E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pediatric Acute Respiratory Distress Syndrome necessitating mechanical ventilation |
Pediatrisch Acuut Respiratoir Distress syndroom, waarvoor mechanische beademing noodzakelijk is. |
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E.1.1.1 | Medical condition in easily understood language |
Severe lung injury that requires mechanical ventilation |
Een ernstige longaandoening, waarvoor mechanische beademing noodzakelijk is |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to test the hypothesis that early use of neuromuscular blocking agents for 48 hours in paediatric patients younger than 5 years of age with moderate – to – severe paediatric acute respiratory distress syndrome will lead to a reduction in respiratory morbidity 12 months after discharge from the paediatric intensive care unit (PICU).
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Het primaire doel is om de hypothese te toetsen dat vroegtijdig gebruik van neuromusculaire blokkers gedurende 48 uur bij kinderen onder de 5 jaar met matig tot ernstig pediatrisch acuut respiratoir distress syndroom leidt tot een reductie in respiratoire morbiditeit 12 maand na ontslag van de pediatrische intensive care unit (PICU). |
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E.2.2 | Secondary objectives of the trial |
1. Effects of neuromuscular blocking agents on pulmonary and systemic inflammation
2. Effects of neuromuscular blocking agents on oxygenation and ventilation
3. Effects of neuromuscular blocking agents on respiratory system mechanics
4. Incidence of adverse drug reactions related to rocuronium
a. Occurrence of hypotension or tachycardia with the need for intervention by means of medication or fluid challenge
b. Number of re-intubations
5. Concomitant use of sedatives and/or analgesics
6. Prevalence of critical illness polyneuropathy and myopathy
7. Prevalence of ventilator – associated pneumonia
8. Number of hours on mechanical ventilation
9. Number of ventilator-free days
10. Length of PICU stay
11. Association between midazolam exposure (including metabolites) and inflammation and its contribution to clinical endpoints |
1. Effect van neuromusculaire blokkers op de pulmonale en systemische inflammatie
2. Effect van neuromusculaire blokkers op oxygenatie en ventilatie
3. Effect van neuromusculaire blokkers op mechanica van het respiratoire systeem
4. Incidentie van bijwerkingen op rocuronium
a. Voorkomen van hypotensie of tachycardie, waarvoor interventie middels medicatie of fluid challenge nodig is
b. Aantal herintubatie
5. Gebruik van sedativa en/of analgetica
6. Prevalentie van critical illness polyneuropathie en myopathie
7. Prevalentie van ventilator-geassocieerde pneumonie
8. Aantal uren aan mechanische beademing
9. Aantal ventilatorvrije dagen op dag 28
10. Duur van PICU-opname
11. Associatie tussen midazolam exposure (inclusief metabolieten) en inflammatie en de bijdrage aan klinische eindpunten |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Informed consent
- Age younger than 5 years
- Need for invasive mechanical ventilation with PEEP 5 cmH2O
- Early moderate – to – severe paediatric acute respiratory distress syndrome originating from any cause: - Acute onset of disease, and - Oxygenation index > 12, and - One or more (bilateral) infiltrates on chest radiograph, and - No evidence of left ventricular failure or fluid overload, and - Within the first 96 hours of PICU admission
- Sedation defined by Comfort – B scale between 11 - 17 |
- Informed consent
- Leeftijd onder de 5 jaar
- Invasieve mechanische beademing met PEEP 5 cm H2O noodzakelijk
- Vroeg matig tot ernstig pediatrisch acuut respiratoir distress syndroom, ongeachte welke oorzaak: - plotseling beging van ziekte, - oxygenatie index > 12, - één of meer (bilaterale) infiltraten op thoraxradiografie, - geen aanwijzingen voor linker ventrikel falen of overvulling, - binnen de eerste 96 uur van opname op de PICU
- Sedatie gedefineerd door Comfort-B scale tussen 11 - 17 |
|
E.4 | Principal exclusion criteria |
- No informed consent
- Known allergy or intolerance to rocuronium
- Continuous administration of neuromuscular blockade prior at the time of meeting the criteria for paediatric acute respiratory distress syndrome
- Bolus administration of neuromuscular blockade within 1 hour before meeting PARDS criteria
- Chronic respiratory failure on home ventilation
- Intracranial hypertension
- Bone marrow transplantation
- Pre-existing pulmonary hypertension
- Congenital heart disease with left - to - right shunting
- Cyanotic congenital heart disease
- Expected duration of mechanical ventilation less than 48 hours
- Withdrawal of life–sustaining treatment |
- Geen informed consent
- Bekende allergie of intolerantie voor rocuronium
- Continue toediening van neuromusculaire blokker voorafgaand aan het tijdstip dat voldaan wordt aan de criteria voor pediatrisch acuut respiratoir distress syndroom
- Toediening van een bolus van neuromusculaire blokker voorafgaand aan het tijdstip dat voldaan wordt aan de criteria voor pediatrisch acuut respiratoir distress syndroom.
- Chronisch respiratoir falen aan thuisbeadming
- Intracraniële hypertensie
- Beenmergtransplantatie
- Pre-existente pulmonale hypertensie
- Congenitale hartafwijking met link-rechts shunting
- Cyanotische congenitale hartafwijking
- Verwachte duur van mechanische beademing minder dan 48 uur
- Staken van levenverlengende behandeling |
|
E.5 End points |
E.5.1 | Primary end point(s) |
At least a 20% reduction in the cumulative respiratory morbidity score 12 months after PICU discharge, adjusted for confounding by age, gestational age, family history of asthma and/or allergy, season in which questionnaire was filled out and parental smoking.
