Value-based comparison of ambulatory children with respiratory diseases in an emergency department and a walk-in clinic: a retrospective cohort study in Québec, Canada.

OBJECTIVE: To compare health outcomes and costs given in the emergency department (ED) and walk-in clinics for ambulatory children presenting with acute respiratory diseases. DESIGN: A retrospective cohort study. SETTING: This study was conducted from April 2016 to March 2017 in one ED and one walk-in clinic. The ED is a paediatric tertiary care centre, and the clinic has access to lab tests and X-rays. PARTICIPANTS: Inclusion criteria were children: (1) aged from 2 to 17 years old and (2) discharged home with a diagnosis of upper respiratory tract infection (URTI), pneumonia or acute asthma. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of patients returning to any ED or clinic within 3 and 7 days of the index visit. The secondary outcome measures were the mean cost of care estimated using time-driven activity-based costing and the incidence of antibiotic prescription for URTI patients. RESULTS: We included 532 children seen in the ED and 201 seen in the walk-in clinic. The incidence of return visits at 3 and 7 days was 20.7% and 27.3% in the ED vs 6.5% and 11.4% in the clinic (adjusted relative risk at 3 days (aRR) (95% CI) 3.17 (1.77 to 5.66) and aRR at 7 days 2.24 (1.46 to 3.44)). The mean cost (95% CI) of care (CAD) at the index visit was $C96.68 (92.62 to 100.74) in the ED vs $C48.82 (45.47 to 52.16) in the clinic (mean difference (95% CI): 46.15 (41.29 to 51.02)). Antibiotic prescription for URTI was less common in the ED than in the clinic (1.5% vs 16.4%; aRR 0.10 (95% CI 0.03 to 0.32)). CONCLUSIONS: The incidence of return visits and cost of care were significantly higher in the ED, while antibiotic use for URTI was more frequent in the walk-in clinic. These data may help determine which setting offers the highest value to ambulatory children with acute respiratory conditions.

Randomized phase III trial of metabolic imaging-guided dose escalation of radio-chemotherapy in patients with newly diagnosed glioblastoma (SPECTRO GLIO trial).

BACKGROUND: Glioblastoma (GBM) systematically recurs after a standard 60 Gy radio-chemotherapy regimen. Since magnetic resonance spectroscopic imaging (MRSI) has been shown to predict the site of relapse, we analyzed the effect of MRSI-guided dose escalation on overall survival (OS) of patients with newly diagnosed GBM. METHODS: In this multicentric prospective phase III trial, patients who had undergone biopsy or surgery for a GBM were randomly assigned to a standard dose (SD) of 60 Gy or a high dose (HD) of 60 Gy with an additional simultaneous integrated boost totaling 72 Gy to MRSI metabolic abnormalities, the tumor bed and residual contrast enhancements. Temozolomide was administered concomitantly and maintained for 6 months thereafter. RESULTS: One hundred and eighty patients were included in the study between March 2011 and March 2018. After a median follow-up of 43.9 months (95% CI [42.5; 45.5]), median OS was 22.6 months (95% CI [18.9; 25.4]) versus 22.2 months (95% CI [18.3; 27.8]) for HD, and median progression-free survival was 8.6 (95% CI [6.8; 10.8]) versus 7.8 months (95% CI [6.3; 8.6]), in SD versus HD, respectively. No increase in toxicity rate was observed in the study arm. The pseudoprogression rate was similar across the SD (14.4%) and HD (16.7%) groups. For O(6)-methylguanine-DNA methyltransferase (MGMT) methylated patients, the median OS was 38 months (95% CI [23.2; NR]) for HD patients versus 28.5 months (95% CI [21.1; 35.7]) for SD patients. CONCLUSION: The additional MRSI-guided irradiation dose totaling 72 Gy was well tolerated but did not improve OS in newly diagnosed GBM. TRIAL REGISTRATION: NCT01507506; registration date: December 20, 2011. https://clinicaltrials.gov/ct2/show/NCT01507506?cond=NCT01507506&rank=1.

Quality of reporting of adverse events in clinical trials of covid-19 drugs: systematic review.

