E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
We investigate the efficacy of two pharmaceutical interventions for reducing mortality and organ damage, and shortening length of hospital stay in patients undergoing heart surgery (i.e. coronary artery bypass grafting and/or heart valve replacement). |
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E.1.1.1 | Medical condition in easily understood language |
Patients undergoing heart surgery are vulnerable to organ damage occurring during the operation. We investigate interventions to limit this damage. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008937 |
E.1.2 | Term | Chronic ischemic heart disease, unspecified |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061994 |
E.1.2 | Term | Heart valve operation |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10011085 |
E.1.2 | Term | Ischaemic coronary artery disorders |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this trial is to determine the efficacy of dexamethasone compared with placebo on the primary endpoint days alive outside hospital within 90 days in adult subjects undergoing elective or subacute isolated CABG, isolated AVR, or CABG plus any concomitant valve surgery. The coprimary objectives are to determine the efficacy of olanzapine versus placebo administered preoperatively, the efficacy of flow-targeted versus pressure-targeted hemodynamic management during CPB, and the efficacy of low tidal volume ventilation versus no ventilation during CPB, on the endpoint days alive outside hospital within 90 days in adult subjects undergoing elective or subacute isolated CABG, isolated AVR, or CABG plus any concomitant valve surgery. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this trial are to determine the efficacy of the interventions on mortality as well as morbidity assessed by either manifest organ damage or by surrogate markers (ex. biomarkers) of organ damage. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A pre-defined substudy is planned. All trial participants from one site (Rigshospitalet) will participate in the substudy. All relevant data will be collected as part of the primary trial eCRF, and accordingly, the substudy will not include any other investigations or interventions than the primary trial. Cardiac CT is a relatively new modality, and at present it is not routinely being applied after open heart surgery. Standardized cardiac CT images will enable us to investigate a number of unanswered research questions involving graft patency, myocardial resting perfusion, and ventricular function. Specifically, this substudy will use the cardiac CT images to investigate the following: 1. Graft patency after three months, assessed by cardiac CT. 2. Predictors of graft patency after three months, assessed by cardiac CT 3. Associations between myocardial resting perfusion, graft patency and outcomes 4. Predictors of left and right ventricular function three months after surgery, assessed by cardiac CT Descriptive statistics as well as generalized linear models will be applied to investigate predictors of graft patency, ventricular function and associations between myocardial resting perfusion, graft patency, and outcomes.
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E.3 | Principal inclusion criteria |
1) Adult, i.e., above 18 years of age 2) Scheduled for CABG and/or AVR, irrespective of other concomitant valve surgery.
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E.4 | Principal exclusion criteria |
1) Acute surgery (i.e. off hours surgery) 2) Pregnancy or currently breastfeeding 3) Known endocarditis at time of screening 4) Previous participation in the trial 5) Active infection, including bacterial, viral, and/or fungal infection 6) Known hepatic cirrhosis 7) Known severe thrombocytopenia with thrombocyte levels < 50 x 109/L 8) Known severe neutropenia with neutrocyte levels < 2 x 109/L 9) On the waiting list for a heart transplant 10) Recipient of any major organ transplant 11) Obstructive hypertrophic cardiomyopathy, active myocarditis, constrictive pericarditis, untreated hypothyroidism or hyperthyroidism 12) Having received cytotoxic/cytostatic chemotherapy or radiation therapy for treatment of malignancy within the last 6 months. 13) Clinical evidence of current malignancy except for basal or localized squamous cell carcinoma, cervical intraepithelial neoplasia or stable prostate cancer. 14) Known narrow-angle glaucoma 15) Known phenylketonuria 16) Type I diabetes 17) Known long QT syndrome 18) Known allergy for any of the included study drugs 19) Any condition, where participation in the study, in the investigator’s opinion could put the subject at risk, confound the study results or interfere significantly with participation in the study
Specific exclusion criteria Patients with extracardiac arteriopathy (assessed as part of the pre-operative EuroSCORE) will be excluded from the intervention ‘flow-targeted vs. pressure-targeted hemodynamic management during CPB’. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be number of days alive and outside hospital within 90 days after surgery. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1) Time in days to occurrence of any component in a composite secondary endpoint during follow-up (6 months after last included subject) consisting of a) Death from any cause b) Stroke, defined as persisting (>24 hours) of any neurological symptoms of neurological dysfunction during the 6 months follow-up period. The diagnosis is determined by the treating physician. c) Acute kidney injury requiring any type of renal replacement therapy during the follow-up period. d) New onset or worsening heart failure, defined as persistent (> 24 hours from initiation) need for vasopressor/inotropic hemodynamic support, need for mechanical circulatory support after surgery, inability to close the sternotomy due to hemodynamic instability after surgery or readmission for acute heart failure during follow-up.
2) Severe post-operative complications during index admission, defined as a Clavien-Dindo class of 3 to 5.
3) Delirium during the first 7 days after surgery, defined as a positive Confusion Assessment Method for the ICU (CAM-ICU) score or a positive Confusion Assessment Method (CAM) score for the general wards
4) Quality of Recovery-15 (QoR-15) score 3 days, or as soon as possible, after surgery
6) 90-day outcomes a) Survival b) Change in modified Rankin Scale (mRS) from baseline c) Health-related quality of life (EQ-5D-5L) d) Change in self-perceived function “two simple questions”* e) Days alive outside ICU within 90 days
7) 180-day outcomes a) Survival
*) ’Two simple questions’ asked to the participant in Danish: ’Har du, inden for de sidste to uger, haft brug for hjælp fra en anden person til hverdags-aktiviteter?’ ’Føler du selv, at du er kommet dig helt efter din operation?’
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Follow-up at 90 days. Registry-based mortality being assessed at 180 days. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Aside from the two pharmaceutical interventions, we are investigating two mechanical interventions |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |