Here is the design of a clinical trial:

Official Title: Opioid-Free Anesthesia in Cardiac Surgery

Included conditions:
- Anesthesia

Study Armgroups:
- {'label': 'Standard arm', 'type': 'ACTIVE_COMPARATOR', 'description': 'General anesthesia strategy with morphine:\n\n* Within 10 minutes before the induction of general anesthesia: administration of a placebo of 50 mL of 0.9% NaCl by slow IV\n* The anesthetic induction will be carried out by an intravenous hypnotic (propofol or etomidate) combined with IV curare and remifentanil (morphine derivative) IV for a concentration target of 4 ng / mL.\n* Maintenance of anesthesia will be carried out with propofol or a halogenated gas (sevoflurane or desflurane) in continuous administration (qs bispectral index 40-60) and remifentanil (target concentration 1-10 ng / mL). The administration of curare will be carried out as needed. In order to anticipate the sudden end of the analgesia, an administration of morphine 0.15 mg / kg IV will be carried out 30 minutes before the end of the intervention as recommended', 'interventionNames': ['Drug: Remifentanil']}
- {'label': 'OFA arm', 'type': 'EXPERIMENTAL', 'description': 'General anesthesia strategy without morphine\n\n* Within 10 minutes before the induction of general anesthesia: pre-induction dose of dexmedetomidine 0.5 g / kg and lidocaine 1.5 mg / kg by slow IV.\n* The anesthetic induction will be carried out by an intravenous hypnotic (propofol or etomidate) combined with an IV curare\n* The maintenance of the anesthesia will be carried out by propofol or a halogenated gas (sevoflurane or desflurane) in continuous administration (qsp bispectral index 40-60), dexmedetomidine 0.5-1.0 g / kg / h, lidocaine 2 mg / kg / h. The administration of curare will be carried out as needed.', 'interventionNames': ['Drug: Dexmédétomidine 0.5 g/kg + lidocaine 1.5 mg/kg']}

Interventions:
- {'type': 'DRUG', 'name': 'Dexmédétomidine 0.5 g/kg + lidocaine 1.5 mg/kg', 'description': 'The patient will be anesthetized with Dexmedetomidine 0.5 g / kg + lidocaine 1.5 mg / kg for the induction instead of morphin.', 'armGroupLabels': ['OFA arm'], 'otherNames': ['experimental']}
- {'type': 'DRUG', 'name': 'Remifentanil', 'description': 'The patient will be anesthetized with morphin.', 'armGroupLabels': ['Standard arm'], 'otherNames': ['Control']}

Primary Outcomes:
- {'measure': 'To assess the impact of general anesthesia strategy without the use of opioids (OFA) on the incidence of major postoperative complications related to opioids compared to the reference strategy using opioids.', 'description': 'Composite criterion consisting of the appearance 48 hours after the surgery of an intestinal ileus, and / or of an alteration of the neurological state, and / or of an acute respiratory failure, and / or of a death', 'timeFrame': '48 hours post-surgery'}

Please estimate the sample size based on the assumption: 
The sample size calculation is based on a one-sided Pearson's χ2 test at a 0.05 significance level, with 80% power. The analysis will follow the intention-to-treat principle, and missing values for the primary endpoint will be imputed according to the maximal bias assumption. All statistical tests are two-sided with a 0.05 level required for statistical significance.
Sample size calculation, statistics and allocation
        
          Sample size calculation
          The primary endpoint of this study is a composite endpoint defined by the occurrence of at least one of the four major opioid-related complications within 48 hours after cardiac surgery. The sample size was calculated with respect to Pearsonâs Ï2 test at a one-sided 0.05 level, to compare the occurrence of complication between the two groups. In a recent French national survey, 50% of patients presented at least one complication among POCD, ileus or respiratory distress (data not published). In order to obtain 80% power for the difference given by the respective composite endpoint probabilities of 35% and 50% in the OFA and OBA arms, respectively, with one-sided type I error of 5% (reduction in complications of at least 30%), 134 patients will have to be included in each group, hence 268 patients overall. The unilateral characteristic of the test is justified by a previous retrospective study from Guinot et al, where OFA showed a reduction in postoperative outcomes. These data have been recently confirmed by another cohort study from the same authors.32 33

        
        
          Statistics
          The main analysis will be carried out on all randomised patients according to the treatment group drawn at random (intention-to-treat principle).
          Patient characteristics will be described using standard parameters: mean, SD, median, IQR and extreme values for quantitative variables and frequencies and percentages for categorical variables.
          The proportion of patients experiencing the main outcome and its 95% CI will be estimated in each group and compared by means of Pearsonâs Ï2 test.
          This analysis will be complemented by a comparison using the logistic regression model with the main outcome (patients meeting the primary endpoint within 48 hours after cardiac surgery) as the response and the treatment group (OFA or OBA) and potential factors associated with the response as explanatory variables such as age, body mass index, Euroscore 2, type of surgery (CABG or combined surgery) and duration of CPB.
          The same general approach as outlined above will be used to compare the secondary qualitative outcomes (nauseaâvomiting, pain, arrhythmia, shock, relative adrenal insufficiency, acute kidney injury, mortality) and Studentâs t-test will be used to compare quantitative parameters (length of stay).
          No interim analysis will be performed.
          Since this is an intention-to-treat analysis, in cases of missing value for the primary endpoint, imputation will be used according to the maximal bias assumption for incomplete observations. Namely, patients will be considered to experience the main outcome in the OFA group, and conversely in the OBA group.
          All statistical tests are two sided, with a two-sided 0.05 level required for statistical significance.
        