Objective: To assess the quality of reporting of adverse events in clinical trials of covid-19 drugs based on the CONSORT (Consolidated Standards of Reporting Trials) harms extension and according to clinical trial design, and to examine reporting of serious adverse events in drug trials published on PubMed versus clinical trial summaries on ClinicalTrials.gov. Design: Systematic review. Data sources: PubMed and ClinicalTrials.gov registries were searched from 1 December 2019 to 17 February 2022. Eligibility criteria for selecting studies: Randomised clinical trials evaluating the efficacy and safety of drugs used to treat covid-19 disease in participants of all ages with suspected, probable, or confirmed SARS-CoV-2 infection were included. Clinical trials were screened on title, abstract, and text by two authors independently. Only articles published in French and English were selected. The Cochrane risk of bias tool for randomised trials (RoB 2) was used to assess risk of bias. Results: The search strategy identified 1962 randomised clinical trials assessing the efficacy and safety of drugs used to treat covid-19, published in the PubMed database; 1906 articles were excluded after screening and 56 clinical trials were included in the review. Among the 56 clinical trials, no study had a high score for quality of reporting of adverse events, 60.7% had a moderate score, 33.9% had a low score, and 5.4% had a very low score. All clinical trials with a very low score for quality of reporting of adverse events were randomised open label trials. For reporting of serious adverse events, journal articles published on PubMed under-reported 51% of serious adverse events compared with clinical trial summaries published on ClinicalTrials.gov. Conclusions: In one in three published clinical trials on covid-19 drugs, the quality of reporting of adverse events was low or very low. Differences were found in the number of serious adverse events reported in journal articles versus clinical trial summaries. During the covid-19 pandemic, risk assessment of drugs in clinical trials of covid-19 drugs did not comply with good practice recommendations for publication of results. Systematic review registration: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) EUPAS45959.

Hypofractionated Stereotactic Re-irradiation and Anti-PDL1 Durvalumab Combination in Recurrent Glioblastoma: STERIMGLI Phase I Results.

BACKGROUND: Hypofractionated stereotactic radiotherapy (hFSRT) is a salvage option for recurrent glioblastoma (GB) which may synergize anti-PDL1 treatment. This phase I study evaluated the safety and the recommended phase II dose of anti-PDL1 durvalumab combined with hFSRT in patients with recurrent GB. METHODS: Patients were treated with 24 Gy, 8 Gy per fraction on days 1, 3, and 5 combined with the first 1500 mg Durvalumab dose on day 5, followed by infusions q4weeks until progression or for a maximum of 12 months. A standard 3 + 3 Durvalumab dose de-escalation design was used. Longitudinal lymphocytes count, cytokines analyses on plasma samples, and magnetic resonance imaging (MRI) were collected. RESULTS: Six patients were included. One dose limiting toxicity, an immune-related grade 3 vestibular neuritis related to Durvalumab, was reported. Median progression-free interval (PFI) and overall survival (OS) were 2.3 and 16.7 months, respectively. Multi-modal deep learning-based analysis including MRI, cytokines, and lymphocytes/neutrophil ratio isolated the patients presenting pseudoprogression, the longest PFI and those with the longest OS, but statistical significance cannot be established considering phase I data only. CONCLUSION: Combination of hFSRT and Durvalumab in recurrent GB was well tolerated in this phase I study. These encouraging results led to an ongoing randomized phase II. (ClinicalTrials.gov Identifier: NCT02866747).

A value-based comparison of the management of respiratory diseases in walk-in clinics and emergency departments.

OBJECTIVES: Our aim was to compare some of the health outcomes and costs associated with value of care in emergency departments (ED) and walk-in clinics for ambulatory patients presenting with an acute respiratory disease. METHODS: A health records review was conducted from April 2016 through March 2017 in one ED and one walk-in clinic. Inclusion criteria were: (i) ambulatory patients at least 18 years old, (ii) discharged home with a diagnosis of upper respiratory tract infection (URTI), pneumonia, acute asthma, or acute exacerbation of chronic obstructive pulmonary disease. Primary outcome was the proportion of patients returning to any ED or walk-in clinic within three and seven days of the index visit. Secondary outcomes were the mean cost of care and the incidence of antibiotic prescription for URTI patients. The cost of care was estimated from the Ministry of Health's perspectives using time-driven activity-based costing. RESULTS: The ED group included 170 patients and the walk-in clinic group 326 patients. The return visit incidences at three and seven days were, respectively, 25.9% and 38.2% in the ED vs. 4.9% and 14.7% in the walk-in clinic (adjusted relative risk (arr) of 4.7 (95% CI 2.6-8.6) and 2.7 (1.9-3.9)). The mean cost ($Cdn) of the index visit care was 116.0 (106.3-125.7) in the ED vs. 62.5 (57.7-67.3) in the walk-in clinic (mean difference of 56.4 (45.7-67.1)). Antibiotic prescription for URTI was 5.6% in the ED vs. 24.7% in the walk-in clinic (arr 0.2, 0.01-0.6). CONCLUSIONS: This study is the first in a larger research program to compare the value of care between walk-in clinics and the ED. The potential advantages of walk-in clinics over EDs (lower costs, lower incidence of return visits) for ambulatory patients with respiratory diseases should be considered in healthcare planning.

