NEOBIFI: Clinical Trial for the Prevention and/or Reduction of the Incidence of Colics in Infants

Gut Microbiome Clinical Trial

— NEOBIFI  

Official title:

Effects of an Association of the Two Bifidobacteria Probiotics Bifidobacterium Breve B632 and Bifidobacterium Breve BR03 in Intestinal Bacterial Colonization and in the Prevention and/or Reduction of the Incidence of Colics in Infants

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03219931
• Other study ID #: CE 63/13
• Status: Completed
• Phase: Phase 4
• First received: July 14, 2017
• Last updated: January 10, 2018
• Start date: October 1, 2013
• Est. completion date: July 31, 2017

Study information

• Verified date: January 2018
• Source: Azienda Ospedaliero Universitaria Maggiore della Carita
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Infant colics represent a clinical condition in childhood, characterized by an uncontrollable crying that occurs without any apparent organic cause.1 They can be associated with face redness, closed fists, thighs flexion, meteorism, and gas emission. They are generally diagnosed according to Wessel's "rule of three" (>3 h of crying a day, for >3d a week, for >3wk in a row).2 These crises tend to reach their maximum intensity at 6 weeks of age, in most cases.3 They represent a serious source of anxiety for the family, increasing hospital admissions (5.8% of infants),4 postpartum depression risk, with higher stress levels for up to 3 years from these events. The etiology is still unknown. Anyway, it's assumed that the following factors may be involved: (1) Lactose intolerance. (2) Food hypersensitivity. (3) Feeding difficulties. (4) Disorders of the enteric nervous system. (5) Alterations of pain transmission. (6) Gastroesophageal reflux. (7) Intestinal hormones. (8) Psychosocial factors. (9) Alteration of the intestinal microbiota. In 1994, Lehtonen was the first to suggest that an altered intestinal microbiota composition in the very first months may induce intestinal colics in infants. Human intestinal microbiota is composed of about 1013 to 1014 microorganisms, mainly bacteria. The total number of microbiota genes is called "microbioma" and it is estimated to be 150 times the number of genes in the human genome.5 It acts as a real organ, whose activity can be influenced by diet, lifestyle, prebiotics, probiotics, and antibiotics. Several studies revealed the predominance of bifidobacteria in breastfed infants, whereas bottle-fed infants show a mixed population where bifidobacteria are less represented. the intestinal microbiota composition in a 3-year-old child is already similar to that of an adult.6 Other factors conditioning the microbiota are gestational age and type of birth. Colicky infants have a microbiota with a slow development and a lower stability over time.7 It also contains less lactobacilli and bifidobacteria, and a prevalence of gram-negative bacteria. The stools of these children often show increased levels of calprotectin, an intestinal index of inflammation.

RISK FACTORS ARE SEVERAL: Smoking: The exposure to cigarette smoke may be related to colics; this might be connected to the increase of plasma and intestinal levels of motilin. Maternal smoking during pregnancy seems to increase the risk of developing colics, more than postnatal exposition to smoke.8

Psychosocial: Infant colics may be more frequent with an instable psychosocial family environment. Maternal stress, anxiety, and depression are important risk factors.8 Breastfeeding: The difference between breastfeeding and bottlefeeding for colicky infants is controversial. Many studies have shown contrasting results,17 but the majority of the authors agree to attribute an important role to bottlefeeding. 9 A melatonin role was assumed too. This hormone is not secreted in infants, but only in adults, and has a hypnotic and relaxing role on the gastrointestinal smooth muscle. Its concentration shows a clear circadian rhythm, with a pick during night hours. Its presence in breast milk may be related to the lower occurrence of colics in breastfed infants compared with the bottle-fed infants.9 Recent literature shows an increasing attention toward probiotics,10 for the intestinal microbiota modulation. Some Lactobacillus reuteri strains were studied, with contrasting results in different studies; other probiotics as bifidobacteria showed in vitro anti-inflammatory properties and the ability to inhibit coliforms growth, whose presence is significant in colicky infants. Some probiotics exert a direct action on the bacterial growth, through bacteriocins production and final fermentation products.11 Bifidobacterium breve was isolated from healthy infants' feces.12 Aloisio et al13 tested in vitro ability of this strain and of other 45 bifidobacteria strains to oppose the growth of several microorganisms such as E. coli, S. enteriditis, C. difficile, K. pneumoniae, and Enterobacter cloacae. B. breve BR03, in a randomized clinical study, proved to have a beneficial effect on constipation in adults, it also seemed effective for the reduction of gas formation and for abdominal distension, and no side effects were shown during the treatment, while the beneficial effects lasted for up to 15 days after the end of the treatment.14,15 Both bifidobacteria strains showed, during an in vitro study, the ability to oppose 4 strains of E. coli; in particular, BR03 displayed an activity against E. coli O157:H7, an enterohemorrhagic strain that through Shiga toxin causes a potentially lethal infection.16

Description:

Type of Study: Interventional single-center, double-blind, randomized study, with treatment and placebo controlled.

Population: Only healthy babies were accepted. They were not treated with antibiotics, enrolled within 15 days from birth, and with an informed consent signed by the parents.

Parents were asked to make an initial recruitment examination within 15 days from birth and a second one at the 91st day of age, at the clinic of Pediatric Gastroenterology.

During the 90 days of the study, parents were asked to give 5 drops of active product (108 viable cells/strain) or placebo and to daily take note of minutes of crying, number, color, and consistency of evacuations, and number of regurgitations or vomits.

Probiotical S.p.A. (Novara, Italy) supplied the active product and the placebo. All data were collected in a database. Randomization was performed by an external operator of the study.

STATISTIC ANALYSIS:

Categorical variables were analyzed with the Fischer exact test. Comparisons between numeric variables between various groups were performed with the Kruskal-Wallis test (in the case of >2 groups) and with the Wilcoxon test for independent samples (in the case of only 2 groups being compared). A probability value of P<0.05 was considered as the limit of statistical significance.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 320
• Est. completion date: July 31, 2017
• Est. primary completion date: July 31, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A to 15 Days

Eligibility

Inclusion Criteria:

• Only healthy babies term born

• Between 6 days and 15 days of life

• With a Birth weight between 2500 gr and 4000 gr

• With natural childbirth

Exclusion Criteria:

• Adverse reactions to the product or component of the product (allergies…)

• Antibiotic treatments

• Chronic diseases, hepatic or gastroenterological diseases

• Medical treatment for chronic diseases

• Probiotic or prebiotic therapies

Related Conditions & MeSH terms

• Bifidobacterium Breve
• Colic
• Colic, Infantile
• Gut Microbiome
• Probiotic

Intervention

Drug:
• Bifidobacterium breve BR03 and Bifidobacterium breve B632
This is the active product containing 108 viable cells/strain
• Placebos
This is the placebo product containing a similar product without bifidobacterium inside.

Locations

Country	Name	City	State
Italy	AOU Maggiore della Carità - Clinica Pediatrica - Ambulatorio di Gastroenterologia Pediatrica	Novara

Sponsors (1)

Lead Sponsor	Collaborator
Azienda Ospedaliero Universitaria Maggiore della Carita

Country where clinical trial is conducted

Italy, 

References & Publications (23)

Aloisio I, Santini C, Biavati B, Dinelli G, Cencic A, Chingwaru W, Mogna L, Di Gioia D. Characterization of Bifidobacterium spp. strains for the treatment of enteric disorders in newborns. Appl Microbiol Biotechnol. 2012 Dec;96(6):1561-76. doi: 10.1007/s00253-012-4138-5. Epub 2012 May 17. — View Citation

Brooks GF, Carroll KC, Butel JS, et al. Jawetz, Melnick, & Adelberg's Medical Microbiology, 26e. Columbus, OH: McGraw-Hill; 2013.

Cohen Engler A, Hadash A, Shehadeh N, Pillar G. Breastfeeding may improve nocturnal sleep and reduce infantile colic: potential role of breast milk melatonin. Eur J Pediatr. 2012 Apr;171(4):729-32. doi: 10.1007/s00431-011-1659-3. Epub 2011 Dec 29. — View Citation

de Weerth C, Fuentes S, Puylaert P, de Vos WM. Intestinal microbiota of infants with colic: development and specific signatures. Pediatrics. 2013 Feb;131(2):e550-8. doi: 10.1542/peds.2012-1449. Epub 2013 Jan 14. — View Citation

Del Piano M, Carmagnola S, Anderloni A, Andorno S, Ballarè M, Balzarini M, Montino F, Orsello M, Pagliarulo M, Sartori M, Tari R, Sforza F, Capurso L. The use of probiotics in healthy volunteers with evacuation disorders and hard stools: a double-blind, randomized, placebo-controlled study. J Clin Gastroenterol. 2010 Sep;44 Suppl 1:S30-4. doi: 10.1097/MCG.0b013e3181ee31c3. — View Citation

Iacono G, Merolla R, D'Amico D, Bonci E, Cavataio F, Di Prima L, Scalici C, Indinnimeo L, Averna MR, Carroccio A; Paediatric Study Group on Gastrointestinal Symptoms in Infancy. Gastrointestinal symptoms in infancy: a population-based prospective study. Dig Liver Dis. 2005 Jun;37(6):432-8. Epub 2005 Mar 2. — View Citation

Iemoli E, Trabattoni D, Parisotto S, Borgonovo L, Toscano M, Rizzardini G, Clerici M, Ricci E, Fusi A, De Vecchi E, Piconi S, Drago L. Probiotics reduce gut microbial translocation and improve adult atopic dermatitis. J Clin Gastroenterol. 2012 Oct;46 Suppl:S33-40. doi: 10.1097/MCG.0b013e31826a8468. — View Citation

Indrio F, Di Mauro A, Riezzo G, Civardi E, Intini C, Corvaglia L, Ballardini E, Bisceglia M, Cinquetti M, Brazzoduro E, Del Vecchio A, Tafuri S, Francavilla R. Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr. 2014 Mar;168(3):228-33. doi: 10.1001/jamapediatrics.2013.4367. — View Citation

Kheir AE. Infantile colic, facts and fiction. Ital J Pediatr. 2012 Jul 23;38:34. doi: 10.1186/1824-7288-38-34. Review. Retraction in: Ital J Pediatr. 2014;40(1):9. — View Citation

Mogna L, Del Piano M, Deidda F, Nicola S, Soattini L, Debiaggi R, Sforza F, Strozzi G, Mogna G. Assessment of the in vitro inhibitory activity of specific probiotic bacteria against different Escherichia coli strains. J Clin Gastroenterol. 2012 Oct;46 Suppl:S29-32. doi: 10.1097/MCG.0b013e31826852b7. — View Citation

Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Doré J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J; MetaHIT Consortium, Bork P, Ehrlich SD, Wang J. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010 Mar 4;464(7285):59-65. doi: 10.1038/nature08821. — View Citation

Rhoads JM, Fatheree NY, Norori J, Liu Y, Lucke JF, Tyson JE, Ferris MJ. Altered fecal microflora and increased fecal calprotectin in infants with colic. J Pediatr. 2009 Dec;155(6):823-828.e1. doi: 10.1016/j.jpeds.2009.05.012. Epub 2009 Jul 22. — View Citation

Roger LC, Costabile A, Holland DT, Hoyles L, McCartney AL. Examination of faecal Bifidobacterium populations in breast- and formula-fed infants during the first 18 months of life. Microbiology. 2010 Nov;156(Pt 11):3329-41. doi: 10.1099/mic.0.043224-0. Epub 2010 Sep 23. — View Citation

Sanders ME. Impact of probiotics on colonizing microbiota of the gut. J Clin Gastroenterol. 2011 Nov;45 Suppl:S115-9. doi: 10.1097/MCG.0b013e318227414a. Review. — View Citation

Savino F, Cordisco L, Tarasco V, Calabrese R, Palumeri E, Matteuzzi D. Molecular identification of coliform bacteria from colicky breastfed infants. Acta Paediatr. 2009 Oct;98(10):1582-8. doi: 10.1111/j.1651-2227.2009.01419.x. Epub 2009 Jul 9. — View Citation

Savino F, Cordisco L, Tarasco V, Palumeri E, Calabrese R, Oggero R, Roos S, Matteuzzi D. Lactobacillus reuteri DSM 17938 in infantile colic: a randomized, double-blind, placebo-controlled trial. Pediatrics. 2010 Sep;126(3):e526-33. doi: 10.1542/peds.2010-0433. Epub 2010 Aug 16. — View Citation

Savino F. Focus on infantile colic. Acta Paediatr. 2007 Sep;96(9):1259-64. Review. — View Citation

Scardovi V, Casalicchio F, Vincenzi N. Multiple electrophoretic forms of transaldolase and 6-phosphogluconic dehydrogenase and their relationships to the taxonomy and ecology of the bifidobacteria. Int J Syst Bacteriol. 1979;29:312-327.

Sung V, Hiscock H, Tang ML, Mensah FK, Nation ML, Satzke C, Heine RG, Stock A, Barr RG, Wake M. Treating infant colic with the probiotic Lactobacillus reuteri: double blind, placebo controlled randomised trial. BMJ. 2014 Apr 1;348:g2107. doi: 10.1136/bmj.g2107. — View Citation

Van Niel CW. Probiotics: not just for treatment anymore. Pediatrics. 2005 Jan;115(1):174-7. — View Citation

WESSEL MA, COBB JC, JACKSON EB, HARRIS GS Jr, DETWILER AC. Paroxysmal fussing in infancy, sometimes called colic. Pediatrics. 1954 Nov;14(5):421-35. — View Citation

WHO. WHO European Ministerial Conference on Nutrition and Noncommunicable Diseases in the Context of Health 2020. Vienna: WHO; 2013.

Yalçin SS, Orün E, Mutlu B, Madendag Y, Sinici I, Dursun A, Ozkara HA, Ustünyurt Z, Kutluk S, Yurdakök K. Why are they having infant colic? A nested case-control study. Paediatr Perinat Epidemiol. 2010 Nov;24(6):584-96. doi: 10.1111/j.1365-3016.2010.01150.x. Epub 2010 Aug 17. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in infants crying - reduction of infants crying	The primary endpoint of the study was the assessment of the effectiveness of B. breve B632 and BR03 association in the reduction of infants crying over time. Both breastfed and bottle-fed babies were studied.	Change from Baseline (V0) of infant crying at 3 months (V1)
Secondary	Change in gastrointestinal symptoms	The second endpoint was to observe the effect of these probiotics on daily evacuations and on the number of regurgitations and vomits.	Change from Baseline (V0) of fecal evacuations, regurgitations and vomits at 3 months (V1)
Secondary	Change in fecal microbiome	Evaluate any variation of fecal microbiome	Change from Baseline of fecal microbiome (V0) at 3 months (V1)