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Lactobacillus Reuteri Versus Placebo in the Treatment and Prevention of Infantile Colic

Primary Purpose

Infantile Colic

Status
Unknown status
Phase
Not Applicable
Locations
Italy
Study Type
Interventional
Intervention
Lactobacillus reuteri DSM 17938
Placebo
L.reuteri + Vit D
Vit D placebo
Sponsored by
Azienda Ospedaliera Ospedale Infantile Regina Margherita Sant'Anna
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infantile Colic focused on measuring infantile colic, lactobacillus, gut microflora, FISH, toll like receptor, T reg, messenger RNA, CC-chemokine receptor 7, interleukin 10

Eligibility Criteria

4 Weeks - 16 Weeks (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • clinical diagnosis of infantile colic according to Wessel's criteria
  • gestational age between 37 and 42 weeks
  • age between 4 and 16 weeks
  • birth weight between 2500 and 4000 g
  • exclusively breastfed

Exclusion Criteria:

  • clinical evidence of chronic illness or gastrointestinal disorders
  • administration of probiotics and antibiotics

Sites / Locations

  • Ospedale Infantile Regina MargheritaRecruiting
  • Ospedale Infantile Regina MargheritaRecruiting
  • Ospedale Infantile Regina MargheritaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Arm Label

Lactobacillus reuteri

Placebo

L.reuteri + vit D

Vit D Placebo

Arm Description

Lactobacillus reuteri DSM 17938 is administered at a dose of 1.000.000.000 colony forming units (CFU) in V drops of a commercially available oil suspension, 30 min before feeding, once a day for 30 days.

Placebo is administered in V drops once a day for 30 days. Placebo is inactive, similar to the studied treatment with the same package, taste, characteristics of colour and consistency.

L. reuteri DSM 17938 (10^8 CFU) plus vitamin D3 (400 UI) five drops/day for 3 months

vitamin D3 (400 UI) five drops/day for 3 months

Outcomes

Primary Outcome Measures

Reduction of the daily average crying time from baseline to the end of the treatment period, to less than 3 hours a day, the cut-off proposed by Wessel and number of responders versus non-responders in each group at the end of the treatment
diary crying Barr

Secondary Outcome Measures

Responders to treatment
was defined as the number of responders in each group on days 7, 14 , 21 and 30 . Responders (defined in the protocol) were those who experienced a decrease in the daily average crying time of 50% from baseline. Diary Crying Barr.
To analyze intestinal microflora
The intestinal microflora of the infants will be analyzed the effect of the probiotic on selected intestinal microbiota (Escherichia coli, Clostridium butyricum, Lactobacillus, Bifidobacterium), using fluorescent in situ hybridization (FISH) or using with Real-Time PCR Taqman.
Assay of Th17/Treg balance
For the analyses of mRNA FOXP3 and RORγ in peripheral blood RT-PCR Real Time Taqman will be used

Full Information

First Posted
May 5, 2009
Last Updated
March 2, 2021
Sponsor
Azienda Ospedaliera Ospedale Infantile Regina Margherita Sant'Anna
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1. Study Identification

Unique Protocol Identification Number
NCT00893711
Brief Title
Lactobacillus Reuteri Versus Placebo in the Treatment and Prevention of Infantile Colic
Official Title
Lactobacillus Reuteri Versus Placebo in the Treatment and Prevention of Infantile Colic: a Clinical and Microbiological, Double-blind, Prospective, Randomised, Controlled Study
Study Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Unknown status
Study Start Date
March 2008 (undefined)
Primary Completion Date
November 2021 (Anticipated)
Study Completion Date
December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Azienda Ospedaliera Ospedale Infantile Regina Margherita Sant'Anna