RéSUMé: OBJECTIFS: Notre objectif était de comparer certains des résultats sanitaires et des coûts associés à la valeur des soins dans les services d'urgence et les cliniques sans rendez-vous pour les patients ambulatoires souffrant d'une maladie respiratoire aiguë. MéTHODES: Une revue des dossiers médicaux a été réalisée d'avril 2016 à mars 2017 dans un service d'urgence et une clinique sans rendez-vous. Les critères d'inclusion étaient les suivants : (i) patients ambulatoires âgés d'au moins 18 ans, (ii) renvoyés chez eux avec un diagnostic d'infection des voies respiratoires supérieures (IVRS), de pneumonie, d'asthme aigu ou d'exacerbation aiguë de la maladie pulmonaire obstructive chronique. Le résultat primaire était la proportion de patients retournant à un service d'urgence ou à une clinique sans rendez-vous dans les trois et sept jours suivant la visite de référence. Les résultats secondaires étaient le coût moyen des soins et l'incidence de la prescription d'antibiotiques pour les patients atteints d'IVRS. Le coût des soins a été estimé à partir des perspectives du ministère de la santé, en utilisant la méthode de calcul des coûts par activité en fonction du temps. RéSULTATS: Le groupe des urgences comprenait 170 patients et le groupe des cliniques sans rendez-vous 326 patients. Les incidences des visites de retour à trois et sept jours étaient respectivement de 25,9 % et 38,2 % dans le service des urgences contre 4,9 % et 14,7 % à la clinique sans rendez-vous (risque relatif ajusté (arr) de 4,7 (IC à 95 % 2,6 à 8,6) et 2,7 (1,9-3,9)). Le coût moyen ($CAN) de la visite de référence était de 116,0 (106,3-125,7) aux urgences contre 62,5 (57,7-67,3) dans la clinique sans rendez-vous (différence moyenne de 56,4 (45,7-67,1)). La prescription d'antibiotiques pour l'IVRS était de 5,6 % aux urgences contre 24,7 % dans la clinique sans rendez-vous (arr 0,2, 0,01-0,6). CONCLUSIONS: Cette étude est la première d'un programme de recherche plus vaste visant à comparer la valeur des soins entre les cliniques sans rendez-vous et les urgences. Les avantages potentiels des cliniques sans rendez-vous par rapport aux services d'urgence (coûts moindres, incidence plus faible des visites de retour) pour les patients ambulatoires souffrant de maladies respiratoires devraient être pris en compte dans la planification des soins de santé.

Overview of literature monitoring practice of clinical trials vigilance units in French institutional sponsors - A study from the REVISE working group.

INTRODUCTION: The evaluation of clinical trial (CT) safety is the main task of CT vigilance units. In addition to the management of adverse events, the units must review the literature to identify information that may impact the benefit-risk assessment of studies. In this survey, we investigated the literature monitoring (LM) activity of French Institutional Vigilance Units (IVU) from the working group "REflexion sur la VIgilance et la SEcurite des essais cliniques" (REVISE). MATERIAL AND METHODS: We sent a questionnaire of 26 questions, divided into four themes, to the 60 IVU: (1) Presentation of the IVU and the LM activity; (2) Used sources, queries and criteria for selecting articles; (3) Valuation of the LM and (4) Practical organisation. RESULTS: Of the 27 IVU that responded to the questionnaire, 85% of them carried out LM. This was mainly provided by medical staff to improve general knowledge (83%), to detect Adverse Reactions (AR) not listed in the reference documents (70%) and to detect new safety information (61%). Due to lack of time, staff, available recommendations and sources, only 21% of IVU conducted LM for all CT. On average, units reported four sources: ANSM information (96%), PubMed database (83%), EMA alerts (57%) and the subscription to APM international (48%). The LM had an impact on the CT of 57% of the IVU such as changing the conditions of a study (39%) or suspending a study (22%). DISCUSSION/CONCLUSION: LM is an important but time-consuming activity with heterogeneous practices. According to the results of this survey, we proposed seven ways to improve this practice: (1) Target the highest risk CT; (2) Refine the PubMed queries; (3) Use other tools; (4) Create a decision flowchart for the selection of PubMed articles; (5) Improve training; (6) Value the activity and (7) Outsource the activity.

