Endoscopic En Bloc Versus Piecemeal Resection of Large Nonpedunculated Colonic Adenomas : A Randomized Comparative Trial.

BACKGROUND: Endoscopic resection of adenomas prevents colorectal cancer, but the optimal technique for larger lesions is controversial. Piecemeal endoscopic mucosal resection (EMR) has a low adverse event (AE) rate but a variable recurrence rate necessitating early follow-up. Endoscopic submucosal dissection (ESD) can reduce recurrence but may increase AEs. OBJECTIVE: To compare ESD and EMR for large colonic adenomas. DESIGN: Participant-masked, parallel-group, superiority, randomized controlled trial. (ClinicalTrials.gov: NCT03962868). SETTING: Multicenter study involving 6 French referral centers from November 2019 to February 2021. PARTICIPANTS: Patients with large (≥25 mm) benign colonic lesions referred for resection. INTERVENTION: The patients were randomly assigned by computer 1:1 (stratification by lesion location and center) to ESD or EMR. MEASUREMENTS: The primary end point was 6-month local recurrence (neoplastic tissue on endoscopic assessment and scar biopsy). The secondary end points were technical failure, en bloc R0 resection, and cumulative AEs. RESULTS: In total, 360 patients were randomly assigned to ESD (n = 178) or EMR (n = 182). In the primary analysis set (n = 318 lesions in 318 patients), recurrence occurred after 1 of 161 ESDs (0.6%) and 8 of 157 EMRs (5.1%) (relative risk, 0.12 [95% CI, 0.01 to 0.96]). No recurrence occurred in R0-resected cases (90%) after ESD. The AEs occurred more often after ESD than EMR (35.6% vs. 24.5%, respectively; relative risk, 1.4 [CI, 1.0 to 2.0]). LIMITATION: Procedures were performed under general anesthesia during hospitalization in accordance with the French health system. CONCLUSION: Compared with EMR, ESD reduces the 6-month recurrence rate, obviating the need for systematic early follow-up colonoscopy at the cost of more AEs. PRIMARY FUNDING SOURCE: French Ministry of Health.

Tacrolimus Exposure Before and After a Switch From Twice-Daily Immediate-Release to Once-Daily Prolonged Release Tacrolimus: The ENVARSWITCH Study.

LCP-tacrolimus displays enhanced oral bioavailability compared to immediate-release (IR-) tacrolimus. The ENVARSWITCH study aimed to compare tacrolimus AUC0-24 h in stable kidney (KTR) and liver transplant recipients (LTR) on IR-tacrolimus converted to LCP-tacrolimus, in order to re-evaluate the 1:0.7 dose ratio recommended in the context of a switch and the efficiency of the subsequent dose adjustment. Tacrolimus AUC0-24 h was obtained by Bayesian estimation based on three concentrations measured in dried blood spots before (V2), after the switch (V3), and after LCP-tacrolimus dose adjustment intended to reach the pre-switch AUC0-24 h (V4). AUC0-24 h estimates and distributions were compared using the bioequivalence rule for narrow therapeutic range drugs (Westlake 90% CI within 0.90-1.11). Fifty-three KTR and 48 LTR completed the study with no major deviation. AUC0-24 h bioequivalence was met in the entire population and in KTR between V2 and V4 and between V2 and V3. In LTR, the Westlake 90% CI was close to the acceptance limits between V2 and V4 (90% CI = [0.96-1.14]) and between V2 and V3 (90% CI = [0.96-1.15]). The 1:0.7 dose ratio is convenient for KTR but may be adjusted individually for LTR. The combination of DBS and Bayesian estimation for tacrolimus dose adjustment may help with reaching appropriate exposure to tacrolimus rapidly after a switch.

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.

Compliance of French academic clinical trials with the Clinical Trial Facilitation and Coordination Group recommendations on contraception and pregnancy testing requirements.

