E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Intestinal malabsorption in pre-term infants |
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E.1.1.1 | Medical condition in easily understood language |
Intestinal malabsorption in pre-term infants |
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E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
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 2 different doses of NTRA-2112 as compared to placebo, given for up to 28 days on intestinal malabsorption in pre-term infants as measured by the time to full enteral feeding. |
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E.2.2 | Secondary objectives of the trial |
Key secondary objective: To assess the effect of 2 doses of NTRA-2112 compared to placebo on number of days to achieve discharge from hospital or readiness for discharge from hospital, whichever comes first. Readiness for discharge from the hospital is defined as achieving all of the below:
- Infant weight ≥1800g
- Stable body temperature*
- Capable of oral feeding (not through nasogastric or orogastric tube
Other secondary objectives:
To compare 2 doses of NTRA-2112 to placebo with respect to the following:
1. Growth parameters
2. Number and percentage of infants reaching full enteral feeding within 6, 8, and 10 days from initiation of treatment
3. Mean enteral feeding (ml/kg) on days 6, 8 and 10 from initiation of treatment
Exploratory secondary objective: To compare 2 doses of NTRA-2112 to placebo with respect to the number of days to end gastric residuals over 2ml. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The sub study is available to sites in the Netherlands only. |
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E.3 | Principal inclusion criteria |
1. Male or female pre-term infants 26 and up to 32 weeks gestation (32 weeks + 0 day maximum). Gestational age matching (±2 weeks) between maternal dates and/or early antenatal ultrasound*.
2. Birth weight ≥ 500g.
3. Singleton, or twin birth.
4. Postnatal age up through and including Day 5 (up to 120 hours post birth).
5. Fraction of inspired oxygen ≤ 0.60 at enrolment.
6. Subjects must demonstrate cardiovascular stability at time of enrolment and would be considered unstable if they require >40% oxygen with blood pressure support and the need for umbilical artery cauterization.
7. Infant is able to tolerate enteral feed.
8. Infant is expected to wean off PN at the primary hospital.
9. Informed consent form (ICF) signed by parents or legal guardian.
10. In the Investigator’s opinion, the infant is able to comply with the study procedures and sufficiently stable to partake in the trial as required until trial completion.
* If both exist and difference > 2 weeks, based on early antenatal ultrasound |
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E.4 | Principal exclusion criteria |
1. Complete enteral feeding.
2. Major congenital malformation (e.g., Infants with genetic, metabolic, and/or endocrine disorder diagnosed before enrolment).
3. High index of suspicion of infection before enrolment-
Defined as positive blood culture, Leukocytosis >30,000 and Leukopenia <4,000.
4. Intra-uterine growth retardation (IUGR) defined as either weight for gestational age less than the third percentile or less than the 10th percentile with Doppler abnormalities in utero. According to Fenton preterm growth chart (see Appendix D). If no in utero Doppler study is available for infants with IUGR between third and 10’th percentile of Fenton preterm growth charts, the infant will be eligible to participate in the study.
5. Confirmed necrotizing enterocolitis (NEC).NEC is characterized by the sudden onset of gastrointestinal distress that may include symptoms such as vomiting, abdominal distention, bloody stools, or dilated loops of bowel that leads to cessation of enteral feedings.
6. Maternal diabetes (Type I/II or gestational) requiring insulin during pregnancy or in mothers past medical history.
7. Hyperinsulinemia requiring glucose administration of more than 12mg/kg/min at randomization.
8. Any systemic insulin administration at randomization.
9. Nothing per os (NPO) for any reason at the study entry.
10. Heart and chest compression or any resuscitation drugs given to the infant during delivery.
11. Subjects at risk for significant GI complications such as twin-to-twin transfusion syndrome (TTTS) or monochorionic monoamniotic twins.
12. Participation in another interventional clinical study that may interfere with the results of this trial |
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E.5 End points |
E.5.1 | Primary end point(s) |
Numbers of days to achieve full enteral feeding, defined as the ability of the preterm infant to achieve enteral feeding at least 150 ml/kg/day for 3 consecutive days |
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E.5.2 | Secondary end point(s) |
Number of days to discharge from the hospital or readiness-for-discharge from hospital, whichever occurs first
Readiness-for-discharge is defined as meeting all the following criteria:
1. Infant weight ≥ 1800g
2. Stable body temperature
3. Capable of oral feeding (reached full enteral feeding and not dependent on PN)
Additional secondary endpoints:
4. Growth velocity (g/kg/day)
5. Change in Z-score at 6, 8 and 10 days from initiation of treatment
6. Gain in body weight during the treatment and follow-up periods
7. Number and percentage of infants reaching full enteral feeding within 6, 8, and 10 days from initiation of treatment.
8. Total number of days receiving parenteral nutrition
9. Number of days to 120Kcal/kg/day
10. Number of days to wean-off PN1
Exploratory secondary endpoints:
11. Number of days to end gastric residuals over 2 ml/measurement according to the feeding protocol (Appendix A).
12. Gain in length during the treatment period and follow up period (long term follow-up period)
13. Gain in head circumference during the treatment period and follow up period (long term follow-up period)
14. Percent enteral feedings from total nutrition
15. Percent parenteral nutrition from total nutrition |
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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 | Yes |
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) | 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 | Yes |
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 | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 31 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 16 |