Adaptation of time-driven activity-based costing to the evaluation of the efficiency of ambulatory care provided in the emergency department.

Objectives: The aim of this study was: (1) to adapt the time-driven activity-based costing (TDABC) method to emergency department (ED) ambulatory care; (2) to estimate the cost of care associated with frequently encountered ambulatory conditions; and (3) to compare costs calculated using estimated time and objectively measured time. Methods: TDABC was applied to a retrospective cohort of patients with upper respiratory tract infections, urinary tract infections, unspecified abdominal pain, lower back pain and limb lacerations who visited an ED in Québec City (Canada) during fiscal year 2015-2016. The calculated cost of care was the product of the time required to complete each care procedure and the cost per minute of each human resource or equipment involved. Costing based on durations estimated by care professionals were compared to those based on objective measurements in the field. Results: Overall, 220 care episodes were included and 3080 time measurements of 75 different processes were collected. Differences between costs calculated using estimated and measured times were statistically significant for all conditions except lower back pain and ranged from $4.30 to $55.20 (US) per episode. Differences were larger for conditions requiring more advanced procedures, such as imaging or the attention of ED professionals. Conclusions: The greater the use of advanced procedures or the involvement of ED professionals in the care, the greater is the discrepancy between estimated-time-based and measured-time-based costing. TDABC should be applied using objective measurement of the time per procedure.

Arabin pessary to prevent adverse perinatal outcomes in twin pregnancies with a short cervix: a multicenter randomized controlled trial (PESSARONE).

BACKGROUND: The number of twin pregnancies continues to increase worldwide as both the number of pregnancies obtained by medically assisted reproduction and age at first pregnancy keep rising. Preterm delivery is the major complication associated with twin pregnancies. The effectiveness of preventive treatments such as progesterone or cervical cerclage for women with a short cervix is doubtful in twin pregnancies. The effectivity of cervical pessaries in preventing preterm birth and its associated morbidity and mortality is also controversial. OBJECTIVE: We sought to investigate if the Arabin pessary reduces adverse neonatal outcomes in twin pregnancies with a short cervix. STUDY DESIGN: This open-label, multicenter, randomized controlled trial on twin pregnancies with a cervical length of <35 mm compared pessary placement at 16+0 to 24+0 weeks' gestation with standard care alone. The primary endpoint was a composite of adverse neonatal outcomes, namely peripartum or neonatal death or significant neonatal morbidity before hospital discharge, defined as at least 1 of the following complications: bronchopulmonary dysplasia, intraventricular hemorrhage grade III to IV, periventricular leukomalacia, necrotizing enterocolitis grade II or higher, culture-proven sepsis, and retinopathy requiring treatment. A sample size of 308 pregnancies was planned to ensure 80% power to compare the proportions of women with at least 1 infant with an adverse neonatal outcome. The intention-to-treat analysis after multiple imputation of missing data, was supplemented with a secondary analysis that controlled for gestational age and cervical length, both at inclusion. The primary endpoint was also compared between randomization groups in the per-protocol population, which excluded patients with prespecified major protocol violations (mostly cervical cerclage and/or progesterone after inclusion). Secondary endpoints included preterm birth, spontaneous preterm birth, and pessary side effects. RESULTS: In total, 315 women were randomized to either receive a pessary (n=157) or standard management (n=158). Overall, 10.8% (34 women) of participants had a missing value for the primary endpoint, mostly (79%) because of the lack of paternal consent for neonatal data collection. In the intention-to-treat analysis, the adverse neonatal outcome occurred in 16.8% of the pessary group vs in 22.5% of the control group (risk ratio, 0.69; 95% confidence interval, 0.39-1.23; P=.210). The per-protocol analysis did not show any significant difference between groups (risk ratio, 0.78; 95% confidence interval, 0.47-1.28; P=.320). The occurrence of preterm birth or spontaneous preterm birth did not differ significantly between groups. No serious side effects were associated with pessary use. CONCLUSION: Pessary use in our study did not significantly reduce adverse neonatal outcomes in twin pregnancies with a short cervix.

Overview of clinical trials vigilance units in French institutional sponsors - A study from the REVISE working group.

PURPOSE: To follow the European Directive 2001/20/EC, institutional sponsors created or reinforced their vigilance units. Since 2007, the working group "REflexion sur la VIgilance et la Sécurité des Essais" (REVISE) rallies French institutional vigilance units (IVUs) to share their experience. The group decided to elaborate a collective work to provide a real-life descriptive picture of French IVUs activities and resources over the 2011-2016 period. METHOD: A questionnaire was sent to the 60 IVUs of the group. It included questions on staff and activities, such as the number of received and analyzed serious adverse events (SAEs). All results and proposals were discussed and consensus was achieved in general meeting. RESULTS/CONCLUSION: The results highlight the commitment of IVU staffs at many steps of CTs, but also the frailty of some units, leading to 6 proposals intended to institutional sponsors and competent authorities for ensuring (1) IVU visibility to all actors; (2) sustainable IVU staff; (3) IVU resources adapted to sponsor's ambitions; (4) valorization of IVUs in publications; (5) recognition of IVU's value in clinical research quality; (6) involvement of IVUs in regulatory changes and their procedures of implementation.

Induction of labor at term with vaginal misoprostol or a prostaglandin E2 pessary: a noninferiority randomized controlled trial.

BACKGROUND: Induction of labor is among the most common procedures for pregnant women. Only a few randomized clinical trials with relatively small samples have compared misoprostol with dinoprostone. Although their efficacy seems similar, their safety profiles have not been adequately evaluated, and economic data are sparse. OBJECTIVE: This study aimed to test the noninferiority of vaginal misoprostol (prostaglandin E1) (25 µg) to a slow-release dinoprostone (prostaglandin E2) pessary (10 µg) for induction of labor with an unfavorable cervix at term. STUDY DESIGN: This was an open-label multicenter randomized noninferiority trial at 4 university hospitals of the Research Group in Obstetrics and Gynecology between 2012 and 2015. We recruited women who underwent induction of labor for medical reasons, those with a Bishop score of ≤5 at ≥36 weeks' gestation, and those with a cephalic-presenting singleton pregnancy with no previous cesarean delivery. Women were randomly allocated to receive either vaginal misoprostol at 4-hour intervals (25 µg) or a 10-mg slow-release dinoprostone pessary. The primary outcome was the total cesarean delivery rate. Noninferiority was defined as a difference in the cesarean delivery rates between the groups of no more than 5%. Secondary outcomes included neonatal and maternal morbidity, vaginal delivery at <24 hours after starting the induction of labor process, and maternal satisfaction. RESULTS: The study included 1674 randomized women. The per-protocol analysis included 790 women in each group. The total cesarean delivery rates were 22.1% (n=175) in the misoprostol group and 19.9% (n=157) in the dinoprostone group, a difference of 2.2% (with an upper-bound 95% confidence limit of 5.6%) (P=.092). Results in the intention-to-treat analysis were similar. Neonatal and maternal morbidity rates were similar between groups. Vaginal delivery within 24 hours was significantly higher in the misoprostol group (59.3% vs 45.7%; P<.001) as was maternal satisfaction, assessed in the postpartum period by a visual analog scale (mean score, 7.1±2.4 vs 5.8±3.1; P<.001). CONCLUSION: The noninferiority of a 25-µg dose of vaginal misoprostol every 4 hours to the dinoprostone pessary for cesarean delivery rates after induction of labor at term could not be demonstrated, although the confidence limit of the difference barely exceeded the noninferiority margin. Nonetheless, given the small difference between these cesarean delivery rates and the similarity of neonatal and maternal morbidity rates in this large study, the clinical risk-to-benefit ratio justifies the use of both drugs.

Multicentric phase II trial of TI-CE high-dose chemotherapy with therapeutic drug monitoring of carboplatin in patients with relapsed advanced germ cell tumors.

BACKGROUND: High-dose chemotherapy (HDCT) with TI-CE regimen is a valid option for the treatment of relapsed advanced germ cell tumors (GCT). We report a phase II trial with therapeutic drug monitoring of carboplatin for optimizing area under the curve (AUC) of this drug. METHODS: Patients with unfavorable relapsed GCT were treated according to TI-CE regimen: two cycles combining paclitaxel and ifosfamide followed by three cycles of HD carboplatin plus etoposide administered on 3 days. Carboplatin dose was adapted on day 3 based on carboplatin clearance (CL) at day 1 in order to reach a target AUC of 24 mg.min/mL per cycle. The primary endpoint was the complete response (CR) rate. RESULTS: Eighty-nine patients who received HDCT were included in the modified intent-to-treat (mITT) analysis. Measured mean AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 mg.min/mL for 10th and 90th percentiles). Thirty-five (44.3%) patients achieved a CR with or without surgery of residual masses and 20 patients achieved a partial response with negative tumor markers. With a median follow-up of 44 months (m), median PFS was 12.3 m (95% CI: 7.5-25.9) and OS was 46.3 m (95% CI: 18.6-not reached). For high- and very high-risk patients, according to the International Prognostic Score at first relapse or treated after at least one salvage treatment (n = 51), 2-year PFS rate was 41.1%. CONCLUSION: The rates of complete and favorable responses were clinically relevant in this very poor risk population. Individual monitoring of carboplatin plasma concentration permitted to control more accurately the target AUC and avoided both underexposure and overexposure to the drug.

