E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bloodpressure during anaesthesia |
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E.1.1.1 | Medical condition in easily understood language |
Bloodpressure during narcosis |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03] |
MedDRA Classification |
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 |
To assess the effect of the administration of norepinephrine on ABP while subjects are awake and subsequently, to study the effects of the interactions of norepinephrine and anesthetics (propofol and remifentanil) on ABP under steady-state conditions during general anesthesia. |
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E.2.2 | Secondary objectives of the trial |
- Evaluation of the effect of the interaction between propofol, remifentanil and norepinephrine on hemodynamics during general anesthesia.
- Evaluation of the effect(s) of endogenous norepinephrine plasma concentration on the relationship between administered dose (and plasma concentration) of norepinephrine and induced hemodynamic alteration(s).
- Evaluation of the Beloeil norepinephrine PKPKD model.
- Assessment of changes in mean systemic filling pressure prior to and after induction of general anesthesia, as assessed by arm stop-flow measurements by application of a rapidly inflated tourniquet.
- Evaluation of the dose-dependent effect of administered norepinephrine on plasma melatonin concentrations prior to and after induction of general anaesthesia.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- American Society of Anesthesiologists (ASA) Physical Status I or II
- No exclusion criterion is present
- Informed, and willing to give written informed consent.
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E.4 | Principal exclusion criteria |
- Refusal of the volunteer to participate
- Pregnancy
- Diseases involving the cardiovascular system (hypertension, coronary artery disease, prior acute myocardial infarction, any valvular and/or myocardial disease involving decrease in ejection fraction, arrhythmias, which are either symptomatic or require continuous medication/pacemaker/automatic internal cardioverter defibrillator)
- A difference > 15 mmHg in measured systolic or diastolic blood pressure value (SBP, DBP) between the left and right upper arm, as determined by non-invasive cuff oscillometry during the screening visit.
- An increased risk of difficult mask ventilation or tracheal intubation, as judged by the anesthesiologist-researcher.
- Pulmonary disease
- Gastric or endocrinologic diseases
- End-stage liver or kidney failure
- Use of tricyclic antidepressive medication or MAO inhibitors.
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E.5 End points |
E.5.1 | Primary end point(s) |
- The relationship between plasma concentrations of norepinephrine and hemodynamics in terms of heart rate, cardiac index (CI), stroke volume index (SVI), and systolic, diastolic and mean arterial blood pressure (SAP, DAP, MAP, respectively) in awake circumstances.
- The relationship between plasma concentrations of norepinephrine and hemodynamics in terms of heart rate, cardiac index (CI), stroke volume index (SVI), and systolic, diastolic and mean arterial blood pressure (SAP, DAP, MAP, respectively) during standardized general anesthesia using propofol and remifentanil administration.
- The hemodynamic effects will be related to drug concentrations using PKPD analysis / modelling.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1 (awake state):
- norepinephrine (nor): Baseline; before and after Ringerlactate bolus (at 5 min); at the end of infusion of nor bolus (at 15 min) and 2 and 5 min thereafter; just before start of continuous infusion of nor (at 30 min); just before every incremental step of continuous nor infusion (at 45, 60, 75, 90 and 105 min); 2, 5 and 30 min after continuous infusion of nor stopped.
For phase 2, see ‘other language’
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Phase 2 (general anaesthesia:
- nor: 15 min after start of propfol/remifentanil (pf/rf) infusion; at the end of infusion of nor bolus (at 15 min) and 2 and 5 min thereafter; just before start of continuous infusion of nor (at 30 min); just before every incremental step of continuous nor infusion (at 30, 60, 90, 120, 150 and 180 min) and after the noxious stimuli half way during each step (45, 75, 105, 135 and 165 min); when continuous infusion of nor and pf/rf stopped and 2, 5, 10, 20 and 30 min thereafter.
- pf/rf: same as nor except for after nor bolus and after each noxious stimuli
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E.5.2 | Secondary end point(s) |
- Evaluation of the effect of the interaction between propofol, remifentanil and norepinephrine on hemodynamics during the induction of general anesthesia.
- Evaluation of the effect(s) of endogenous norepinephrine plasma concentration and observed arousal on the relationship between administered dose (and plasma concentration) of norepinephrine and induced hemodynamic alteration(s).
- Internal validation of the Beloeil norepinephrine TCI PKPD model and acquisition of data in order to improve this model performance.
- Assessment of changes in mean systemic filling pressure prior to and after induction of general anesthesia, as assessed by arm stop-flow measurements by application of a rapidly inflated tourniquet.
- Evaluation of the dose-dependent effect of administered norepinephrine on plasma melatonin concentrations prior to and after induction of general anaesthesia.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1 (awake state)
- melatonin: just before start of continuous infusion of norepinephrin (at 30 minutes), just before some incremental steps of continuous norepinephrin infusion (at 60, 90 and 105 minutes); 30 minutes after continuous infusion of epinephrin stopped.
Phase 2 (general anaesthesia)
- melatonin: just before start of continuous infusion of norepinephrin (at 30 minutes), just before every incremental step of continuous norepinephrin infusion (at 30, 60, 90, 120, 150 and 180 minutes); 30 minutes after continuous infusion of epinephrin stopped.
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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 | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
awale vs general anaesthesia |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |