Abstract
Introduction The healthy eubiosis' microbiome in infancy is regarded as the microbiome derived from term, vaginally delivered, antibiotic free, breastfed infants at 4-6 months. Dysbiosis is regarded as a deviation from a healthy state with reduced microbial diversity and deficient capacity to control drug-resistant organisms. Preterm infants are highly sensitive to early gut dysbiosis. Latter has been associated with sepsis and necrotising enterocolitis, but may also contribute to long-term health problems. Probiotics hold promise to reduce the risk for adverse short-term outcomes but the evidence from clinical trials remains inconclusive and none has directly assessed the effects of probiotics on the microbiome at high resolution. Methods and analysis A randomised, double blind, placebo-controlled study has been designed to assess the safety and efficacy of the probiotic mix of Bifidobacterium longum and infantis and Lactobacillus acidophilus in the prevention of gut dysbiosis in preterm infants between 28+0 and 32+6 weeks of gestation. The study is conducted in 18 German neonatal intensive care units. Between April 2018 and March 2020, 654 preterm infants of 28+0-32+6 weeks of gestation will be randomised in the first 48 hours of life to 28 days of once daily treatment with either probiotics or placebo. The efficacy endpoint is the prevention of gut dysbiosis at day 30 of life. A compound definition of gut dysbosis is used: (1) colonisation with multidrug-resistant organisms or gram-negative bacteria with high epidemic potential or (2) a significant deviation of the gut microbiota composition as compared with healthy term infants. Dysbiosis is determined by (1) conventional microbiological culture and (2) phylogenetic microbiome analysis by high-throughput 16S rRNA and metagenome sequencing. Persistence of dysbiosis will be assessed at 12-month follow-up visits. Side effects and adverse events related to the intervention will be recorded. Key secondary endpoint(s) are putative consequences of dysbiosis. A subgroup of infants will be thoroughly phenotyped for immune parameters using chipcytometry. Ethics and dissemination Ethics approval was obtained in all participating sites. Results of the trial will be published in peer-review journals, at scientific meetings, on the website (www.primal-study.de) and via social media of parent organisations. Trial registration number DRKS00013197; Pre-results.
| Original language | English |
|---|---|
| Article number | e032617 |
| Journal | BMJ Open |
| Volume | 9 |
| Issue number | 11 |
| ISSN | 2044-6055 |
| DOIs | |
| Publication status | Published - 01.11.2019 |
Funding
This is the first large-scale trial to assess the role of probiotics in the prevention of early gut dysbiosis in vulnerable preterm infants. We propose to improve clinical outcomes in preterm infants by modifying the early microbiome-immunity interaction through a biologically plausible mechanism, the administration of potentially microbiome-stabilising bacteria. Probiotics are widely used in extremely preterm infants as a prophylaxis for NEC. However, the results of several high-quality studies using different formulations remain inconclusive. In addition, long-term costs and benefits of probiotics are unclear. Thus, the key question in the PRIMAL clinical trial is whether probiotics reduce the development of gut dysbiosis in preterm infants. The second major question is whether probiotics promote the development of antimicrobial immunity, both with respect to molecular and clinical endpoints. Several elements that were not adequately addressed in previous studies will be incorporated into this RCT: (1) microbiome studies with high-resolution sequencing tools in a multicentre network, (2) sequencing of the maternal microbiome and (3) thorough immunological phenotyping. If probiotics are found to prevent gut dysbiosis and improve clinical outcomes, this may result in a change in nutritional strategies for preterm infants. It is particularly valuable to study the efficacy of PIPS, because they are exposed to many factors which can lead to dysbiosis. Preventive measures in the early neonatal period may have a lifelong impact. Previous observational studies indicate that probiotics are safe and well tolerated in an adequate clinical setting. 22 The administration of placebo as comparator is necessary to clarify efficacy and safety of probiotics. Bias will be limited by strict adherence to current CONSORT and SPIRIT recommendations and blinding of participants, families, healthcare providers, data collectors, outcome adjudicators and data analysts. The verum and placebo are prepared at the University of Lübeck pharmacy to guarantee similarity in colour, texture, odour and taste. To address a potential confounding effect due to poor compliance and non-random loss of participants, we will perform an ITT analysis. Several cointerventions, such as feeding, antibiotics and invasive measures are recorded to adjust for potential confounding effects. In summary, the PRIMAL clinical study is a unique opportunity to evaluate the efficacy of probiotics for preterm infants and is independent from the influence and commercial interests of the pharmaceutical industry. We thank all parents and their infants for participating in this study. We would like to thank the study coordinator Irene Fischer, the ZKS staff Marina Bleskina, Nicole Dohrmann, Alicia Illen, the research coordinators, nurses and clinicians at all participating sites for their excellent support to conduct the study. We also thank the members of our DSMB, Peter Bartmann (chair of the DSMB), Barbara Mitschdörfer, Markus Pfirrmann and Bernd Roth. JM and AH contributed equally. Contributors CH, JM, PH, MZ, SG, PB and EH conceptualised the study, obtained funding, obtained endorsement by PRIMAL consortium and wrote the protocol. IK and MV provided statistical expertise. AH, JM and CH wrote the first draft of the manuscript. CM, TVR, LMB, DF, CG, SG-F, WG, HH, JP, SP, BS, DV and EH provided critical review of the protocol and built enrolment capacity at their sites. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work. Funding This study is supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) grant (01GL1746B). Competing interests The verum was kindly provided by the company Metagenics (Aliso Viejo, California, USA). Patient consent for publication Not required. Ethics approval Institutional review board approvals have been obtained at all participating sites, specifically Ethical Board of the Medical Chamber of the Hansestadt Bremen, Ethical Board of the University of Bonn, Ethical Board of the Medical Chamber of the federal state of Mecklenburg-Vorpommern, Ethical Board of the University of Tübingen, Ethical Board of the Medical School Hannover, Ethical Board of the University of Cologne, Ethical Board of the University of Essen, Ethical Board of the Medical Chamber of the Westphalia-Lippe region, Ethical Board of the Medical Chamber of Hessen, Ethical Board of the Medical Chamber of Hamburg, Ethical Board of the University of Bochum, Ethical Board of the University of Freiburg, Ethical Board of the Medical Chamber of the federal state of Bavaria, Ethical Board of the University of Heidelberg, Ethical Board of the EMBL Heidelberg, Ethical Board of the University of Lübeck, Ethical Board of the University of Jena, Ethical Board of the Saar University Homburg. Provenance and peer review Not commissioned; externally peer reviewed.
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