BACKGROUND/AIMS: The Clinical Trials Coordination and Facilitation Group has issued recommendations on contraception and pregnancy testing to help sponsors meet regulatory expectations and harmonize practices to limit embryofetal risks in clinical trials. Our objective was to assess the compliance of French academic clinical trials with these recommendations and to describe the mitigation measures required by sponsors in their trials. METHODS: A cross-sectional study was performed on the French academic drug trials authorized by the national competent authority between January 2015 and June 2018. We included trials which tested systemic administration of drugs and enrolled men or women of childbearing potential. RESULTS: Data from 97 trials included were compiled. One-third of the trials (23.8%-43.3%, 95% confidence interval) complied with the Clinical Trial Facilitation and Coordination Group recommendations. No improvement over time or according to embryofetotoxic status or drug duration exposure was found. Contraception was required in 56.7% of trials and was more often required in case of potentially embryofetotoxic drugs (68.5% vs 41.9%, p = 0.013) or exposure over 1 month (71.7% vs 43.8%, p = 0.006). Pregnancy testing at inclusion was required in 59.1% of trials and additional testing in 17.2%. Pregnancy testing at inclusion was more often required in trials with drug exposure above 1 month (67.4% vs 45.8%, p = 0.035). CONCLUSION: French academic sponsors barely met the recommendations on contraception and pregnancy testing potentially leading to potential embryofetal risks in case of pregnancy. They need to implement these recommendations quickly.

Peroral endoscopic pyloromyotomy is efficacious and safe for refractory gastroparesis: prospective trial with assessment of pyloric function.

BACKGROUND: Gastroparesis is a functional disorder with a variety of symptoms that is characterized by delayed gastric emptying in the absence of mechanical obstruction. A recent series of retrospective studies has demonstrated that peroral endoscopic pyloromyotomy (G-POEM) is a promising endoscopic procedure for treating patients with refractory gastroparesis. The aim of this prospective study was to evaluate the feasibility, safety, and efficacy of G-POEM. METHODS: 20 patients with refractory gastroparesis (10 diabetic and 10 nondiabetic) were prospectively included in the trial. Patients were treated by G-POEM after evaluation of pyloric function using an endoscopic functional luminal imaging probe. Clinical responses were evaluated using the Gastroparesis Cardinal Symptom Index (GCSI), and quality of life was assessed using the Patient Assessment of Upper Gastrointestinal Disorders - Quality of Life scale and the Gastrointestinal Quality of Life Index scores. Gastric emptying was measured using 4-hour scintigraphy before G-POEM and at 3 months. RESULTS: Feasibility of the procedure was 100 %. Compared with baseline values, G-POEM significantly improved symptoms (GCSI: 1.3 vs. 3.5; P < 0.001), quality of life, and gastric emptying (T½: 100 vs. 345 minutes, P < 0.001; %H2: 56.0 % vs. 81.5 %, P < 0.001; %H4: 15.0 % vs. 57.5 %, P = 0.003) at 3 months. The clinical success of G-POEM using the functional imaging probe inflated to 50 mL had specificity of 100 % and sensitivity of 72.2 % (P = 0.04; 95 % confidence interval 0.51 - 0.94; area under the curve 0.72) at a distensibility threshold of 9.2 mm2/mmHg. CONCLUSION: G-POEM was efficacious and safe for treating refractory gastroparesis, especially in patients with low pyloric distensibility.

Pectoral I Block Does Not Improve Postoperative Analgesia After Breast Cancer Surgery: A Randomized, Double-Blind, Dual-Centered Controlled Trial.

BACKGROUND AND OBJECTIVES: General anesthesia for breast surgery may be supplemented by using a regional anesthetic technique. We evaluated the efficacy of the first pectoral nerve block (Pecs I) in treating postoperative pain after breast cancer surgery. METHODS: A randomized, double-blind, dual-centered, placebo-controlled trial was performed. One hundred twenty-eight patients scheduled for unilateral breast cancer surgery were recruited. A multimodal analgesic regimen and surgeon-administered local anesthetic infiltration were used for all patients. Ultrasound-guided Pecs I was performed using bupivacaine or saline. The primary outcome was the patient pain score (numerical rating scale [NRS]) in the recovery unit 30 minutes after admission or just before the morphine administration (NRS ≥4/10). The secondary outcomes were postoperative opioid consumption (ie, in the recovery unit and after 24 hours). RESULTS: During recovery, no significant difference in NRS was observed between the bupivacaine (n = 62, 3.0 [1.0-4.0]) and placebo (n = 65, 3.0 [1.0-5.0]) groups (P = 0.55). However, the NRS was statistically significantly different, although not clinically significant, for patients undergoing major surgeries (mastectomies or tumorectomies with axillary clearance) (n = 29, 3.0 [0.0-4.0] vs 4.0 [2.0-5.0], P = 0.04). Morphine consumption during recovery did not differ (1.5 mg [0.0-6.0 mg] vs 3.0 mg [0.0-6.0 mg], P = 0.20), except in the major surgery subgroup (1.5 mg [0.0-6.0 mg] vs 6.0 mg [0.0-12.0 mg], P = 0.016). Intraoperative sufentanil and cumulative morphine consumption up to 24 hours did not differ between the 2 groups. Three patients experienced complications related to the Pecs I. CONCLUSIONS: Pecs I is not better than a saline placebo in the presence of multimodal analgesia for breast cancer surgery. However, its role in extended (major) breast surgery may warrant further investigation. CLINICAL TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov, identifier NCT01670448.