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is: to study the intestinal microflora of colicky infants before and after L. reuteri or placebo administration, evaluating the effect of Lactobacillus reuteri on the growth of the main intestinal microbiota (coliforms, Clostridium butyricum, Lactobacilli, Bifidobacteria) with fluorescent in situ hybridization (FISH) technique or with Real-Time PCR Taqman; Further, the global intestinal microflora composition, using large-scale DNA sequencing of 16S rRNA genes ( 454-pyrosequencing technique. to evaluate the improvement of colicky symptoms by the oral administration of Lactobacillus reuteri (primary outcome: reduction of the daily average crying time from baseline to the end of the treatment period, to less than 3 hours a day, the cut-off proposed by Wessel; secondary outcome: number of responders versus non-responders in each group at the end of the treatment). to evaluate fecal calprotectin values at the beginning and at the end of the study. BÜHLMANN Quantum Blue® Calprotectin High Range (Schönenbuch, Switzerland). A quantitative immunoassay. to evaluate Th17/Treg balance at time 0 and t 30 ( days) investigating mRNA FOXP3 and RORγ in peripheral blood using RT-PCR Real Time Taqman. the measurement of the expression level of CC-chemokine receptor 7 messenger RNA using the real-time TaqMan reverse transcription polymerase chain reaction method. the measurement of expression of interleukin 10 (IL-10) messenger RNA using the real-time TaqMan reverse transcription polymerase chain reaction method. Parental satisfaction at the end of the study period ( 30 day ) with a numerc scale from 1 to 10.
Detailed Description
Infantile colic is one of the most common problems within the first three months of life. It consists of a behavioural syndrome characterised by paroxysmal, excessive and inconsolable crying without identifiable cause. Although infantile colic is commonly reported and causes appreciable distress for both parents and paediatricians, despite forty years of research, its aetiology still remains unclear. Recently the role of intestinal microflora has growing importance, and a lower count of intestinal lactobacilli has been observed in colicky infants compared to healthy ones. In a recent study we have observed that Lactobacillus reuteri improved colicky symptoms in breast-fed infants within one week of treatment compared to Simethicone, suggesting that probiotics may play a role in infantile colic (Savino F, Pelle E, Palumeri E, Oggero R, Miniero R.Lactobacillus reuteri (American Type Culture Collection Strain 55730) versus simethicone in the treatment of infantile colic: a prospective randomized study. Pediatrics 2007; 119:e124-30). The mechanism involved in such finding is only partially understood and, for this reason, we have planned this new study to evaluate not only the clinical improvement but also the microbiological data.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infantile Colic
Keywords
infantile colic, lactobacillus, gut microflora, FISH, toll like receptor, T reg, messenger RNA, CC-chemokine receptor 7, interleukin 10

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
155 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Lactobacillus reuteri
Arm Type
Active Comparator
Arm Description
Lactobacillus reuteri DSM 17938 is administered at a dose of 1.000.000.000 colony forming units (CFU) in V drops of a commercially available oil suspension, 30 min before feeding, once a day for 30 days.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo is administered in V drops once a day for 30 days. Placebo is inactive, similar to the studied treatment with the same package, taste, characteristics of colour and consistency.
Arm Title
L.reuteri + vit D
Arm Type
Active Comparator
Arm Description
L. reuteri DSM 17938 (10^8 CFU) plus vitamin D3 (400 UI) five drops/day for 3 months
Arm Title
Vit D Placebo
Arm Type
Placebo Comparator
Arm Description
vitamin D3 (400 UI) five drops/day for 3 months
Intervention Type
Other
Intervention Name(s)
Lactobacillus reuteri DSM 17938
Other Intervention Name(s)
Reuterin,Noos - Italy; BIOGAIA drops - Sweden
Intervention Description
Lactobacillus reuteri is administered at a dose of 1.000.000.000 colony forming units (CFU) in V drops/day for 21 days
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
Placebo BIOGAIA Sweden
Intervention Description
Placebo is administered in V drops once a day for 21 days. Placebo is inactive, similar to the studied treatment with the same package, taste, characteristics of colour and consistency.
Intervention Type
Dietary Supplement
Intervention Name(s)
L.reuteri + Vit D
Other Intervention Name(s)
Reuterin D3 drops, Noos Italy, Reuflor D3 drops, Recordati Italy
Intervention Type
Dietary Supplement
Intervention Name(s)
Vit D placebo
Primary Outcome Measure Information:
Title
Reduction of the daily average crying time from baseline to the end of the treatment period, to less than 3 hours a day, the cut-off proposed by Wessel and number of responders versus non-responders in each group at the end of the treatment
Description
diary crying Barr
Time Frame
time 0 - 7 - 21 - 30 days
Secondary Outcome Measure Information:
Title
Responders to treatment
Description
was defined as the number of responders in each group on days 7, 14 , 21 and 30 . Responders (defined in the protocol) were those who experienced a decrease in the daily average crying time of 50% from baseline. Diary Crying Barr.
Time Frame
30 day
Title
To analyze intestinal microflora
Description
The intestinal microflora of the infants will be analyzed the effect of the probiotic on selected intestinal microbiota (Escherichia coli, Clostridium butyricum, Lactobacillus, Bifidobacterium), using fluorescent in situ hybridization (FISH) or using with Real-Time PCR Taqman.
Time Frame
day 0 and day 30
Title
Assay of Th17/Treg balance
Description
For the analyses of mRNA FOXP3 and RORγ in peripheral blood RT-PCR Real Time Taqman will be used
Time Frame
time 0- 30 days
Other Pre-specified Outcome Measures:
Title
Preventive effects of L.reuteri on infantile colic
Description
action on: use of pain relieving agents, switch to infant formula, number of paediatric consultations for infantile colic
Time Frame
5 months
Title
Fecal calprotectin values
Description
BÜHLMANN Quantum Blue® Calprotectin High Range (Schönenbuch, Switzerland). It is a quantitative determination of fecal calprotectin through a sandwich immunoassay.
Time Frame
0-30 days
Title
Parental satisfacion
Description
numeric scale from 1to 10
Time Frame
day 30

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Weeks
Maximum Age & Unit of Time
16 Weeks
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: clinical diagnosis of infantile colic according to Wessel's criteria gestational age between 37 and 42 weeks age between 4 and 16 weeks birth weight between 2500 and 4000 g exclusively breastfed Exclusion Criteria: clinical evidence of chronic illness or gastrointestinal disorders administration of probiotics and antibiotics
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Francesco Savino, MD, PhD
Phone
00390113135618
Email
francesco.savino@unito.it
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francesco Savino, MD, PhD
Organizational Affiliation
Ospedale Infantile Regina Margherita - Dipartimento di Pediatria.S.S.D. SAPI, Torino
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ospedale Infantile Regina Margherita
City
Torino
State/Province
TO
ZIP/Postal Code
10126
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Francesco Savino, MD PhD
Phone
+39 0113135618
Email
francesco.savino@unito.it
First Name & Middle Initial & Last Name & Degree
Francesco Savino, MD PhD
Facility Name
Ospedale Infantile Regina Margherita
City
Torino
ZIP/Postal Code
10126
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Francesco Savino, MD, PhD
Phone
00390113135224
Email
francesco.savino@unito.it
First Name & Middle Initial & Last Name & Degree
Valentina Tarasco, MD
First Name & Middle Initial & Last Name & Degree
Elisabetta Palumeri, MD
First Name & Middle Initial & Last Name & Degree
Emanuela Locatelli, MD
First Name & Middle Initial & Last Name & Degree
Diego Matteuzzi, Professor
First Name & Middle Initial & Last Name & Degree
Lisa Cordisco, PhD
First Name & Middle Initial & Last Name & Degree
Roberto Oggero, MD
First Name & Middle Initial & Last Name & Degree
Emanuele Castagno, MD
First Name & Middle Initial & Last Name & Degree
Roberto Calabrese, PhD
First Name & Middle Initial & Last Name & Degree
Stefan Roos, PhD
First Name & Middle Initial & Last Name & Degree
Simone Ceratto, MD
First Name & Middle Initial & Last Name & Degree
Angela De Marco, MD
First Name & Middle Initial & Last Name & Degree
Maria Garro, MD
First Name & Middle Initial & Last Name & Degree
Massimiliano Bergallo, BS
First Name & Middle Initial & Last Name & Degree
Paola Montanari, BS
First Name & Middle Initial & Last Name & Degree
Ilaria Galliano, BS
First Name & Middle Initial & Last Name & Degree
Silvia Nicoli, MD
First Name & Middle Initial & Last Name & Degree
Cristina Calvi, BS
First Name & Middle Initial & Last Name & Degree
Valentina Daprà, BS
Facility Name
Ospedale Infantile Regina Margherita
City
Torino
ZIP/Postal Code
10126
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Francesco Savino, MD, PhD
Phone
+390113135618
Email
francesco.savino@unito.it
First Name & Middle Initial & Last Name & Degree
Francesco Savino, MD, PhD
First Name & Middle Initial & Last Name & Degree
Maria Garrro, MD
First Name & Middle Initial & Last Name & Degree
Massimiliano Bergallo, BS

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
to partecipe to an individual partecipant data meta- analysis.
Citations:
PubMed Identifier
17718777
Citation
Savino F. Focus on infantile colic. Acta Paediatr. 2007 Sep;96(9):1259-64. doi: 10.1111/j.1651-2227.2007.00428.x.
Results Reference
background
PubMed Identifier
17498186
Citation
Savino F, Pelle E, Castagno E, Palumeri E, Oggero R. Must infants with colic really be hospitalized? Acta Paediatr. 2007 Jul;96(7):1109; author reply 1110. doi: 10.1111/j.1651-2227.2007.00328.x. Epub 2007 May 10. No abstract available.
Results Reference
background
PubMed Identifier
17200238
Citation
Savino F, Pelle E, Palumeri E, Oggero R, Miniero R. Lactobacillus reuteri (American Type Culture Collection Strain 55730) versus simethicone in the treatment of infantile colic: a prospective randomized study. Pediatrics. 2007 Jan;119(1):e124-30. doi: 10.1542/peds.2006-1222.
Results Reference
background
PubMed Identifier
16754557
Citation
Savino F, Grassino EC, Guidi C, Oggero R, Silvestro L, Miniero R. Ghrelin and motilin concentration in colicky infants. Acta Paediatr. 2006 Jun;95(6):738-41. doi: 10.1080/08035250500522654.
Results Reference
background
PubMed Identifier
16736065
Citation
Savino F, Palumeri E, Castagno E, Cresi F, Dalmasso P, Cavallo F, Oggero R. Reduction of crying episodes owing to infantile colic: A randomized controlled study on the efficacy of a new infant formula. Eur J Clin Nutr. 2006 Nov;60(11):1304-10. doi: 10.1038/sj.ejcn.1602457. Epub 2006 May 31.
Results Reference
background
PubMed Identifier
16214780
Citation
Savino F, Castagno E, Bretto R, Brondello C, Palumeri E, Oggero R. A prospective 10-year study on children who had severe infantile colic. Acta Paediatr Suppl. 2005 Oct;94(449):129-32. doi: 10.1111/j.1651-2227.2005.tb02169.x.
Results Reference
background
PubMed Identifier
16041731
Citation
Savino F, Cresi F, Castagno E, Silvestro L, Oggero R. A randomized double-blind placebo-controlled trial of a standardized extract of Matricariae recutita, Foeniculum vulgare and Melissa officinalis (ColiMil) in the treatment of breastfed colicky infants. Phytother Res. 2005 Apr;19(4):335-40. doi: 10.1002/ptr.1668.
Results Reference
background
PubMed Identifier
15693915
Citation
Savino F, Bailo E, Oggero R, Tullio V, Roana J, Carlone N, Cuffini AM, Silvestro L. Bacterial counts of intestinal Lactobacillus species in infants with colic. Pediatr Allergy Immunol. 2005 Feb;16(1):72-5. doi: 10.1111/j.1399-3038.2005.00207.x.
Results Reference
background
PubMed Identifier
15244234
Citation
Savino F, Cresi F, Pautasso S, Palumeri E, Tullio V, Roana J, Silvestro L, Oggero R. Intestinal microflora in breastfed colicky and non-colicky infants. Acta Paediatr. 2004 Jun;93(6):825-9.
Results Reference
background
PubMed Identifier
28969887
Citation
Savino F, Garro M, Montanari P, Galliano I, Bergallo M. Crying Time and RORgamma/FOXP3 Expression in Lactobacillus reuteri DSM17938-Treated Infants with Colic: A Randomized Trial. J Pediatr. 2018 Jan;192:171-177.e1. doi: 10.1016/j.jpeds.2017.08.062. Epub 2017 Sep 29.
Results Reference
derived
PubMed Identifier
23468874
Citation
Roos S, Dicksved J, Tarasco V, Locatelli E, Ricceri F, Grandin U, Savino F. 454 pyrosequencing analysis on faecal samples from a randomized DBPC trial of colicky infants treated with Lactobacillus reuteri DSM 17938. PLoS One. 2013;8(2):e56710. doi: 10.1371/journal.pone.0056710. Epub 2013 Feb 28.
Results Reference
derived

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Lactobacillus Reuteri Versus Placebo in the Treatment and Prevention of Infantile Colic

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