VOTRAGE study: Phase I dose-escalation study of pazopanib in unfit older patients.

BACKGROUND: Pazopanib is a tyrosine kinase inhibitor given at the approved dose of 800 mg orally once daily (OD), but often requiring individual dose adjustment due to toxicity. Limited data is available to guide prescription in older patients especially the unfit according to geriatric assessment. PATIENTS AND METHODS: VOTRAGE is a 3 + 3 dose-escalation, open-label phase I trial of continuous OD oral administration of pazopanib to evaluate safety, PK and PD data in unfit older patients with advanced solid tumors. The primary objective was to determine the maximum tolerated dose (MTD). PK data were compared with those obtained in younger adult patients in a population PK analysis. RESULTS: Eighteen patients with a median age of 82.5 years (range 75-91) were included in three dosing cohorts (400, 600, and 800 mg daily). Three dose-limiting toxicities (DLT) were observed in five patients at 800 mg and one DLT at 600 mg in six evaluable patients. MTD was defined as level 2 dose (600 mg). Individual oral clearance was not correlated with age. A relationship was observed between the occurrence of DLT and pazopanib plasma exposure. Decreased oral bioavailability of pazopanib when given with proton-pump inhibitors was confirmed in this group of patients. CONCLUSION: We recommend performing geriatric assessment in patients older than 75 and starting pazopanib at 600 mg per day in unfit older patients. Therapeutic drug monitoring appears very helpful in this population.

Combining Nivolumab and Ipilimumab with Infliximab or Certolizumab in Patients with Advanced Melanoma: First Results of a Phase Ib Clinical Trial.

PURPOSE: TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in patients with advanced melanoma. Our preclinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors. PATIENTS AND METHODS: TICIMEL (NTC03293784) is an open-label, two-arm phase Ib clinical trial. Fourteen patients with advanced and/or metastatic melanoma (stage IIIc/IV) were enrolled. Patients were treated with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) combined to infliximab (5 mg/kg, N = 6) or certolizumab (400/200 mg, N = 8). The primary endpoint was safety and the secondary endpoint was antitumor activity. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events and response was assessed following RECIST 1.1. RESULTS: Only one dose-limiting toxicity was observed in the infliximab cohort. The two different combinations were found to be safe. We observed lower treatment-related AEs with infliximab as compared with certolizumab. In the certolizumab cohort, one patient was not evaluable for response. In this cohort, four of eight patients exhibited hepatobiliary disorders and seven of seven evaluable patients achieved objective response including four complete responses (CRs) and three partial responses (PRs). In the infliximab cohort, we observed one CR, two PRs, and three progressive diseases. Signs of activation and maturation of systemic T-cell responses were seen in patients from both cohorts. CONCLUSIONS: Our results show that both combinations are safe in human and provide clinical and biological activities. The high response rate in the certolizumab-treated patient cohort deserves further investigations.

Radiofrequency ablation for adenoma in patients with primary aldosteronism and hypertension: ADERADHTA, a pilot study.

OBJECTIVE: To evaluate the efficacy and the feasibility of radiofrequency ablation to treat aldosterone-producing adenomas. METHODS: In an open prospective bicentric pilot study, patients with hypertension on ambulatory blood pressure measurement, a primary aldosteronism, an adenoma measuring less than 4 cm, and confirmation of lateralization by adrenal venous sampling were recruited. The primary endpoint, based on ABPM performed at 6 months after the radiofrequency ablation, was a daytime SBP/DBP less than 135/85 mmHg without any antihypertensive drugs or a reduction of at least 20 mmHg for SBP or 10 mmHg for DBP. RESULTS: Thirty patients have been included (mean age = 51 ±â€Š11 years; 50% women). Mean baseline daytime SBP and DBP were 144 ±â€Š19 / 95 ±â€Š15 mmHg and 80% received at least two antihypertensive drugs. At 6 months: 47% (95% CI 28-66) of patients reached the primary endpoint, mean daytime SBP and DBP were 131 ±â€Š14 (101-154)/87 ±â€Š10 (71-107) mmHg; 43% of them did not take any antihypertensive drug and 70% of them did not take potassium supplements. Few complications were recorded: four cases of back pain at day 1 postablation; three limited pneumothoraxes, which resolved spontaneously; one lesion of a polar renal artery. CONCLUSION: Radiofrequency ablation for hypertensive patients with aldosterone-producing adenomas seems to be an emerging promising alternative to surgery. Its efficacy and its feasibility have to be confirmed in a larger sample of patients.