The reporting of harms in publications on randomized controlled trials funded by the "Programme Hospitalier de Recherche Clinique," a French academic funding scheme.

BACKGROUND/AIMS: Accurate information on harms arising from medical interventions is essential for assessing benefit-risk ratios. Since 2004, there has been an extension of the Consolidated Standards of Reporting Trials statement for reporting harms data in publications on randomized clinical trials. The objective of our study was to assess the quality of this reporting from academic randomized clinical trials on drugs. METHODS: We searched for articles on randomized clinical trials funded between 2004 and 2008 by the "Programme Hospitalier de Recherche Clinique." We included all published randomized clinical trials that assessed drugs. Harm-related data were extracted and compared with the Consolidated Standards of Reporting Trials Harms extension, and the space in the articles devoted to harms data was measured. RESULTS: In total, 37 randomized clinical trials met the inclusion criteria. The median harm score was 9/18. In 73.0% of the randomized clinical trials, the reporting of adverse events was selective. Less than 50% of articles provided information on reasons for drug discontinuation that were related to adverse events. The score and the space allocated to harms were higher in antineoplastic and immunomodulating drugs randomized clinical trials, while the median proportion of the space in the results section allocated to harms was 16.8%. In 67.6% of the articles, the space allocated to the authors' list and affiliations was greater than the space in the results section allocated to descriptions of harms. No significant improvement in the score or the space allocation was observed during the study period. CONCLUSION: Reporting of harms in French academic drug randomized clinical trials is suboptimal; moreover, this shortcoming is a critical barrier to evaluating the benefit-risk ratio of drug randomized clinical trials. Thus, the authors should be encouraged to adhere to the Consolidated Standards of Reporting Trials Harms extension.

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.

[Reporting of harms in clinical trials: Vigilant support to the investigator. A guideline of REVISE' Group]. / Sécurité des essais cliniques : accompagnement de l'investigateur par le vigilant pour la publication des données de sécurité. Une ligne directrice du groupe REVISE.

Since August 9, 2004, the 2001 European Directive for clinical trials is applied to the French law. Since the 2006 implementing decree amending public health law on biomedical researches, safety data are managed by sponsor vigilant. Competent authorities collect sponsor's data, implement the vigilance system (Article L. 1123-12 of French Health Code) and supervise drastically safety data in clinical research from clinical trial authorization to final report. However, although available to competent authorities, final reports are not addressed to scientific community, who has only access to scientific publications for clinical trials safety data. Final report is under sponsor's responsibility (Article R. 1123-60 of French Health Code), but scientific publication is written by the study coordinating investigator. Therefore, at the end of the clinical trial, two actors will interpret safety data from the same database but with different scientific objectives. The lack of reporting of harms in scientific communications impacts the information. The REVISE group (safety officers of French institutional sponsors) suggests help to investigators in the safety data writing for their trial scientific publication. The group published a guideline, based on the international recommendations for publications of safety data in randomized clinical trials and expanded its scope to all clinical trials.

Quality of serious adverse events reporting to academic sponsors of clinical trials: far from optimal.

PURPOSE: The purpose of this study is to evaluate the quality of the serious adverse events (SAE) reported to an academic sponsor. Assessing the safety of a clinical trial relies on information gathering the collection of adverse events reported by the investigators to the sponsor. The accuracy of safety evaluation depends in particular on the quality of the reporting. METHODS: All SAE case report forms, reported in 2012 to the sponsor from all clinical trials, were evaluated for completeness and accuracy with a standardized data quality evaluation form. Several items were assessed: regulatory mandatory information and items concerning the reported events. For statistical comparisons, Chi2/exact Fisher test was performed. RESULTS: Investigators or patients were not identified in <3% of the reports. The investigational product was not identified in 11.2%. In 3.6% of the reports, the seriousness of the event was unknown. The causality assessment was missing in 9.3%. In 15.0%, the verbatim of the event was considered as not consistent with the description of the event. In 32.4%, the sponsor considered there were insufficient data concerning relevant laboratory/additional examinations performed or relevant history required to help in the assessment. The onset date of SAE was not mentioned in 5.7% of the reports and patient outcome in 12.1%. CONCLUSIONS: This study highlighted the far from optimal quality of reporting both in terms of completeness and accuracy. The accurate coding of the events using MedDRA and the safety evaluation by the sponsor can be difficult. The training of investigators in SAE reporting must be improved. Copyright © 2016 John Wiley & Sons, Ltd.