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Een reductie in de cumulative respiratory morbidity score van ten minste 20% 12 maanden na ontslag van de PICU, gecorrigeerd voor leeftijd, zwangerschapsduur, familie historie van astma en/of allergie, seizoen waarin de vragenlijst is ingevuld en roken door ouders. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 months after PICU discharge. |
12 maanden na ontslag van de PICU |
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E.5.2 | Secondary end point(s) |
1. Lung clearance index (LCI)
2. Functional residual capacity (FRC)
3. Level and time course of the cumulative respiratory morbidity score assessed at 3, 6 and 9 months after PICU discharge
4. Level and time course of ventilator settings: peak inspiratory pressure, plateau pressure, mean airway pressure, driving pressure, positive end–expiratory pressure, set rate, total rate, inspiratory time
5. Level and time course of respiratory system mechanics: quasi–static compliance, dynamic compliance, resistance
6. Level and time course of oxygenation: SpO2/FiO2 ratio, PaO2/FiO2 ratio, oxygenation index, oxygen saturation index
7. Level and time course of ventilation: PCO2, pH
8. Level and time course of haemodynamic profile: heart rate, blood pressure, central venous pressure, daily cumulative fluid balance, number of fluid challenges
9. Level and time course of the non-respiratory PELOD–2 score
10. Number of adverse drug reactions
11. Number of re-intubations
12. Daily cumulative dosage sedatives
13. Daily cumulative dosage analgesics
14. Daily type and quantity of nutrition
15. Level and time course of pulmonary inflammatory response
16. Level and time course of systemic inflammatory response
17. Prevalence of critical illness polyneuropathy and myopathy
18. Prevalence of ventilator–associated pneumonia
19. The number of hours on mechanical ventilation
20. The number of ventilator-free days at day 28
21. The length of PICU stay
22. Association between midazolam exposure (including metabolites) and inflammation and its contribution to clinical endpoints |
1. Lung clearance index (LCI)
2. Functionele residuaal capaciteit (FRC)
3. Niveau en verloop in de tijd van de cumulative respiratory morbidity score
4. Niveau en verloop in de tijd van de ventilatorinstellingen: peak inspiratory pressure, plateau pressure, mean airway pressure, driving pressure, positive end-expiratory pressure, ingestelde frequentie, totale frequentie, inspiratietijd
5. Niveau en verloop in de tijd van de mechanica van het respiratoire systeem: quasi-static compliance, dynamic compliance, resistance
6. Niveau en verloop in de tijd van de oxygenatie: SpO2/FiO2 ratio, PaO2/FiO2 ratio, oxygenation index, oxygen saturation index
7. Niveau en verloop in de tijd van de ventilatie: PCO2, pH
8. Niveau en verloop in de tijd van het hemodynamischeprofiel: hartfrequentie, bloeddruk, centraal veneuze druk, dagelijkse vochtbalans, aantal fluid challenges
9. Niveau en verloop in de tijd van de non-respiratory PELOD-2 score
10. Aantal bijwerkingen
11. Aantal herintubaties
12. Dagelijkse cumulatieve dosis sedativa
13. Dagelijkse cumulatieve dosis analgetica
14. Dagelijks type en hoeveelheid voeding
15. Niveau en verloop in de tijd van de pulmonale inflammatoire respons
16. Niveau en verloop in de tijd van de systemische inflammatoire respons
17. Prevalentie van critical illness polyneuropathie en myopathie
18. Prevalentie van ventilator-geassocieerde pneumonie
19. Het aantal uren aan mechanische beademing
20. Het aantal ventilatorvrije dagen op dag 28
21. Duur van de PICU-opname
22. Associatie tussen midazolam exposure (inclusief metabolieten) en inflammatie en de bijdrage aan klinische eindpunten |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 and 2: 12 months after PICU discharge
3. 3, 6, and 9 months after PICU discharge
4, 5, 6, 7, 8: baseline and 12, 24, 36, 48, 72, 96 and 120 hours after randomisation
9. baseline and 24, 72 and 120 hours after randomisation
10, 11, 12, 13, 14: During PICU stay
15, 16: baseline and after 24 and 72 hours after randomisation
17, 18: from 48 hours after randomization untill discharge PICU
19, 20, 21: -
22. During PICU stay |
1 en 2: 12 maanden na ontslag van de PICU
3. 3, 6 en 9 maanden na ontslag van de PICU
4, 5, 6, 7, 8: baseline en 12, 24, 36, 48, 72, 96 en 120 uur na randomisatie
9. baseline en 24, 72 en 120 uur na randomisatie
10, 11, 12, 13, 14: Gedurende opname op de PICU
15, 16: baseline en 24 en 72 uur na randomisatie
17,18: vanaf 48 na randomisatie tot ontslag PICU
19, 20, 21: -
22. Gedurende opname op de PICU |
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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 | 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) | 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 | 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
| 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 | 6 |
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
|
LVLS |
Laatste bezoek van de laatste proefpersoon |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |