Efficacy of Bifidobacterium longum, B. infantis and Lactobacillus acidophilus probiotics to prevent gut dysbiosis in preterm infants of 28+0-32+6 weeks of gestation: a randomised, placebo-controlled, double-blind, multicentre trial: the PRIMAL Clinical Study protocol

TY - JOUR

T1 - Efficacy of Bifidobacterium longum, B. infantis and Lactobacillus acidophilus probiotics to prevent gut dysbiosis in preterm infants of 28+0-32+6 weeks of gestation: a randomised, placebo-controlled, double-blind, multicentre trial: the PRIMAL Clinical Study protocol

AU - Marißen, Janina

AU - Haiß, Annette

AU - Meyer, Claudius

AU - Van Rossum, Thea

AU - Bünte, Lisa Marie

AU - Frommhold, David

AU - Gille, Christian

AU - Goedicke-Fritz, Sybelle

AU - Göpel, Wolfgang

AU - Hudalla, Hannes

AU - Pagel, Julia

AU - Pirr, Sabine

AU - Siller, Bastian

AU - Viemann, Dorothee

AU - Vens, Maren

AU - König, Inke

AU - Herting, Egbert

AU - Zemlin, Michael

AU - Gehring, Stephan

AU - Bork, Peer

AU - Henneke, Philipp

AU - Härtel, Christoph

AU - PRIMAL consortium

N1 - © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2019/11/21

Y1 - 2019/11/21

N2 - 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.

AB - 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.

KW - Bifidobacterium longum

KW - Bifidobacterium longum subspecies infantis

KW - Double-Blind Method

KW - Dysbiosis/prevention & control

KW - Enterocolitis, Necrotizing/prevention & control

KW - Feces/microbiology

KW - Gastrointestinal Microbiome

KW - Gestational Age

KW - Humans

KW - Infant, Newborn

KW - Infant, Premature

KW - Intensive Care Units, Neonatal

KW - Lactobacillus acidophilus

KW - Multicenter Studies as Topic

KW - Probiotics/administration & dosage

KW - RNA, Ribosomal, 16S/analysis

KW - Randomized Controlled Trials as Topic

KW - Sepsis/prevention & control

U2 - 10.1136/bmjopen-2019-032617

DO - 10.1136/bmjopen-2019-032617

M3 - SCORING: Journal article

C2 - 31753895

VL - 9

SP - e032617

JO - BMJ OPEN

JF - BMJ OPEN

SN - 2044-6055

IS - 11

ER -