E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Screening for Retinopathy of Prematurity is an essential yet painful routine test that is performed multiple times in infants who are born prematurely. Premature infants also regularly require heel lance for blood tests. We will conduct a randomised placebo-controlled trial to examine whether morphine is an effective analgesic for these procedures. |
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E.1.1.1 | Medical condition in easily understood language |
Preterm babies regularly require eye exams and blood tests, both of which are considered painful procedures. We will test morphine compared with placebo for both these procedures. |
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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 test whether administration of morphine reduces clinical pain scores (PIPP-R) compared with a placebo (inactive solution) 30 seconds after an eye examination to test for retinopathy of prematurity (ROP).
To test whether administration of morphine reduces pain-related brain activity compared with a placebo (inactive solution) following a clinically-essential heel lance.
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E.2.2 | Secondary objectives of the trial |
To test whether administration of morphine improves clinical stability after ROP screening in the 6-hour and 24-hour period following the start of the examclinical intervention (heel lance followed by retinopathy of prematurity (ROP) screening).
To test whether administration of morphine reduces clinical pain scores (PIPP-R) and motor reflex withdrawal activity compared with a placebo (inactive solution) following a clinically-essential heel lance compared with a placebo (inactive solution).
To test whether administration of morphine is safe by determining whether it results in episodes of respiratory depression or hypotension that require intervention compared with a placebo.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The study will be conducted in the neonatal unit at the John Radcliffe Hospital, Oxford.
Inclusion Criteria • Participants will be in-patients on the neonatal unit at the John Radcliffe Hospital, Oxford. • Infants born less than 32 weeks’ gestation or birth weight <1501 g • At the time of study, infants will be between 34 and 42 weeks gestational age (GA) and will be studied if they require a clinical heel lance and retinopathy of prematurity (ROP) screening on the same test occasion. We will study infants during a single test occasion when they are greater than or equal to 34 weeks’ gestation. Infants for whom parents/guardians have given written informed consent for inclusion in the trial. Parents/guardians have consented to inclusion in the trial.Senior clinician considers inclusion in trial to be medically appropriate.
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E.4 | Principal exclusion criteria |
Exclusion Criteria:
• intraventricular haemorrhage > grade II • short bowel syndrome • receiving nil by mouth due to documented gut pathology • received opiates in the last 72 hours • received other analgesics or sedatives in the last 24 hours • previously documented episode of morphine sensitivity • congenital malformation or genetic condition known to affect neurological development • born to mothers who regularly use opiates during pregnancy or while breastfeeding or expressing breast milk.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcome measure: Clinical pain score (PIPP-R) score 30seconds after ROP screening. Co-primary outcome measure: Magnitude of nociceptive-specific brain activity evoked by heel lance. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary outcome measure: 30 seconds after ROP screening Co-primary outcome measure: Immediately following heel lance |
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E.5.2 | Secondary end point(s) |
(1) Clinical stability in the 6-hour and 24-hour period following the start of the clinical intervention (heel lance followed by ROP screening). (Clinical stability assessment is calculated from pulse oximetry and blood pressure recordings and the need for increased respiratory support.)
(2) Premature infant pain profile-Revised (PIPP-R) score and amplitude of reflex withdrawal following heel lance.
(3) Drug safety will be assessed by calculating the number of incidences of apnoea that require intervention using NeoPuff or ‘bag and mask’ and the number of incidences of hypotension that requires treatment with inotropes in the 24-hour period following the administration of the IMP or placebo.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1) Clinical stability: 24-hours after ROP screening.
(2) Premature infant pain profile-revised (PIPP-R) score and amplitude of reflex withdrawal: immediately following heel lance.
(3) Drug safety: 24-hour period following the administration of the IMP or placebo. |
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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 | No |
E.6.5 | Efficacy | No |
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) | 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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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The end of the trial is defined as the point after data has been collected from the last participant in the study and once the database has been locked. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 16 |