical ripening before oxytocin administration is recommended to increase the likelihood of vaginal delivery, but no particular method is currently recommended for cervical ripening of prolonged pregnancies. This trial evaluates whether the use of mechanical cervical ripening with a silicone double balloon catheter for induction of labour in prolonged pregnancies reduces the cesarean section rate for nonreassuring fetal status compared with pharmacological cervical ripening by a vaginal pessary for the slow release of dinoprostone (prostaglandin E2). This is a multicentre, superiority, open-label, parallel-group, randomised controlled trial conducted in 15 French maternity units. Women with singleton pregnancies, a vertex presentation, ≥41+0 and ≤42+0 weeks' gestation, a Bishop score <6, intact membranes, and no history of cesarean delivery for whom induction of labour was decided were randomised to either mechanical cervical ripening with a Cook Cervical Ripening Balloon or pharmacological cervical ripening by a Propess vaginal pessary serving as a prostaglandin E2 slow-release system. The primary outcome was the rate of cesarean for nonreassuring fetal status, with an independent endpoint adjudication committee determining whether the fetal heart rate was nonreassuring. Secondary outcomes included delivery (time from cervical ripening to delivery, number of patients requiring analgesics), maternal and neonatal outcomes. Between January 2017 and December 2018, 1,220 women were randomised in a 1:1 ratio, 610 allocated to a silicone double balloon catheter, and 610 to the Propess vaginal pessary for the slow release of dinoprostone. The mean age of women was 31 years old, and 80% of them were of white ethnicity. The cesarean rates for nonreassuring fetal status were 5.8% (35/607) in the mechanical ripening group and 5.3% (32/609) in the pharmacological ripening group (proportion difference: 0.5%; 95% confidence interval (CI) -2.1% to 3.1%, p = 0.70). Time from cervical ripening to delivery was shorter in the pharmacological ripening group (23 hours versus 32 hours, median difference 6.5 95% CI 5.0 to 7.9, p < 0.001), and fewer women required analgesics in the mechanical ripening group (27.5% versus 35.4%, difference in proportion -7.9%, 95% CI -13.2% to -2.7%, p = 0.003). There were no statistically significant differences between the 2 groups for other delivery, maternal, and neonatal outcomes. A limitation was a low observed rate of cesarean section. In this study, we observed no difference in the rates of cesarean deliveries for nonreassuring fetal status between mechanical ripening with a silicone double balloon catheter and pharmacological cervical ripening with a pessary for the slow release of dinoprostone. ClinicalTrials.gov NCT02907060.

Efficacy and Safety of Human Fibrinogen Concentrate for the Treatment of Patients with Congenital Fibrinogen Deficiency: Combined Results of the FORMA-02 and FORMA-04 Clinical Trials

Introduction: Congenital fibrinogen deficiency (CFD) is a rare disorder which results from a complete lack (afibrinogenemia) or low levels (hypofibrinogenemia) of functional fibrinogen. Treatment with human fibrinogen concentrate (HFC) can treat bleeding episodes and prevent blood loss in surgical treatment in patients with CFD. Herein we report combined data from two clinical studies on the efficacy and safety of HFC for the treatment of bleeding episodes (BEs) and surgical prophylaxis in adult, adolescent and pediatric patients. Methods: Both FORMA-02 and FORMA-04 were multinational, multicenter, prospective, open-label, uncontrolled Phase 3 studies for the use of HFC in adult and pediatric patients with CFD. They reported the hemostatic efficacy and safety of human fibrinogen concentrate (HFC: Fibryga® Octapharma) for on-demand treatment of BEs and surgical prophylaxis using objective criteria. Efficacy was assessed by the trial investigators and adjudicated by an independent data monitoring and end-point adjudication committee (IDMEAC). All adverse events (AEs) and serious AEs were recorded. Results: The two studies included a total of 39 patients who received HFC. The median (range) age across both studies was 17 (1-54) years, with 14 pediatric (aged 0-11), 6 adolescent (aged 12-18) and 19 adult patients (aged &amp;gt;18). Treatment of Bleeding Events 32 patients received HFC for the treatment of 99 bleeding events (BEs), 97 minor and 4 major. Of these, 72 were spontaneous, and 27 were due to trauma. 10 BEs occurred in pediatric patients (8 minor, 2 major), and 89 in adult/adolescents (87 minor, 2 major). The mean (±SD) total dose per BE was 65.51 mg/kg (±26.47) for adult/adolescent patients (ages 12-54) and 93.78 (±64.60) for pediatric patients (ages 0-11). Investigator-assessed and IDMEAC rated hemostatic efficacy are shown in Table 1. Overall hemostatic efficacy was rated as success (rating of excellent or good) for 99.0% of BEs by the IDMEAC. Treatment efficacy results were comparable when analyzed by age subgroup of adult (≥18 years), adolescent (&amp;gt;12-&amp;lt;18 years) and in two groups of pediatric patients (&amp;lt;6 years and 6-12 years). Surgical prophylaxis A total of 12 patients received HFC across 15 surgeries (13 minor and 2 major), 3 in pediatric patients (major: splenectomy; minor: circumcision and pulpectomy), and 12 in adults/adolescents (major: eye enucleation with socket reconstruction; minor: knee radioisotope synovectomy [n=2], dental extraction [n=3], circumcision [n=2], excision of circumcision scar bud, root canal operation, skin biopsy, and debridement of superficial necrosis). Mean (±SD) loading dose administered prior to surgery was 77.39 (±20.22) in adult/adolescent patients and 78.50 mg/kg (±27.96) for pediatric patients. Seven surgeries required multiple infusions, with the two major surgeries requiring 5 and 7 maintenance infusions, and the five minor surgeries requiring median (range) 3 (1-4) maintenance infusions. Intra- and post-operative hemostatic efficacy for all surgeries is shown in Table 1. Overall hemostatic efficacy of all the procedures was rated 100% successful by both the investigator and IDMEAC assessment. Safety A total of 101 AEs occurred in 23 patients (59.0%), including 16 serious AEs in 6 patients. Of these, 5 AEs in 4 patients were considered to be possibly related to treatment. These included a mild skin reaction (itchiness and redness), ischemia due to digital microthrombi, peripheral phlebitis of the upper limbs, and a portal vein thrombosis following splenectomy. No allergic/hypersensitivity reactions or deaths were observed during either of the studies. Conclusions: HFC treatment was shown to be efficacious for on-demand treatment of BEs and perioperative prophylaxis in this rare CFD population, across two Phase 3 clinical trials. Efficacy was comparable for adult, adolescent and pediatric patients. A favorable safety profile was seen for the treatment of patients with congenital afibrinogenemia with HFC. Disclosures Djambas Khayat: Octapharma: Research Funding. Kruzhkova:Octapharma: Current Employment. Solomon:Octapharma: Current Employment. Schwartz:Octapharma: Current Employment. Peyvandi:Octapharma: Research Funding. OffLabel Disclosure: On label use: Fibryga for treatment of bleeding episodes Off label use: Use of Fibryga as surgical prophylaxis in the US

Diagnostic accuracy of the magnetocardiograph for patients with suspected acute coronary syndrome

BackgroundWe aimed to estimate the diagnostic accuracy of the VitalScan magnetocardiograph (MCG) for suspected acute coronary syndrome (ACS).MethodsWe undertook a prospective cohort study evaluating the diagnostic accuracy of the MCG...

S0703 Tofacitinib for the Treatment of Ulcerative Colitis: Up to 6.8 Years of Safety Data From Global Clinical Trials

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Efficacy and safety of tofacitinib were evaluated in randomized, placebo-controlled Phase (P)2 (NCT00787202) and P3 (NCT01465763; NCT01458951; NCT01458574) studies, and in an ongoing, open-label, long-term extension (OLE) study (NCT01470612) (1–3). We report updated tofacitinib safety analyses from the tofacitinib UC clinical program, with exposure up to 6.8 years. METHODS: Two cohorts were analyzed: P3 Maintenance (N = 592; patients [pts] receiving placebo, tofacitinib 5 or 10 mg twice daily [BID]) and Overall (N = 1,157; pts receiving tofacitinib 5 or 10 mg BID in P2/P3/OLE studies; data as of May 2019, database not locked). Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) were evaluated for adverse events (AEs) of special interest. Opportunistic infections (OIs), malignancies, major adverse cardiovascular events (MACE), and gastrointestinal (GI) perforations were reviewed by independent adjudication committees. RESULTS: Demographics, clinical characteristics, and safety data are shown in the table. In the Overall Cohort, 1,157 pts received ≥ 1 dose of tofacitinib 5 or 10 mg BID; most pts (N = 959, 83%) received an average dose of 10 mg BID. Median treatment duration was 623 (range 1–2,494) days (2,581.3 PY of exposure). IRs (95% confidence interval) for AEs of special interest were: deaths, 0.19 (0.06, 0.44); serious infections, 1.70 (1.24, 2.27); herpes zoster (non-serious and serious), 3.48 (2.79, 4.30); OIs, 1.07 (0.71, 1.55); malignancies (excl. non-melanoma skin cancer [NMSC]), 0.75 (0.46, 1.16); NMSC, 0.73 (0.44, 1.13); MACE, 0.26 (0.11, 0.54); deep vein thrombosis, 0.04 (0.00, 0.21); pulmonary embolism, 0.15 (0.04, 0.38); GI perforations, 0.11 (0.02, 0.33). Results in the Overall Cohort as per the previous Nov 2017 data cut are presented for context (4). CONCLUSION: The safety profile of tofacitinib in pts with UC was manageable and consistent with that of other UC therapies incl. biologics. Overall, IRs for AEs of interest have generally remained stable in the tofacitinib UC clinical program over an extended period of time (up to 6.8 years).Table 1

S0787 An Update on the Analysis of Non-Melanoma Skin Cancer in the Tofacitinib Ulcerative Colitis Clinical Program as of May 2019

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. We present an updated [1] analysis of non-melanoma skin cancer (NMSC) events in the tofacitinib UC clinical program as of May 2019. METHODS: NMSC events were evaluated from 3 randomized, placebo-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951] and 1 maintenance P3 study [NCT01458574]) and an ongoing, open-label, long-term extension (OLE) study (NCT01470612). Three cohorts were analyzed: Induction (P3 induction studies), Maintenance (P3 maintenance study), and Overall (patients [pts] receiving tofacitinib 5 or 10 mg twice daily [BID] in P3 or OLE studies). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose < 15 mg or ≥ 15 mg, respectively (82.4% of pts assigned PD 10 mg BID). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) were evaluated for NMSC. A Cox proportional hazards model was used for risk factor analysis. RESULTS: 1,124 pts were evaluated for NMSC (2,576.4 PY of tofacitinib exposure; ≤ 6.8 years of treatment). NMSC events in the Induction and Maintenance Cohorts were previously reported (Table) [1]. NMSC occurred in 19 Overall Cohort pts (IR 0.73 [95% confidence interval (CI) 0.44, 1.13]; PD tofacitinib 5 mg BID, n = 3, IR 0.45 [0.09, 1.30]; PD tofacitinib 10 mg BID, n = 16, IR 0.82 [0.47, 1.34]) (Table); no new cases since Sep 2018 [1]. No NMSC was metastatic or led to discontinuation. Prior NMSC (hazard ratio [HR] 9.09 [95% CI 2.98, 27.73]), prior tumor necrosis factor inhibitor (TNFi) failure (HR 3.32 [1.08, 10.20]), and age (per 10-year increase, HR 2.03 [1.37, 3.02]) were significant risk factors for NMSC. CONCLUSION: NMSC events were infrequent with tofacitinib treatment and more likely to occur in pts with prior NMSC, prior TNFi failure, and with increasing age – known NMSC risk factors [2]. Dose dependency of NMSC IR could not be concluded here, as dose changes were permitted. NMSC IRs were similar to those previously reported in the tofacitinib UC clinical program [1] and in pts with UC treated with biologics [3].Table 1

Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial

BackgroundThe efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19.MethodsWe did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278.Findings447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94–1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups.InterpretationIn patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19.FundingCOALITION COVID-19 Brazil and EMS.

