German Clinical Trials Register

Acronym/abbreviation of the study

NeoVitaA

URL of the study

No Entry

Brief summary in lay language

Bronchopulmonary dysplasia (BPD) affects as many as 35% of extremely low birth weight infants (ELBW; birth weight < 1000 g). BPD is defined as the need for oxygen supplementation at 36 weeks postmenstrual age (PMA). The disease is marked by respiratory compromise and is associated with high mortality and severe long-term morbidity, including cerebral palsy. Unfortunately, many therapeutic approaches are non-effective (e.g., inhaled nitric oxide) or have significant side effects (administration of steroids). The beneficial role of intramuscular (i.m.) vitamin A (VA) supplementation has been demonstrated in a recent Cochrane meta-analysis; however, because of the substantial pain associated with repetitive i.m. injection, this form of VA supplementation is not common practice. Moreover, recent data indicate that there is substantial variation in how and how much VA is given to preterm infants in different Neonatal Intensive Care Units (NICUs). The aim of this study is to assess the role of early postnatal additional high-dose oral VA supplementation versus placebo for 28 days for preventing BPD or death in ELBW infants. Bronchopulmonary dysplasia is associated with an increased mortality rate and continues to carry significant long-term morbidity. Although a variety of medical interventions have been examined, most of them have proven to be futile (e.g., inhaled nitric oxide), or the interventions themselves carry substantial side effects (e.g., early administration of steroids). The intra-muscular administration of VA has been shown to be effective in significantly reducing the rate of BPD in preterm infants. However, given the fact that i.m. VA injections are painful, and that they have to be repeated several times, this practice has not been widely accepted in neonatal intensive care medicine. Therefore, a randomized controlled trial (RCT) that will assess the role of early postnatal additional high-dose oral VA supplementation to reduce and prevent the occurrence of BPD or death in this susceptible cohort (ELBW infants) is warranted. Study TreatmentsTest product: 5000 IU/kg/d of vitamin A oral solution (retinyl palmitate in peanut oil, Vitadral® Drops) Reference therapy: Placebo oral solution (peanut oil) Treatment of study medication is applied for 28 days commencing within 72hrs after birth Primary objectiveTo investigate whether early postnatal additional high dose oral vitamin A supplementation (5000 IU/kg body weight/day) for 28 days reduces the absolute risk of bronchopulmonary dysplasia (moderate/severe) or death at 36+0 weeks PMA in ELBW infants when compared to placebo treatment. Secondary objectivesTo assess the impact on high dose oral vitamin A supplementation on: 1. All-cause mortality 2. All grade BPD (mild/moderate/severe) 3. Duration of PPV and PPS 4. Duration of supplemental oxygen since birth 5. Serum VA status 6. Retinopathy of prematurity (ROP) 7. Intraventricular hemorrhage (IVH) 8. Periventricular leukomalacia (PVL) 9. Necrotizing enterocolitis (NEC) 10. Safety and tolerability of study medication 11. Total number of antibiotic treatments at 12 and 24 months of c.a. 12. Total number of antibiotic treatments for pulmonary infections at 12 and 24 months of c.a. 13. Total number of hospital admissions at 12 and 24 months of c.a. 14. Total number of hospital admissions for pulmonary infections at 12 and 24 months of c.a. 15. Results of Bayley-II scale at 24 months of c.a. 16. Anthropometric data at 12 and 24 months of c.a. 17. Neurological and non-neurological diseases during the first 12 and 24 months c.a. 18. Use of supportive therapies and specific drug treatment Trial designA prospective, multicenter, double-blind, randomized, placebo-controlled parallel group trial