Adverse drug reactions of statins in children and adolescents: a descriptive analysis from VigiBase, the WHO global database of individual case safety reports.

In adults, statins safety profile is well known. However, literature data on their adverse drug reactions (ADRs) remain scarce in children in real-life setting. In order to better characterize ADRs related to 'real-life' use of statins in children, we reviewed statin-related ADRs recorded in the World Health Organization (WHO) global database of individual case safety reports (ICSRs), VigiBase. Methods. Individual case safety reports (ICSRs) in children (2-11 years) and adolescents (12-17 years) associated with statins from January 1, 1987, to July 18, 2017, were extracted from VigiBase. Characteristics of ICSRs, type of ADRs according to MedDRA classification (SOC and PT), and ICSR seriousness were described using SAS 9.4. A total of 311 ICSRs were identified for 8 statins with 712 ADRs. Musculoskeletal disorders (n = 85, 27.3%) were the first registered ADRs followed by general disorders (n = 67, 21.5%; mainly asthenia and pain). More than 1 out of 5 ADRs were 'injury, poisoning and procedural complications' (n = 67), mainly accidental or intentional exposures (n = 44, 14.1%), overdoses (n = 14, 4.5%), or off-label use (n = 11, 3.5%). Overall, 133 (42.8%) reports were 'serious', including 11 deaths. Deaths mainly involved adolescents with intentional overdose and completed suicide with other associated drugs in 75% of reports. Our study identified rare but serious safety issues (rhabdomyolysis, myalgia, and hepatocellular injury). These ADRs can impact quality of life or lead to life-threatening complications in children. Our results should be supplemented with other data sources. Spontaneous statin ADR reports in children to pharmacovigilance networks must be promoted.

Adverse Drug Reactions Involving Protein Kinase Inhibitors: A French Pharmacovigilance Database Study Comparing Safety in Younger and Older Patients (≥ 75 years) with Cancer.

BACKGROUND: Despite the increasing incidence of cancers in elderly people, this population remains under-represented in clinical trials. As a result, data describing the safety and efficacy of protein kinase inhibitors (PKIs) specifically in older patients with cancer are lacking. Advanced age may have a significant impact on drug pharmacology, but data on PKI safety in older patients remain poorly described in "real life". OBJECTIVES: We performed an observational study describing adverse drug reactions (ADRs) related to PKIs and compared the results for younger and older (aged ≥ 75 years) patients. METHODS: We extracted all notifications considered to be related to PKIs from our regional pharmacovigilance database between March 2003 and November 2015. Information about patients, drug exposure, and ADRs were captured. After a descriptive analysis of ADRs, we compared their characteristics between older and younger patients. RESULTS: In total, 214 patients experienced 320 ADRs related to PKIs. Slightly over half the patients were male (57%). The mean age was 64.1 years (range 15-90), and 52 (24.3%) patients were aged ≥ 75 years. Cutaneous reactions were the most frequently reported ADRs (22.9%), followed by gastrointestinal (16.8%) and respiratory (12.1%) ADRs. The most often involved PKIs were imatinib [54 patients (25.2%)], dasatinib [25 (11.7%)], sunitinib [25 (11.7%)], erlotinib [25 (11.7%)], and sorafenib [24 (11.2%)], followed by vemurafenib [17 (7.9%)] and everolimus and nilotinib, with 11 patients (5.1%) each. These drugs were administered mostly for three therapeutic indications: chronic myeloid leukemia [56 patients (26.2%)], malignant urinary tract cancer [31 (14.5%)], and bronchial cancer [27 (12.6%)]. Comparison of PKI-related ADRs between older and younger patients showed no significant difference, except for the mean number of coadministered drugs (5.3 vs. 4.2; p = 0.03) and the proportion of vascular ADRs (17.3 vs. 4.3%; p = 0.005), mainly arterial hypertension, which were both significantly more frequent in the older group. CONCLUSIONS: Our work showed that PKI-related ADRs in older patients were similar to those in younger adults, except for vascular ADRs, which were significantly more frequent in the older population. Our results require confirmation by larger studies but could lead physicians to be more vigilant about cardiovascular comorbidities during initiation of PKIs in elderly people.

Detection of drug safety signals from clinical trials data: Role of SUSARs.