Low rate of adverse events in a randomized controlled trial addressing the surgical treatment of femoroacetabular impingement (FAI) syndrome.

The femoroacetabular impingement randomised controlled trial (FIRST) is a multi-center randomized controlled trial (RCT), comparing arthroscopic osteochondroplasty with arthroscopic lavage in adults aged 18-50years diagnosed with non-arthritic femoroacetabular impingement (FAI) syndrome. The purpose of the present study is to report the prevalence, distribution and severity of adverse events during and within 24-month follow-up period. Of the 220 patients included, 6 were adjudicated as ineligible, for a total of 214 patients included in the final analysis. An independent Adjudication Committee evaluated operatively treated and non-operatively treated adverse events that were related to the hip. Adverse events were also reported directly by each participating clinical site. Continuous variables were reported as mean and standard deviation, categorical variables were reported as counts and percentages. There were a total of 52 (24.2%, 52/214) adverse events in 46 (21.5%) patients (mean age 34.2 ± 7.9years, 58.7% male) during the 24-month follow-up. There were 12.6% (27/214) operatively treated adverse events for: hip pain, re-injury of labrum and heterotopic ossification. There were 11.7% (25/214) non-operatively treated adverse events for predominantly: hip pain, hip tendinopathy and hip popping/snapping. Approximately, 87% of adverse events resolved within the 24-month follow-up time. Given the inherent challenges with conducting RCTs, the results of this adverse event study from the FIRST trial demonstrate that it is safe to perform an RCT addressing FAI syndrome. Level III.

CML-089: Retrospective Independent Review of Arterial Occlusive Events (AOEs) in the Ponatinib Phase 2 PACE Trial (NCT01207440) in Patients with Philadelphia Chromosome Positive (Ph+) Leukemia

Objectives In the PACE trial 5-year analysis evaluating use of ponatinib in patients with refractory chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia, a 25% incidence of AOEs was identified (Cortes, Blood 2018) using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs). We performed a retrospective review using a charter-based independent Adjudication Committee (AC) to better understand clinically relevant AOE rates in PACE. Methods The AC (3 cardiologists, 1 hematologist, and 1 neurologist) evaluated AOEs (identified using >500 terms) in PACE using established definitions developed by the American College of Cardiology/American Heart Association (ACC/AHA), US Food and Drug Administration (FDA), and Standardized Data Collection for Cardiovascular Trials Initiative (SCTI). The AC also reviewed patient profiles including event, severity, concomitant medication, and hospitalization data. These adjudicated results were compared with pre-adjudication MedDRA PT search results. The AC was blind to dose, dose modification, and investigator causality opinion. Events not associated with a cardiovascular etiology or that failed to meet the ACC/AHA, FDA, and SCTI definitions were determined by the AC not to be AOEs. Results This review included all 449 heavily pretreated patients with Ph+ leukemia enrolled in PACE (median age, 59 y; 47% female; 93% ≥2 tyrosine kinase inhibitors). At a median follow-up of 37.3 months, adjudicated AOEs occurred in 17.4% of the overall patient population compared with 24.7% pre-adjudication. The majority of the pre-adjudication serious AOEs were adjudicated as serious AOEs (20% pre-adjudication vs 16% adjudicated). The most common adjudicated AOE (>2%) was peripheral arterial occlusive disease. Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Analyses by baseline risk factors demonstrated that patients with the following baseline risk factors had higher incidence rates of adjudicated AOEs than those without ischemic cardiac disease, hypertension, hypercholesterolemia, and diabetes. Conclusions Independent AC review of the PACE trial identified a lower rate of clinically relevant AOEs than previously reported, suggesting an earlier possible overestimation that may not accurately reflect the risk of AOEs with ponatinib. The ongoing ponatinib dose-ranging OPTIC study will further evaluate dose-dependent AOE incidence rates.

Biomarkers and antithrombotic treatment in cervical artery dissection - Design of the TREAT-CAD randomised trial.