Brief summary in scientific language

Synopsis: Titlle: A prospective, multicenter, double blind, placebo-controlled, two-arm parallel group phase 3 trial to evaluate the effect of early postnatal additional high dose oral vitamin A supplementation of 5000 IU/kg/d versus placebo for 28 days for preventing bronchopulmonary dysplasia (BPD) or death in extremely low birth weight (ELBW) infants. Short title NeoVitaA Trial EudraCT 2013-001998-24 Sponsor trial code ME 3827/1-1 IZKS trial code 2012-008 NeoVitaA Indication Bronchopulmonary Dysplasia Phase III Study Treatments Test product: 5000 IU/kg/d of vitamin A oral solution (retinyl palmitate in peanut oil, Vitadral® Drops) Reference therapy: Placebo oral solution (peanut oil) Treatment of study medication is applied for 28 days commencing within 72hrs after birth Primary objective To investigate whether early postnatal additional high dose oral vitamin A supplementation (5000 IU/kg body weight/day) for 28 days reduces the absolute risk of bronchopulmonary dysplasia (moderate/severe) or death at 36+0 weeks PMA in ELBW infants when compared to placebo treatment. Secondary objectives To assess the impact on high dose oral vitamin A supplementation on: 1.All-cause mortality 2.All grade BPD (mild/moderate/severe) 3.Duration of PPV and PPS 4.Duration of supplemental oxygen since birth 5.Serum VA status 6.Retinopathy of prematurity (ROP) 7.Intraventricular hemorrhage (IVH) 8.Periventricular leukomalacia (PVL) 9.Necrotizing enterocolitis (NEC) 10.Safety and tolerability of study medication 11.Total number of antibiotic treatments at 12 and 24 months of c.a. 12.Total number of antibiotic treatments for pulmonary infections at 12 and 24 months of c.a. 13.Total number of hospital admissions at 12 and 24 months of c.a. 14.Total number of hospital admissions for pulmonary infections at 12 and 24 months of c.a. 15.Results of Bayley-II scale at 24 months of c.a. 16.Anthropometric data at 12 and 24 months of c.a. 17.Neurological and non-neurological diseases during the first 12 and 24 months c.a. 18.Use of supportive therapies and specific drug treatment Trial design A prospective, multicenter, double-blind, randomized, placebo-controlled parallel group trial Trial population Inclusion criteria: Subjects meeting all of the following criteria will be considered for enrolment in the trial: -Neonates with a birth weight <1000 g -Who require receive any oxygen supplementation or respiratory support after admission to the NICU within 72 hours following birth -Who receive a basic VA supplementation of 1000 IU/kg body weight/day -Postnatal age <72 hours of life -Minimal/enteral feeds commenced -Signed and dated informed parental consent Exclusion criteria: Subjects presenting with any of the following criteria will not be enrolled in the trial: -≥1 major congenital abnormalities -Congenital nonbacterial infection with overt signs at birth -Terminal illness as evidenced by pH <7.0 for >2 hours or persistent bradycardia (heart rate <100 bpm) associated with hypoxia for >2 hours -Birth weight <400 g -Participation in another clinical trial Trial duration and dates First subject in: Q2 Q4 2014 Last subject out: Q1 Q4 2017 Duration of the trial 36 months Number of subjects Enrollment of approximately 1000 subjects accounting for a screening failure rate of 10% / 914 patients to be randomized. To be screened: 1000 subjects To be enrolled/randomized: 914 subjects (expected screening failure rate of 10%) Number of sites > 25 trial sites are planned to participate. Primary endpoint Combined Incidence of BPD (moderate/severe) or death at 36+0 weeks PMA. Secondary endpoints 1. Any death 2.Any occurrence of BPD (mild/moderate/severe) 3.Days of PPV or PPS 4.Days of oxygen supplementation therapy 5.Serum retinol levels, RBP, RE 6.Diagnosis of ROP using ophthalmological examination 7.Diagnosis of all grades of IVH using cranial ultrasound investigation 8.Diagnosis of PVL using cranial ultrasound investigation 9.Diagnosis of NEC using clinical examination and X-ray investigation 10.Occurrence of any adverse Event 11. Total number of infections and pulmonary infections at 12 and 24 months corrected gestational age (12) Total number of antibiotic treatments for pulmonary infections at 12 and 24 months corrected gestational age (13) Total number of hospital admissions at 12 and 24 months corrected gestational age (14) Total number of hospital admissions for pulmonary infections at 12 and 24 months corrected gestational age (15) Results from Bayley-II scale at 24 months corrected gestational age (16) Anthropometric data at 12 and 24 months corrected gestational age (17) Neurological and non-neurological diseases during the first 12 and 24 months corrected gestational age (18) Use of supportive therapies and specific drug treatment Statistical analysis Primary analysis variable: - Evaluation of the primary endpoint is planned in the ITT population by a logistic regression analysis with treatment group and trial site as covariates. The global, two-sided significance level is set to 0.05. Secondary analysis variables: - Evaluation of secondary outcomes is explorative. Descriptive statistical analyses are used for each of the two study groups separately. For quantitative variables mean and standard deviation and for qualitative variables absolute and relative frequencies are computed, respectively. Interim analysis: There is one interim analysis after 50% of patients have reached 36+0 weeks PMA. 2 sequential tests are made and the O'Brien-Fleming alpha spending function is used to account for the issue of multiple testing. The global two-sided significance level is 0.05. No stop for futility is incorporated in this design.