Early postnatal high-dose fat-soluble enteral vitamin A supplementation for moderate or severe bronchopulmonary dysplasia or death in extremely low birthweight infants (NeoVitaA): a multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial.

BACKGROUND: Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation. METHODS: This prospective, multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial conducted at 29 neonatal intensive care units in Austria and Germany assessed early high-dose enteral vitamin A supplementation (5000 international units [IU]/kg per day) or placebo (peanut oil) for 28 days in ELBW infants. Eligible infants had a birthweight of more than 400 g and less than 1000 g; gestational age at birth of 32+0 weeks postmenstrual age or younger; and the need for mechanical ventilation, non-invasive respiratory support, or supplemental oxygen within the first 72 h of postnatal age after admission to the neonatal intensive care unit. Participants were randomly assigned by block randomisation with variable block sizes (two and four). All participants received basic vitamin A supplementation (1000 IU/kg per day). The composite primary endpoint was moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age, analysed in the intention-to-treat population. This trial was registered with EudraCT, 2013-001998-24. FINDINGS: Between March 2, 2015, and Feb 27, 2022, 3066 infants were screened for eligibility at the participating centres. 915 infants were included and randomly assigned to the high-dose vitamin A group (n=449) or the control group (n=466). Mean gestational age was 26·5 weeks (SD 2·0) and mean birthweight was 765 g (162). Moderate or severe bronchopulmonary dysplasia or death occurred in 171 (38%) of 449 infants in the high-dose vitamin A group versus 178 (38%) of 466 infants in the control group (adjusted odds ratio 0·99, 95% CI 0·73-1·55). The number of participants with at least one adverse event was similar between groups (256 [57%] of 449 in the high-dose vitamin A group and 281 [60%] of 466 in the control group). Serum retinol concentrations at baseline, at the end of intervention, and at 36 weeks postmenstrual age were similar in the two groups. INTERPRETATION: Early postnatal high-dose fat-soluble enteral vitamin A supplementation in ELBW infants was safe, but did not change the rate of moderate or severe bronchopulmonary dysplasia or death and did not substantially increase serum retinol concentrations. FUNDING: Deutsche Forschungsgemeinschaft and European Clinical Research Infrastructures Network (ECRIN).

Assessment of an umbilical venous catheter dwell-time of 8-14 days versus 1-7 days in very low birth weight infacts (UVC - You Will See): a pilot single-center, randomized controlled trial.

BACKGROUND: Umbilical venous catheters (UVCs) are used for central vascular access in preterm infants, but controversy exits with regard to the optimum dwell-time. PATIENTS AND METHODS: Prospective, randomized controlled trial at a level III University neonatal intensive care unit (NICU), comparing a UVC dwell-time of 1-7 days (control group) to 8-14 days (intervention group) in very low birth weight (VLBW) infants. PRIMARY OUTCOME PARAMETER: Number of infants requiring additional peripherally inserted central catheters (PICC) after removal of UVC. SECONDARY OUTCOME PARAMETERS: Total number of central lines (CL = UVC and PICCs) until time point of full enteral feeds (130-160 mL/kg/d), total number of intravenous vascular catheters, number of CL-associated complications (infection, thrombosis/emboli, organ injury, secondary CL dislocation), number of X-rays for assessment of CL positioning, and days of therapy (DOT) (teicoplanin) for CL-associated blood stream infections (CLABSI). RESULTS: Of 116 patients screened for eligibility, 63 patients were enrolled - control group: 31 infants, mean gestational age (GA) 280 weeks (standard deviation (SD) 2.6 weeks), mean birth weight (BW) 988.9 g (SD 322.0 g); intervention group: 32 infants, mean GA 285 weeks (SD 3.0 weeks), mean BW 1078.9 g (SD 324.6 g). In the control group, 28 infants required additional PICCs versus 16 in the intervention group (p < 0.001); total number of CLs: control group n = 58 versus intervention group n = 28; p < 0.001, and the total number of venous vascular devices was also significantly higher in the control group (109 versus 61; p = 0.04). No significant differences were seen with regard to CL-associated complications (p = 0.09). The number of X-rays for assessment of correct CL-position significantly lower in the intervention group (144 versus 96; p = 0.03). In the intervention group, length of hospital stay was significantly shorter (88.1 (SD: 35.3 days) versus 68.1 (SD: 32.6 days); p = 0.03) and GA significantly lower at discharge from the hospital (404: SD: 33 weeks) versus 385: SD: 25 weeks; p = 0.02. No differences existed with regard to neonatal morbidities and mortality at 36 weeks gestational age. CONCLUSIONS: A longer UVC dwell-time of up to 14 days significantly decreased the number of painful invasive vascular procedures and radiation exposure, and shortened the length of the hospital stay. The findings of our pilot study should be confirmed in a larger, multi-center RCT with the primary focus on catheter-associated complications.

Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program.

BACKGROUND: To date, the cornerstone of treatment in patients with advanced or metastatic cholangiocarcinoma (CCA) is systemic chemotherapy based on a combination of gemcitabine and a platinum derivative. Other therapeutic approaches including targeted agents and tyrosine kinase inhibitors (TKI) have demonstrated disappointing results, highlighting the complexity of CCA. Recently, drugs aiming at the inhibition of HER-receptors have shown first therapeutic benefit in patients with late stage disease. The aim of this phase I study was to test the dose level toxicities (DLTs), safety and efficacy of afatinib, a highly specific panErbB family receptor TKI, in chemotherapy naive patients with advanced CCA in conjunction with an extensive biomarker program. METHODS: Afatinib was administered continuously p. o. as add-on in patients with advanced CCA who received conventional chemotherapy with gemcitabine/cisplatin. A classical 3 + 3 phase I study was employed, while the maximum tolerated dose (MTD) of oral afatinib was determined in a 2 step dose escalation. Safety, overall survival (OS) and progression free survival (PFS) were evaluated for all patients. Finally, a translational biomarker analysis was conducted for the EGFR and VEGF signalling cascades. RESULTS: Overall, 9 patients were enrolled. Further recruitment was discontinued due to lack of efficacy results of the tested drug in other indications. 30 mg afatinib could be safely administered as add-on to 80% of standard dose gemcitabine/cisplatin. The mOS and mPFS were 7.7 and 6.0 months, respectively. Diarrhoea and haematological disorders were the most common observed AEs. Almost all patients overexpressed EGFR on their tumour tissues, whereas none of them expressed mutations in Exons 18, 19 and 21. Non-responders showed a higher variation of VEGF-C, -D, leptin and sEGFR in their sera. CONCLUSIONS: Afatinib failed to show survival benefits in combination with gemcitabine/cisplatin in patients with advanced CCA. Mutational analysis of EGFR and pathways associated with VEGF-C, -D and leptin might show promising results in future studies. CLINICAL TRIALS REGISTRATION: NCT01679405 August, 2012.