Probable drug-induced liver injury associated with aliskiren: case report and review of adverse event reports from pharmacovigilance databases.

PURPOSE: A case of probable drug-induced liver injury (DILI) attributed to use of the antihypertensive agent aliskiren is reported. SUMMARY: A 61-year-old woman undergoing routine liver function monitoring in conjunction with long-term antiepileptic therapy was noted to have an asymptomatic acute hepatic cytolysis 1 month after the initiation of concomitant aliskiren therapy (150 mg/day). Liver enzyme testing showed dramatically elevated aspartate transaminase (AST) and alanine transaminase (ALT) concentrations, with substantial rises also noted in γ-glutamyltransferase (GGT) and alkaline phosphatase (ALP) levels. The calculated ALT:ALP value indicated hepatocellular injury. On discontinuation of aliskiren use, rapid biological improvement occurred, including normalization of serum AST and a sharp decline in serum ALT within one week and the return of GGT and ALP levels to baseline a few weeks later; the patient's AST and ALT concentrations remained normal during 18 months of subsequent monitoring. Using the algorithm of Naranjo et al. and a DILI-specific causality assessment instrument, it was determined that aliskiren use was the probable cause of the patient's liver injury. While this is believed to be the first report of aliskiren-associated DILI in the professional literature, a review of information from several European and North American pharmacovigilance databases (through October 2012) identified 117 reports of suspected aliskiren hepatotoxicity, including 6 reports of liver failure and 12 reports of deaths. CONCLUSION: Asymptomatic acute hepatic cytolysis was observed in a 61-year-old woman approximately one month after initiation of aliskerin for treatment of hypertension. Improvement in AST and ALT concentrations was observed shortly after the drug was discontinued.

Pancreatitis associated with the use of GLP-1 analogs and DPP-4 inhibitors: a case/non-case study from the French Pharmacovigilance Database.

In the recent past, concerns have raised regarding the potential risk of acute pancreatitis among type 2 diabetic patients using incretin-based drugs such as glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors. The aim of this study is to investigate the association between exposure to incretin-based drugs and the occurrence of pancreatitis reported in the French Pharmacovigilance Database. The case/non-case method was performed from serious adverse drug reactions (ADRs) involving antihyperglycemic agents (except insulin alone) reported to the French pharmacovigilance system between March 2008 (first marketing of an incretin-based drug in France) and March 2013. Cases were defined as reports of pancreatitis, and all other serious ADRs were considered non-cases. Disproportionality was assessed by calculating reporting odds ratios (ROR) adjusted for age, gender, history of pancreatitis, other antihyperglycemic drugs and other drugs associated with a higher risk of pancreatitis. Among 3,109 serious ADRs, 147 (4.7 %) reports of pancreatitis were identified as cases and 2,962 reports (95.3 %) of other ADRs as non-cases. Among the cases, 122 (83.0 %) involved incretin-based drugs. Disproportionality was found for all incretin-based drugs (adjusted ROR: 15.7 [95 % CI 9.8-24.9]), all GLP-1 analogs (29.4 [16.0-53.8]), exenatide (28.3 [12.8-62.3]), liraglutide (30.4 [15.4-60.0]), all DPP-4 inhibitors (12.1 [7.3-20.0]), sitagliptin (12.4 [7.3-21.0]), saxagliptin (15.1 [4.3-52.7]), and vildagliptin (7.4 [3.1-17.6]). Temporal analysis found disproportionality for incretin-based drugs since their first year of marketing in France. Compared with other antihyperglycemic agents, use of incretin-based drugs is associated with an increased risk of reported pancreatitis in France.

Osteonecrosis of the jaw induced by clodronate, an alkylbiphosphonate: case report and literature review.