        
          Allocation and blinding
          Patients who give written informed consent to participate in the study will be randomly assigned to the control (OBA) and experimental (OFA) groups. Inclusion and randomisation will be performed using the Ennov Clinical trial online software (Ennov, France), and a unique and anonymous number will be attributed to each patient. Randomisation will be stratified by centre in a 1:1 ratio using balanced blocks. All data will be collected and anonymised in an electronic case report form on the Ennov Clinical trial platform by a dedicated clinical research technician. Data will be monitored by a clinical research assistant in the presence of the clinical research technician and the main investigator of the site. Data will be stored for 15 years after the end of the trial in a dedicated secure server by the Clinical Research Department of the Rouen University Hospital.
          Patients will be blinded to the allocated group and a 50 mL vial of 0.9% NaCl will be administrated before induction of anaesthesia in the OBA group to reinforce the blindness. The anaesthesia team will not be blinded to the allocation, but the postoperative care team in ICU will be blinded.
        
        
          Safety concerns
          In accordance with French regulations, every serious adverse event related to the investigational medicinal products or not, expected or unexpected, will be immediately reported to the sponsor (Clinical Research Department of the Rouen University Hospital) by the investigator, with the exception of those that are identified as not requiring immediate reporting in the protocol. A serious adverse event is defined as one that results in death, is life threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, causes significant disability or prolonged incapacity, is a congenital anomaly or birth defect or is a medical event. The investigator will have to complete a âserious adverse eventâ form on which will be indicated the date of onset, criterion of seriousness, intensity, treatment dates, causality relationship with the investigational medicinal products and the outcome. The period in which serious adverse events should be reported begins from the date of the authorisation of the study until 48 hours after the end of the anaesthetic of the patient included in the study or without a time limit if it is possibly related to the investigational medicinal product and/or to the clinical trial.
          As mentioned in the protocol, the following events will not require immediate reporting: complications associated with cardiac surgery and unrelated to investigational medicinal products will not require immediate reporting but will be collected in the case report form.
          Moreover, in order to avoid collection duplication in the case report form, the events POI, acute respiratory failure and POCD will be recorded as the primary endpoint in the case report form but not reported on the âadverse eventâ page. In the same way, nausea and vomiting and bradycardia will be recorded as secondary endpoints in the case report form, with the exception of bradycardia meeting one of the following definitions, which will be reported on the adverse event page and subject to immediate reporting: (1) appearance of profound bradycardia in relation to investigational medicinal products (heart rate below 35 bpm lasting more than 120 s or below 40 bpm with haemodynamic repercussions) will be considered as a serious adverse event; (2) episodes of atropine-refractory bradycardia, defined as failure to normalise heart rate (heart rate greater than or equal to 50 bpm), despite at least two administrations of 1 mg atropine.
          In the case of profound and severe bradycardia (heart rate below 40 bpm), if there is no response to two doses of 1 mg atropine, the treatment will be stopped prematurely, and an alternative anaesthetic technique used to ensure the surgical procedure.
          In addition, serious adverse events will be submitted to the data and safety monitoring board (DSMB). The DSMB is independent of the trial investigators and will perform an ongoing review of safety parameters and overall study conduct.
          This is justified in view of the study population at risk of mortality (independently of this trial), the off-label use of anaesthesia drugs in the OFA group and the high rate of complications associated with cardiac surgery. The DSMB will comprise three experts: an anaesthetist, a drug safety expert and a methodologist. The members will meet before the start of the trial, then on a regular basis (after 10% and half of the patients included, at the end of the study after the database lock), and if necessary, at any time at the sponsorâs request in the case of a significant event. The DSMB will have to assess the benefit/risk ratio of the trial and to give recommendations on whether the study should be discontinued or not. All serious adverse events for which the investigator or the sponsor considers that a causal relationship with the investigational medicinal products can be reasonably considered will be considered as suspected serious adverse reactions (SARs). If they are unexpected, they are qualified as being suspected unexpected SARs and will be notified in a report by the sponsor to EudraVigilance (European pharmacovigilance database) and to the local regulatory agency within the regulatory time periods for reporting: immediate reporting if seriousness criteria are death or life threatening, and reporting within 15 days for other seriousness criteria.