The type of antithrombotic treatment in cervical artery dissection patients is still a matter of debate. Most physicians prefer anticoagulants over antiplatelet agents for stroke prevention. However, this approach is not evidence-based and antiplatelets might be as safe and as effective. The 'Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection' ('TREAT-CAD') trial (clinicaltrials.gov: NCT02046460) compares Aspirin to oral anticoagulants (vitamin K antagonists) with regard to efficacy and safety by using both clinical and imaging surrogate outcome measures. TREAT-CAD tests the hypothesis, that aspirin is as safe and effective as vitamin K antagonists. TREAD-CAD is a Prospective, Randomised controlled, Open-labelled, multicentre, non-inferiority trial with Blinded assessment of outcome Events (PROBE-design). Key eligibility criteria are (i) clinical symptoms attributable to cervical artery dissection and (ii) verification of the cervical artery dissection diagnosis by established magnetic resonance imaging criteria. Patients are randomised to receive either Aspirin 300 mg daily or vitamin K antagonists for 90 days. Primary outcomes are assessed at 14 ± 10 days (magnetic resonance imaging and clinical examination) and at 90 ± 30 days (clinical examinations). The primary endpoint is a composite outcome measure - labelled Cerebrovascular Ischemia, major Hemorrhagic events or Death (CIHD) - and includes (i) occurrence of any stroke (including retinal infarction), (ii) new ischaemic lesions on diffusion-weighted magnetic resonance imaging, (iii) any major extracranial haemorrhage, (iv) any symptomatic intracranial haemorrhage, (v) any new haemorrhagic lesion visible on paramagnetic-susceptible sequences and (vi) death. After database closure, (i) central verification of cervical artery dissection diagnosis will be done by two experienced raters, (ii) adjudication of outcome events will be performed by independent adjudication committees, separately for clinical and imaging outcomes. The primary analysis will be done on the per protocol data set. The targeted sample size consists of 169 evaluable patients in the per protocol data set. TREAT-CAD is testing the non-inferiority of Aspirin versus vitamin K antagonists treatment in patients with symptomatic cervical artery dissection by combined clinical and magnetic resonance imaging outcomes.

An independent review of arterial occlusive events (AOEs) in the ponatinib (PON) phase II PACE trial (NCT01207440) in patients (pts) with Ph+ leukemia.

7550 Background: The final 5-year analysis of the PACE trial, which evaluated use of PON in pts with refractory chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia, identified a 25% incidence of AOEs (Cortes, Blood 2018) from a search utilizing &gt; 400 preferred terms (PTs) defined by MedDRA and related to vascular ischemia or thrombosis. We performed a retrospective review using an independent Endpoint Adjudication Committee (EAC) to better understand clinically relevant AOE rates in PACE. Methods: The EAC consisted of 3 cardiologists, 1 hematologist, and 1 neurologist to review AOEs (identified using &gt; 500 terms) in PACE using American College of Cardiology/American Heart Association (ACC/AHA) definitions for major adverse cardiovascular events (MACE), and to review pt profiles including event, severity, concomitant medication, and hospitalization data. These results were compared with MedDRA PT search results. The EAC was blind to dose, dose modification, and investigator causality opinion. Results: The PACE review included 449 heavily pretreated pts with Ph+ leukemia (median age, 59 y; 47% female; 93% ≥2 tyrosine kinase inhibitors). With median follow-up 37.3 mo in all pts, AOEs were identified by MedDRA PT search in 25% of pts and EAC-verified in 17% (Table). In each category listed in the table, the EAC verification identified fewer AOEs and serious AOEs. Serious AOEs were identified by MedDRA PT search in 20% of pts and EAC-verified in 16%. Events that were not associated with a cardiovascular etiology or failed to meet the MACE definition set forth by the ACC/AHA were determined by the EAC not to be an AOE. Conclusions: The independent EAC review showed a lower rate of clinically relevant AOEs than was reported in PACE, suggesting an earlier possible overestimation that may not accurately reflect the risk of AOEs with PON. The ongoing PON dose-ranging OPTIC study will further evaluate the PON risk:benefit profile. Clinical trial information: NCT01207440 . [Table: see text]

Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adjudication Committee

BackgroundTo derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC).MethodsThe SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI.ResultsA total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI.ConclusionsWe found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies.Trial registrationClinicaltrials.gov NCT 01399281; ENCePP seal: awarded on 25 November 2011.