PURPOSE: To report on a case of osteonecrosis of the jaw (ONJ) in a patient treated with clodronate, an alkylbiphosphonate, and to draw attention to the risk of ONJ following treatment with all biphosphonates, whether they are alkyl- or amino-biphosphonates. CASE REPORT: Beginning at age 58 years, a female patient took clodronate for almost 13 years for a metastatic bone cancer. She also underwent chemotherapy and radiotherapy. Three months after the end of biphosphonate therapy, she suffered from toothache, and tooth 27 (left maxillary second molar) was extracted. A maxillary focus of osteitis with an oral sinus communication was discovered, and a maxillofacial denture prosthesis was grafted in September 2006. Some days later, the patient consulted her dentist for an ulceration of the oral cavity floor in front of tooth 33 (left mandibular canine) extending to the left inferior side of the lip. In October 2006, teeth 33 and 34 (left mandibular first premolar) were extracted. No secondary infection occurred. A complete healing was only observed 3 months after the last extraction. ONJ due to alkylbiphosphonate treatment was diagnosed as bone reconstruction and mucous cicatrisation were delayed. METHODS: A systematic review was carried out to identify all cases of alkylbiphosphonate-induced ONJ by searching the Medline and Cochrane databases using 'osteonecrosis of the jaw', 'jaw diseases', 'osteonecrosis', 'diphosphonate', 'biphosphonate' (amino-, alkyl- or the international nonproprietary name) as the main search items. The search was limited to English- and French-language articles published between 1966 and February 2010. RESULTS: Our search identified 27 cases of alkylbiphosphonate-induced ONJ in the literature. Among these cases, only ten patients were on alkylbiphosphonate monotherapy; in the other cases, aminobiphosphonates had also been used. The clinical presentation of the alkylbiphosphonate-induced ONJ was similar to that most often encountered with aminobiphosphonate treatment. The duration of exposure before onset was higher with alkylbiphosphonates than with aminobiphosphonates, and dental procedures before ONJ were frequent. CONCLUSION: Osteonecrosis of the jaw has been widely reported with various aminobiphosphonates, but data on the role of alkylbiphosphonates are scarce. As these latter drugs are less potent, a high cumulative dose through long-term exposure would appear to be necessary and would favour ONJ. Although the degree of risk for ONJ occurrence in patients on alkylbiphosphonates remains uncertain, it would be wise to reconsider carefully the indications for using these agents and to apply preventive measures as is currently done for aminobiphosphonates.

Malnutrition and epilepsy: a two-way relationship.

BACKGROUND & AIMS: A link between malnutrition and epilepsy has been suspected for many years. METHODS: Different aspects of the question were studied with a review of previous published data. RESULTS: Several studies performed on animal models or humans highlight the possible adverse effects of malnutrition in the onset of seizures. Protein-energy, electrolyte, vitamin or trace element deficiencies may be involved. Conversely, several determinants of epilepsy could lead to malnutrition: food taboos and social exclusion in developing countries as well as some adverse effects of antiepileptic treatments. CONCLUSIONS: Two different hypotheses exist as a vicious circle: malnutrition predisposing to epilepsy or epilepsy predisposing to malnutrition. A better understanding of these interactions is necessary. In the mean time, malnutrition has to be prevented and treated.

Link between epilepsy and malnutrition in a rural area of Benin.

PURPOSE: Epilepsy and malnutrition are both important public health problems in sub-Saharan Africa. A relationship between epilepsy and malnutrition has been suspected for many years. Our objective was to investigate the association between epilepsy and malnutrition in Djidja, Benin. METHODS: A matched population-based cross-sectional case-control survey was performed: cases (patients with epilepsy) were matched to controls according to sex, age +/- 5 years, and village of residence. The World Health Organization's criteria for malnutrition was used. Anthropometric measurements (weight, height, mid arm upper circumference, triceps skinfold thickness) were taken. Bioelectrical impedance analysis, a standardized food and social questionnaire and a clinical examination were done. Statistical analysis (conditional logistic regression) was performed using SAS 8.0. RESULTS: A total of 131 cases and 262 controls were included. The prevalence of malnutrition was higher in cases than in controls (22.1% vs. 9.2%, p = 0.0006). Social factors were significantly different between cases and controls. Feeding difficulties were more frequent and health status was worse in cases. Seven variables were associated with epilepsy: (i) nutritional factors: mid arm upper circumference (prevalence odds ratio (pOR) = 0.7, CI: 0.6-0.9), cereal consumption <3 times during the 3 days before the study (pOR = 4.2, CI: 1.8-10.0), <3 meals/day (pOR = 4.2, CI: 1.6-10.9), tooth decay (pOR = 2.9, CI: 1.1-7.4), food taboos (pOR = 25.0, CI: 8.3-100.0), (ii) social factors: surrogate respondent (pOR = 16.8, CI: 3.1-90.3) and no second job (pOR = 7.1, CI: 2.3-22.3). CONCLUSION: Epilepsy and nutritional status are linked in sub-Saharan Africa. Programs to improve the nutritional status of people with epilepsy are needed.