Opioid-free anaesthesia with dexmedetomidine and lidocaine versus remifentanil-based anaesthesia in cardiac surgery: study protocol of a French randomised, multicentre and single-blinded OFACS trial.

INTRODUCTION: Intraoperative opioids have been used for decades to reduce negative responses to nociception. However, opioids may have several, and sometimes serious, adverse effects. Cardiac surgery exposes patients to a high risk of postoperative complications, some of which are common to those caused by opioids: acute respiratory failure, postoperative cognitive dysfunction, postoperative ileus (POI) or death. An opioid-free anaesthesia (OFA) strategy, based on the use of dexmedetomidine and lidocaine, may limit these adverse effects, but no randomised trials on this issue have been published in cardiac surgery.We hypothesised that OFA versus opioid-based anaesthesia (OBA) may reduce the incidence of major opioid-related complications after cardiac surgery. METHODS AND ANALYSIS: Multicentre, randomised, parallel and single-blinded clinical trial in four cardiac surgical centres in France, including 268 patients scheduled for coronary artery bypass grafting under cardiac bypass, with or without aortic valve replacement. Patients will be randomised to either a control OBA protocol using remifentanil or an OFA protocol using dexmedetomidine/lidocaine. The primary composite endpoint is the occurrence of at least one of the following: (1) postoperative cognitive disorder evaluated by the Confusion Assessment Method for the Intensive Care Unit test, (2) POI, (3) acute respiratory distress or (4) death within the first 48 postoperative hours. Secondary endpoints are postoperative pain, morphine consumption, nausea-vomiting, shock, acute kidney injury, atrioventricular block, pneumonia and length of hospital stay. ETHICS AND DISSEMINATION: This trial has been approved by an independent ethics committee (Comité de Protection des Personnes Ouest III-Angers on 23 February 2021). Results will be submitted in international journals for peer reviewing. TRIAL REGISTRATION NUMBER: NCT04940689, EudraCT 2020-002126-90.

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.

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.