E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Children < 1 year of age undergoing major open abdominal surgery. |
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E.1.1.1 | Medical condition in easily understood language |
Children < 1 year of age undergoing major open abdominal surgery. |
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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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10021298 |
E.1.2 | Term | Ileal atresia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10010526 |
E.1.2 | Term | Congenital large intestinal atresia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002120 |
E.1.2 | Term | Anal atresia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10010626 |
E.1.2 | Term | Congenital small intestinal atresia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10062022 |
E.1.2 | Term | Intestinal atresia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10013812 |
E.1.2 | Term | Duodenal atresia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028210 |
E.1.2 | Term | Multiple gastrointestinal atresias |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 |
In this prospective, double-blind, randomized controlled trial, we investigate the hypothesis that regional anesthesia provided by WCI with ropivacaine will reduce pain postoperatively (as measured with COMFORT behavior scale and Numeric Rating Scale (NRS) Pain scores) and lead to a morphine-sparing effect of at least 30% after major abdominal surgery in infants < 1 year of age.
In this investigation also plasma ropivacaine levels will be measured, during the phase of continuous infusion via the wound catheter, to determine if levels of ropivacaine remain below toxic thresholds.
Primary Objective:
The mean cumulative amount of morphine administered over 48 hours postoperatively, in mcg/kg, will be compared in both groups (R group and control group).
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E.2.2 | Secondary objectives of the trial |
1. Efficacy of treatment of postoperative pain
• Number of patients needing extra morphine boluses (rescue), over 48 hours.
• Total amount of morphine administered postoperatively, until removal of the wound catheter.
• AUC 24 hours COMFORT-B score and NRS, and percentage of high pain scores (NRS ≥ 4 and COMFORT ≥ 17).
2. Safety of the use of WCI with ropivacaine
• Toxicity of local anesthetic:
- hypotension
- arrhythmia
- convulsions
• The incidence of adverse effects related to the wound catheter
- accidental luxation of the wound catheter
- infection
- hematoma of the wound
- delayed healing of the wound
- wound dehiscence
• Plasma concentrations of ropivacaine will be measured, to determine if plasma levels do not exceed toxic thresholds.
2. Adverse events related to the use of opioids
• Signs of respiratory depression:
• Gastro-intestinal
• Hemodynamic
4. Other variables
• Surgical stress score
• The Parents’ Postoperative Pain Measure- Short Form |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must meet all of the following criteria:
- Informed consent
- Children < 1 year of age
- Minimal post-conceptual age of 35 weeks
- Minimal body weight of 1500 grams
- Abdominal (open) surgery
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E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study:
- Withdrawal of informed consent
- Child with neurological disease, renal or hepatic dysfunction
- Chronic (more than one day) opioid or psychotropic drug (e.g. antiepileptics, benzodiazepines, antidepressants) exposure pre- or postnatal, in neonates (maximum 28 days old) presenting for surgery, or < 1 month ago.
- Opioid exposure <24 hours before surgery
- Receiving ECMO therapy
- Known allergy / intolerance for paracetamol or morphine
- Contra-indications for regional analgesia techniques:
o Allergy to local anesthetics
o Local or general infection (sepsis)
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcome measure is mean cumulative morphine dose over 48 hours in mcg/kg. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Children will be randomized for treatment with wound catheter infusion (WCI) with a bolus dose and continuous infusion with ropivacaine (R group) or with placebo (saline) (C). At the end of surgery both groups receive a bolus dose IV: morphine in the C group and placebo (saline) in the R group. Both groups will receive intermittent administration of paracetamol IV (as primary analgesic) and titrated morphine IV in case of documented pain as rescue therapy.
The child's postoeprative pain is assessed every 2 hours, using the validated COMFORT behavior scale and the Numeric Rating Scale Pain (assessed by the attending nurse). Additional morphine is administered whenever the NRS > 4 and COMFORT B scale > 16, which indicates pain. |
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E.5.2 | Secondary end point(s) |
1. Number of patients needing extra morphine boluses (rescue), over 48 hours.
2. Total amount of morphine administered postoperatively, until removal of the wound catheter.
3. AUC 24 hours COMFORT-B score and NRS, and percentage of high pain scores.
4. The incidence of opioid related adverse effects:
- Signs of respiratory depression
- Gastro-intestinal
- Hemodynamic
5. The incidence of ropivacaine related side effects
6. The incidence of adverse effects related to the wound catheter:
- Accidental luxation of the wound catheter
- Infection: wound infection, sepsis
- Hematoma of the wound
- Delayed healing of the wound
- Wound dehiscence
7. Plasma concentrations of ropivacaine:
To determine the PK-PD relationship for paracetamol IV and morphine IV, and to
determine if plasma ropivacaine levels do not exceed toxic levels, blood samples will be
taken from an indwelling arterial line, or at the same time a regular blood sample is taken
by heel prick, concomitant with blood sampling for clinical purposes (in case there is no
arterial line). PK and PD data will be fitted using data from all individuals simultaneously
using non-linear mixed effect modelling (NONMEM). Patients will not suffer extra heel
pricks for only study purposes. With respect to the ethical requirement that not more
than 3% of the total blood volume (80-100 ml/kg) can be drawn from a patient, sampling
will be restricted to maximum three samples per day (0.5 ml each) (maximum six samples
over the whole study period).
Other study parameters
1. Baseline value: post conceptual (PC) age at birth, birth weight, (PC) age at the day of operation, weight at the day of operation, indication for surgery, type of operation, medication use, concomitant disease, ASA classification.
2. Time until discharge from the PICU/ recovery ward
3. Surgical stress:
To classify the surgical stress of the different procedures, the Surgical Stress Score is computed by the surgeon at the end of surgery:
the amount of blood loss (score range 0-3)
site of surgery (score range 0-2)
amount of superficial trauma (score range 1-3)
extent of visceral trauma (score range 1-4)
duration of surgery (score range 1-5)
associated stress factors
hypothermia (score range 0-3)
infection (score range 0-3)
The total scores are used to divide the procedures in minor, moderate or severe surgical stress.
4. PPPM-SF: Parents’ Postoperative Pain Measure – Short Form
One week after the operation, the parents are contacted by telephone to fill out the PPPM-SF, a validated questionnaire, which shows the postoperative recovery of a child after discharge from the hospital.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Number of patients needing extra morphine boluses (rescue), over 48 hours.
2. Total amount of morphine administered postoperatively, until removal of the wound catheter (until 72 hours postop)
3. AUC 24 hours COMFORT-B score and NRS, and percentage of high pain scores.
4. The incidence of opioid related adverse effects: until 72 hours postop
5. The incidence of ropivacaine related side effects: until 72 hours postop
6. The incidence of adverse effects related to the wound catheter: until 72 hours postop
7. Plasma concentrations of ropivacaine: maximum six samples over 72 hours
8. Baseline values: at inclusion
9. Time until discharge from the PICU/ recovery ward: at discharge
10. Surgical stress: postoperatively
11. PPPM-SF: One week after the operation |
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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 | Yes |
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 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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The study will be temporarily terminated when a patients shows signs of clinical toxicity of local anesthetics, or when a serious adverse event, possibly related to the wound catheter or ropivacaine, occurs (SUSAR).
In this case the Data Safety Monitoring Board (DSMB), will do an interim analysis, including analysis of the results of the plasma concentrations of ropivacaine per patient, and they will advise on the complete termination of the study, or if the investigation can proceed.
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |