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Recurrent Wheezing in Infants: Risk Factors and Prevention With Probiotics.

Primary Purpose

Respiratory Tract Diseases, Wheezing

Status
Completed
Phase
Phase 3
Locations
Brazil
Study Type
Interventional
Intervention
Beclomethasone
Probiotics
Placebo
Sponsored by
Universidade Federal de Pernambuco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Respiratory Tract Diseases focused on measuring wheezing, immune system, cytokines, probiotics, infants.

Eligibility Criteria

6 Months - 23 Months (Child)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Infants aged six months to two years incomplete.
  • Infants who have recurrent wheezing in the past 3 months.
  • Infants under use of proper technique of inhaled corticosteroids: beclomethasone HFA spray - 50 mg - 2 times daily (100 mg / day) with spacer and face mask.

Exclusion Criteria:

  • Patients who present congenital airway malformations, cystic fibrosis, chronic diseases in other systems, perinatal respiratory problems, allergy to the protein in cow's milk, intrathoracic tumors, Tuberculosis and Pulmonary Congenital immunodeficiencies, children who were premature: <37 weeks gestational age.
  • Use of other products containing probiotics in its composition with previous exposure or even study period.
  • Infant in use of anti-leukotrienes.
  • Use recent antibiotic.

Sites / Locations

  • Federal University of Pernambuco

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Probiotics & Beclomethasone

Beclomethasone & Placebo

Arm Description

It will be supplied in lyophilized form, in each sachet containing 1 g of the probiotic, to be used in addition to milk, juice or yoghurt in the first morning meal once daily for 60 days. Beclomethasone HFA 50mcg spray - 100 mcg/day as initial treatment for primary and wheezing in this age group, at doses considered minimal, for 4 months.

The placebo will be supplied in the same way with the same organoleptic characteristics of formula with probiotics. It will be supplied in lyophilized form in each sachet containing 1 g of placebo, to be used in addition to milk, juice or yoghurt in the first morning meal once daily for 60 days.

Outcomes

Primary Outcome Measures

Recurrent wheezing and cytokine assay.
After eight weeks of using probiotics, infants will undergo new measurement of cytokines IL-10, IL-12 and INF-γ, with the objective to evaluate the immune response of probiotics in both groups. Before and at the end of each period, the patient will undergo physical examination and parents or guardians to an interview, to assess the occurrence of wheezing attacks. These data will be analyzed to assess whether supplementation with probiotics reduces the frequency of wheezing in infants.

Secondary Outcome Measures

Full Information

First Posted
April 10, 2014
Last Updated
December 3, 2014
Sponsor
Universidade Federal de Pernambuco
Collaborators
Conselho Nacional de Desenvolvimento Científico e Tecnológico
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1. Study Identification

Unique Protocol Identification Number
NCT02113072
Brief Title
Recurrent Wheezing in Infants: Risk Factors and Prevention With Probiotics.
Official Title
Recurrent Wheezing in Infants: Risk Factors and Prevention With Probiotics, a Randomized Clinical Trial, Double-blind, Placebo Controlled.
Study Type
Interventional

2. Study Status

Record Verification Date
December 2014
Overall Recruitment Status
Completed
Study Start Date
April 2014 (undefined)
Primary Completion Date
August 2014 (Actual)
Study Completion Date
November 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Universidade Federal de Pernambuco
Collaborators
Conselho Nacional de Desenvolvimento Científico e Tecnológico

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate whether Probiotics promote reduction of recurrent wheezing in infants, stimulating the immune system to Th1 response.
Detailed Description
OBJECTIVES GENERAL Assess whether probiotic supplementation reduces the frequency of recurrent wheezing in infants . SPECIFIC Identifying the presence of environmental and genetic factors to recurrent wheezing in infants, which may serve as major confounders of the effect of probiotics in the sample studied risk factors . Check the effect of probiotics as the recurrence of wheezing in infants. Evaluate the effects of probiotics on the immune response of the infant wheezing , through the measurement of IL - 10 , IL - 12 and Interferon-gama before and after intervention with the use of probiotics . DESIGN RESEARCH Study Design Inferential, the type longitudinal, randomized trial, double-blind, parallel, placebo-controlled study. Intervention to be held: Patients attended at the Infant Hospital of the Federal University of Pernambuco will undergo clinical investigation and completion of baseline examinations is eligible to participate in the study after informed consent from parents or guardians. Infants with recurrent wheezing, six months to two years of age, will be divided into two groups - one receiving the formula with probiotics (treatment group) and the other formula with similar organoleptic characteristics, placebo (control group). Flowchart of randomization Patients assessed for eligibility verification will be randomized and follow the CONSORT flowchart second Guide - 2011. IMPLEMENTATION OF RESEARCH Local and survey period Hospital das Clinicals, Federal University of Pernambuco - UFPE, Brazil. Period April 2014 to Abril 2015. Population Research Method of Selection of Sample Sample selection of recurring wheezing infants attended at Infant Hospital das Clinicas UFPE, to be considered eligible for admission to the study and meet the criteria for inclusion and exclusion. The wheezing infants selected as eligible for the study remained with wheezing even using inhaled corticosteroids. Type of Randomization and Allocation Mechanism A simple randomization of patients will be by draw of numbers 1 - 60. Randomization was performed by a third person who used a randomization program on the computer. The sequence of random numbers, recruitment and allocation of patients to the intervention by the principal investigator of the study will be conducted. Sample Size The sample size calculation was based on two studies on probiotics and asthma, whereas a level of less than 5% , a power study of 80% and an acceptable error of up to 20%, 60 patients significance can be sufficient to analyze the number of desired effect evaluation of wheezing in infants and reject or accept the null hypothesis. Operationalization Steps The infants were considered eligible for the study, will have the free and informed consent to participate in the study signed by their parents and or guardians. These patients initially attended, shall undergo a medical examination protocol with questions and answers QE - EISL (technical interview with the parents or guardians) and achievement of immediate skin test sensitivity to major aeroallergens and food allergens (mites, cat and dog epithelium, molds, feathers, cockroaches, egg yolk, egg white and cow's milk proteins) through the skin prick test and chest radiography. Patients before starting probiotics or placebos, will the dosage of the cytokines IL-10, IL-12 and INF-gamma, IgE and eosinophils. The wheezing infants will be using the inhaled corticosteroid beclomethasone 50mcg - 02 jets per day (100mcg - dia), found this medication for free, brand name and specifications: Clenil HFA 50mcg spray 200 doses as initial and fundamental treatment for wheezing this age group, at doses considered minimal. The formula with probiotics containing 10 CFU (Colony Forming Unit)/g consortium of probiotic strains of lactobacilli, lactococcus, streptococcus, yeasts and acetobacter type in appropriate concentrations per gram. It will be supplied in lyophilized form, in each sachet containing 1 g of the probiotic, to be used in addition to milk, juice or yoghurt in the first morning meal once daily. The placebo will be supplied in the same way with the same organoleptic characteristics of formula with probiotics. During this period, the infant wheezing present crisis, parents or guardians will note the day of wheezing attacks and treatment used in a standardized form with open answers, which will be provided, and will contact you by telephone, with the researcher. Parents or guardians will receive a daily record of control, to assess the occurrence of wheezing attacks. After eight weeks of using probiotics, infants will undergo new measurement of cytokines IL - 10 , IL - 12 and Interferon - gama, with the objective to evaluate the immune response of probiotics in both groups. Before and at the end of each period, the patient will undergo physical examination and parents or guardians to an interview, to assess the occurrence of wheezing attacks. These data will be analyzed to assess whether supplementation with probiotics reduces the frequency of wheezing in infants. Masking and Allocation Mechanism A third member of the study will assign a number to probiotics and placebo recipients in accordance with the numbers of randomization, without the knowledge of the investigator and the patient. Containers should be equal and contain substances of the same organoleptic characteristics. The containers will be provided in numerical order, as service and previous randomization. Instruments Measurement and Assessments QE- EISL: written questionnaire (International Study of Wheezing in Infants) - see Appendix 01, which is an instrument consisting of 45 questions on demographic characteristics, wheezing and its potential risk factors. Originally developed in Spanish, was translated into Portuguese (Brazilian) and validated. This protocol will be used with closed questions with answers, using the technical interview, conducted by the researcher, the parents or guardians. Statement of Informed Consent Form (ICF) - see apêncice 02 - after approval thereof in having their children participating in the study. Control plug - clinical - see Appendix 03: will be used by parents or guardians to describe the date, " wheezing " and perceived treatment need, while using the probiotic or placebo (08 weeks) and 08 weeks more. Prick Test: standardized extracts dihiclorada histamine (10mg/ml) and 0.9% saline (FDA - Immunotech , Rio de Janeiro , Brazil) will be used. The extracts will be dripped on the volar surface of the forearm and then performed one puncture with sterile lancet. As a positive control we histamine and negative saline control. The diameter of each reaction will be evaluated after 15 minutes and the result expressed as positive if wheal ≥ 3mm negative control. Eosinophil count and total serum IgE Dosage: will be held in peripheral blood collection vessel with qualified professional lab, in the amount of 7.0 ml. The reference values are appropriate for age and standardization of laboratory. Chest radiography: held at the radiology department of the Hospital das Clinicals - UFPE. Dose of IL - 10 , IL - 12 and Interferon-gama: will be held in peripheral blood collection vessel with qualified professional lab in the amount of 5.0 ml. This blood will be taken to the Laboratory Ageu Magalhães, which will be submitted to centrifugation and performed by the supernatant of peripheral blood mononuclear cells (PBMC), the count of cytokines in serum. Then the cultivation of these cells for 48 hours and subsequent counting of cytokine IL - 10 , IL - 12 and Interferon - gama is performed. The peripheral blood mononuclear cells at a concentration of 1 x 106 cells/mL are collected from the patients of the treatment group and the placebo group and are incubated with phytohemaglutinin (PHA ; 10μg/ml) for 48 hours. Production of IL - 10, IL - 12 and Interferon - gama in culture supernatant will be analyzed using enzyme-linked immunosorbent assay (ELISA) kits. The detection limit for these cytokines will be 5ρg/ml . STATISTICAL ANALYSIS Statistical Methods for Data Analysis For statistical analysis Initially , a probability distribution (percent analysis) is performed. Subsequently, the techniques of normal distribution and homogeneity of variances by means of ShapiroWillks and bartlett, respectively, tests will be applied to characterize the use of the parametric Student's t tests or Manny Whitney for independent samples. For categorical variables the chi- square test for association with Yates correction will be used. Data are expressed as mean and standard deviation ( parametric test ) or median and standard error ( nonparametric test ) with a significance level of p < 0.05 . 21 for Windows 2011 - to generate the analyzes , the statistical package SPSS will be used.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Respiratory Tract Diseases, Wheezing
Keywords
wheezing, immune system, cytokines, probiotics, infants.

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
60 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Probiotics & Beclomethasone
Arm Type
Experimental
Arm Description
It will be supplied in lyophilized form, in each sachet containing 1 g of the probiotic, to be used in addition to milk, juice or yoghurt in the first morning meal once daily for 60 days. Beclomethasone HFA 50mcg spray - 100 mcg/day as initial treatment for primary and wheezing in this age group, at doses considered minimal, for 4 months.
Arm Title
Beclomethasone & Placebo
Arm Type
Active Comparator
Arm Description
The placebo will be supplied in the same way with the same organoleptic characteristics of formula with probiotics. It will be supplied in lyophilized form in each sachet containing 1 g of placebo, to be used in addition to milk, juice or yoghurt in the first morning meal once daily for 60 days.
Intervention Type
Drug
Intervention Name(s)
Beclomethasone
Other Intervention Name(s)
Clenil
Intervention Description
The wheezing infants will be using the inhaled corticosteroid beclomethasone 50mcg - 02 jets per day (100mcg/dia).
Intervention Type
Drug
Intervention Name(s)
Probiotics
Other Intervention Name(s)
Lactobacillus, Bifidobacterium, Leveduras, Acetobacter
Intervention Description
Lyophilized form, each sachet containing 1 g of the probiotic, to be used in addition to milk, juice or yoghurt in the first morning meal once daily for 60 days.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Maltodextrose
Intervention Description
The placebo will be supplied in the same way with the same organoleptic characteristics of formula with probiotics, 1 g sachet for 60 days, in the juice, milk or yoghurt.
Primary Outcome Measure Information:
Title
Recurrent wheezing and cytokine assay.
Description
After eight weeks of using probiotics, infants will undergo new measurement of cytokines IL-10, IL-12 and INF-γ, with the objective to evaluate the immune response of probiotics in both groups. Before and at the end of each period, the patient will undergo physical examination and parents or guardians to an interview, to assess the occurrence of wheezing attacks. These data will be analyzed to assess whether supplementation with probiotics reduces the frequency of wheezing in infants.
Time Frame
After 2 months of using probiotic, will be assessed the recurrence of wheezing and cytokine assay.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
23 Months
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Infants aged six months to two years incomplete. Infants who have recurrent wheezing in the past 3 months. Infants under use of proper technique of inhaled corticosteroids: beclomethasone HFA spray - 50 mg - 2 times daily (100 mg / day) with spacer and face mask. Exclusion Criteria: Patients who present congenital airway malformations, cystic fibrosis, chronic diseases in other systems, perinatal respiratory problems, allergy to the protein in cow's milk, intrathoracic tumors, Tuberculosis and Pulmonary Congenital immunodeficiencies, children who were premature: <37 weeks gestational age. Use of other products containing probiotics in its composition with previous exposure or even study period. Infant in use of anti-leukotrienes. Use recent antibiotic.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Geórgia V. Araújo, Doctor
Organizational Affiliation
Universidade Federal de Pernambuco
Official's Role
Principal Investigator
Facility Information:
Facility Name
Federal University of Pernambuco
City
Recife
State/Province
Pernambuco
ZIP/Postal Code
50670-901
Country
Brazil

12. IPD Sharing Statement

Citations:
PubMed Identifier
20604800
Citation
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Results Reference
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PubMed Identifier
18332075
Citation
Kopp MV, Hennemuth I, Heinzmann A, Urbanek R. Randomized, double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical effects of Lactobacillus GG supplementation. Pediatrics. 2008 Apr;121(4):e850-6. doi: 10.1542/peds.2007-1492. Epub 2008 Mar 10.
Results Reference
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PubMed Identifier
24078929
Citation
Ozdemir O, Erol AY. Preventative and therapeutic probiotic use in allergic skin conditions: experimental and clinical findings. Biomed Res Int. 2013;2013:932391. doi: 10.1155/2013/932391. Epub 2013 Sep 1.
Results Reference
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PubMed Identifier
23921494
Citation
Ozdemir O. Any role for probiotics in the therapy or prevention of autoimmune diseases? Up-to-date review. J Complement Integr Med. 2013 Aug 6;10:/j/jcim.2013.10.issue-1/jcim-2012-0054/jcim-2012-0054.xml. doi: 10.1515/jcim-2012-0054.
Results Reference
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PubMed Identifier
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Citation
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Recurrent Wheezing in Infants: Risk Factors and Prevention With Probiotics.

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