One of the main goals of safety management in clinical trials is to detect suspected unexpected serious adverse reactions (SUSARs). The unexpectedness concerns the nature, frequency or severity of an adverse reaction. Drug safety signals could thus be retrieved, and a study was performed to investigate whether SUSARs allow signal detection in pharmacovigilance. Data from six academic safety units were collected from 2005 to 2016. Characteristics of SUSARs were analysed and signals were identified i) by evaluating the presence of other causes, ii) by assessing the summary of product characteristics (SPC), iii) by searching for specific safety information in Pubmed and health agencies, and iv) by investigating the narrative of each case. Pharmacological plausibility was evaluated by compatible mechanism of reaction and time-to-onset. During the study period, 211 SUSARs were collected. They mostly concerned general disorders (26.1%) and protein kinase inhibitors (24.6%). After eliminating SUSARs with other causes or those considered as expected, 50 SUSARs (23.7%), involving a total of 115 drug-reaction pairs, concerned potential safety signals. Among these pairs, 12 (10.4%) were considered as pharmacologically plausible. This study indicates that one quarter of SUSARs collected in academic clinical trials refers to potential safety signals, especially for oncologic drugs. One tenth of drug-reaction pairs was considered to have a pharmacological plausibility and could merit further evaluation. This is the first study suggesting that SUSARs could be a source of safety signals and that their routine analysis should be complementary to spontaneous reporting.

Continuous Infusion of Cilengitide Plus Chemoradiotherapy for Patients With Stage III Non-Small-cell Lung Cancer: A Phase I Study.

INTRODUCTION: Because of our previous preclinical results, we conducted a phase I study associating the specific αvß3/αvß5 integrin inhibitor cilengitide, given as a continuous infusion, with exclusive chemoradiotherapy for patients with stage III non-small-cell lung cancer. PATIENTS AND METHODS: A standard 3+3 dose escalation design was used. Cilengitide was given as a continuous infusion (dose levels of 12, 18, 27, and 40 mg/h), starting 2 weeks before and continuing for the whole course of chemoradiotherapy (66 Gy combined with platinum/vinorelbine), and then at a dose of 2000 mg twice weekly in association with chemotherapy. 2-Deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography (PET) and computed tomography scans were performed before and after the first 2 weeks of cilengitide administration and then every 3 months. RESULTS: Of the 14 patients included, 11 were evaluable for evaluation of the dose-limiting toxicities (DLTs). One DLT, a tracheobronchial fistula, was reported with the 40 mg/h dose. No relevant adverse events related to cilengitide were observed overall. At the PET evaluation 2 months after chemoradiotherapy, 4 of 9 patients had a complete response and 4 had a partial response. The median progression-free and overall survival was 14.4 months (95% confidence interval [CI], 8.4 to not reached) and 29.4 months (95% CI, 11.73 to not reached), respectively. CONCLUSION: Cilengitide, given continuously with chemoradiotherapy, showed acceptable toxicity and gave encouraging clinical results.

Serious adverse drug events related to non-investigational drugs in academic clinical trials: another source of safety data for risk assessment?

AIMS: Sponsors of clinical trials have to analyze serious adverse events (SAEs). Both sponsors and investigators determine the relationship between the investigational medicinal product, the investigational device or procedure and SAEs. SAEs related to another cause, such as a non-investigational medicinal product (NIMP), do not have clear pharmacovigilance reporting requirements. The aim of this study was to evaluate the amount and the nature of NIMP-related SAEs recorded by three French academic sponsors and to propose pharmacovigilance requirements for these cases. METHODS: This was a retrospective descriptive study including all cases of NIMP-related SAEs occurring in clinical trials and reported to three academic sponsors between January 2009 and October 2014. RESULTS: Among 5870 cases of SAEs, 300 (5%) were related to a NIMP in 50 clinical trials. Involved NIMPs were mainly antithrombotics, cytostatics and immunosuppressants. Some of these drugs were currently followed by a risk management plan (e.g. rivoxaban). The most frequent NIMP-related SAEs were neurological, gastrointestinal and infectious disorders. Seven NIMP-related SAEs were known as 'rare' or 'very rare' and two were 'unlabelled'. CONCLUSIONS: As far as we know, this is the first study to focus about NIMP-related SAEs occurring in clinical trials. This work highlights the potential high quality source of safety data via NIMP-related SAE collection. Globally, we propose that NIMP-related SAEs occurring in clinical trials should systematically be notified to the pharmacovigilance system of the concerned country. Clearer procedures of interactions between safety units of academic sponsors and pharmacovigilance systems are needed to allow an effective recording of NIMP-related SAEs.