E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Intestinal Malabsorption in Preterm Infants. |
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E.1.1.1 | Medical condition in easily understood language |
Preterm infants have an under-developed gastrointestinal tract. The final Insulin concentration obtained with NTRA-2112 is physiological and within the range present in breast milk and amniotic fluid. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025479 |
E.1.2 | Term | Malabsorption syndrome |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal 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 | 10025476 |
E.1.2 | Term | Malabsorption |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10017947 |
E.1.2 | Term | Gastrointestinal disorders |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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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 |
To assess the efficacy of 2 doses of NTRA-2112 as compared to placebo on intestinal malabsorption in preterm 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 the number of days to achieve discharge from hospital or readiness for discharge, whichever occurs first. Readiness for discharge from hospital defined as achieving all of the below: 1. Infant weight ≥ 1800g 2. Stable body temperature 3. Capable of oral feeding (reached full EN and not dependent on PN).
Other objectives: To compare 2 doses of NTRA-2112 to placebo with respect to : 4. Growth parameters (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 F/U periods 7. Number and % of infants reaching full EN within 6, 8, and 10 days from initiation of treatment 8. Total number of days receiving PN 9. Number of days to 120Kcal/kg/day 10. Number of days to wean-off PN
Exploratory objective: 1. Number of days to end gastric residuals over 2 ml/measurement according to the feeding protocol. |
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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 |
Name sub-study : Effect of NTRA-2112 on lactase activity and intestinal permeability in preterm infants Clinical Trial Protocol Addendum 1 (Netherlands) -Version 02 -27Aug2017 This sub-study which will be performed in up to sixty infants participating in the FIT-04 study in Academic Medical Center (AMC) in Amsterdam or Isala clinics in Zwolle, The Netherlands.
Primary Objective: To determine whether NTRA-2112 in own mother’s milk, donor human milk or preterm formula for 28 days results in higher lactase activity and lower intestinal permeability compared placebo. Secondary Objective(s): To determine whether 2000 μU/ml NTRA-2112 in own mother’s milk, donor human milk or preterm formula for 28 days results in higher lactase activity and lower intestinal permeability compared to 400 μU/ml NTRA-2112. |
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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** 4. Intra-uterine growth retardation (IUGR) defined as either weight for gestational age less than the third percentile or less than the 10’th percentile with Doppler abnormalities in utero***. 5. Confirmed necrotizing enterocolitis (NEC). 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 **Defined as positive blood culture, Leukocytosis >30,000 and Leukopenia <4,000. ***According to Fenton preterm growth chart (see Appendix D). If no Doppler in utero is available for infants with IUGR between third and 10’th percentile of Fenton preterm growth charts, infant is eligible to participate in the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Numbers of days to achieve full enteral feeding (NFE) is defined as: Number of Days to achieve enteral feeding of at least 150 ml/kg/day for at least 3 consecutive days The NFE is defined as the first of the three consecutive days. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key secondary endpoint: 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 PN
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.5.2.1 | Timepoint(s) of evaluation of this end point |
Up to 24 months corrected age |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Belgium |
Bulgaria |
France |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Spain |
United Kingdom |
United States |
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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 infant will be brought to the study site for a follow-up visit, at 24 months corrected age (±30days). In case the parents withdraw their consent, the infant's participation in the study will be terminated |
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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 | 5 |
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 | 5 |