E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
1. A first PK/PD study will assess the efficacy of fentanyl using a PK/PD model where log concentration of the drug is related to pain score change in response to standardised procedural pain. This will be a feasibility study for the main clinical efficacy and safety NeoOpioid study that will implement the optimal fentanyl dosage derived from this model and will aim at further explaining the impact of dependent and confounding factors on the dosage needed (i.e. immaturity, birth weight, morbidity, physiologic stress responses, hemodynamics, and genetic variability). |
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E.2.2 | Secondary objectives of the trial |
Evaluate cortical and hormonal responses to pain management with fentanyl. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Clinical indication (or pain scoring, see 7.2.1: PIPP ≥ 7, or BIIP ≥ 3, or EDIN ≥ 6) for analgesia before any of following procedure:
a. Insertion of peripheral IV-catheter
b. Insertion of arterial cannula
c. Other skin breaking procedure
d. Insertion of chest tube
Other painful/stressful procedure might be considered if indicated by pain scoring used, eg. endotracheal suction.
2. Possibility to obtain blood sample after the procedure (indwelling line or the procedure is insertion of line as clinically indicated)
3. Infants of all gestational ages (preferably preterm born at a gestational age of 24 0/7 to 32 6/7 weeks and term infants at 38-41 gestational weeks (gw) for the first 65 in the PK/PD model)
4. Postnatal age 0-28 days, ie up to an age corresponding to 44 post conceptional weeks.
5. Informed written parental consent.
The infants will be analyzed in five postconceptional age groups and the target number of infants are:
23-26 gw n= 20
27-28 gw n= 30
29-32 gw n= 40
33-36 gw n= 40
37-42 gw n= 50
The same infant can be included for another painful procedure after at least 2 weeks interval, ie when has reached the next gestational age group. In total maximum three series of blood sampling, according to weight.
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E.4 | Principal exclusion criteria |
1. Concurrent or previous other opioid administration:
a. for morfine a 72 h interval required
b. for remifentanil a 6 h interval required
c. for alfentanil a 24 h interval required
d. (previous fentanyl administration is NOT an exclusion criterion, but baseline concentration needed before study drug administered)
2. Abdominal surgery (since intra-abdominal pressure influences fentanyl metabolism)
3. Major chromosomal anomaly, e.g. trisomy
4. Neonatal encephalopathy (e.g. seizures, lethargy/coma)
5. Use of muscular relaxant
6. Hypothermia treatment after hypoxic-ischemic insult
7. Clinical or biochemical evidence of hepatic failure (e.g. cholestasis, hepatic coagulopathy, hypoalbuminaemia) or renal failure (serum creatinine > 132 micro mol/L corresponding to >1.5 mg/dL42)
8. Participation in other clinical intervention trial (including blood sampling procedures other than clinical routine, and administration of other investigational medicinal product) within 72 hours before study start and throughout the study
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E.5 End points |
E.5.1 | Primary end point(s) |
To assess the fentanyl total body clearance (dose related to concentration AUC) and
derive an algorithm for fentanyl administration from the PK/PD model to be used in the efficacy/safety clinical study (NeoOpioid).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
0, 10 min 2 h, 4h, 8 h and 24 h |
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E.5.2 | Secondary end point(s) |
To investigate cortical hemodynamic responses (NIRS) in relation to neurophysiological
and behavioural responses and blood levels of stress hormones. |
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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 | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
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 | 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 | No |
E.8.2.3 | Other | No |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |