BIFI-OBESE: Clinical Trial in Paediatric Obesity (BIFI-OBESE)

January 10, 2018 updated by: Flavia Prodam, Azienda Ospedaliero Universitaria Maggiore della Carita

BIFI-OBESE: Effect of Probiotic Bifidobacterium Breve BR03 and Bifidobacterium Breve B632 in Paediatric Obesity

Obesity is a major, public health concern that affects at least 400 million individuals and is associated with severe disorders including diabetes and cancers. Worldwide, the prevalence of overweight and obesity combined in children, adolescents and youth, between 1980 and 2013, increased to 47.1%, with alarming data also in developing countries. Obesity is often caused by imbalance between excessive caloric intake and reduced physical activity.

Recently, microbial changes in the human gut was proposed to be another possible cause of obesity and it was found that the gut microbes from fecal samples contained 3.3 million non-redundant microbial genes. However, it is still poorly understood how the dynamics and composition of the intestinal microbiota are affected by diet or other lifestyle factors. Moreover it has been difficult to characterize the composition of the human gut microbiota due to large variations between individuals.

The role of the digestive microbiota in the human body is still largely unknown, but the bacteria of the gut flora do contribute enzymes that are absent in humans for food digestion. Moreover, the link between obesity and the microbiota is likely to be more sophisticated than the simple phylum-level Bacteroidetes: Firmicutes ratio that was initially identified, and it is likely to involve a microbiota-diet interaction.

Obese and lean subjects presented increased levels of different bacterial populations. It is hypothesized that the obese microbiome is set up to extract more calories from the daily intake when compared to the microbiome of lean counterparts. In addition, a caloric diet restriction impacted the composition of the gut microbiota in obese/overweight individuals and weight loss.

In lean subjects there are Coriobacteriaceae, Lactobacillus, Enterococcus, Faecalibacterium prausnitzii, Prevotella, Clostridium Eubacterium, E. coli and Staphilococcus. By contrast, Bifidobacterium, Methanobrevibacter, Xylanibacter, Bacteroides characterize the composition of lean gut microbiota.

For this reason, in a cohort of obese paediatric subjects with visceral adiposity, the aim of the study is to assess the efficacy of a supplementation with probiotic bifidobacteria with respect to a conventional treatment on weight loss and improvement of cardio-metabolic risk factors.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Study design: A single-center pilot open-label randomized control trial. Population: The study will comprise a total of 100 subjects of both sexes, between 6 and 18 years of age, obese, according to the IOTF criteria and with visceral adiposity, as waist circumference ≥ 90th percentile, pubertal stage ≥ 2 according to the Tanner stage, HOMA-IR > 2,5 or insulin > 15 µU/ml, diet naïve or with failure of weight loss (defined as -1 kg/m2 BMI in 1 year).

Inclusion/ Exclusion criteria (see Eligibility Criteria). Intervention: In the first part of the study (Study 1, V0-V1) patients will be randomized in a open-label, into two groups homogeneous for number and sex of the subjects. One group will receive a supplementation of probiotic containing Bifidobacterium breve B632 and Bifidobacterium breve BR03, 15 gtt/die (3x108 CFU/die) and one group will receive a placebo for a total of 2 months of treatment. Both group receives a Standard Diet according to routine care and practice. For patients who wants to continue the study there will be a cross-over study (study 2, V2-V3) after one month of wash-out.

Dietary restriction: The standard diet will be distributed with 55-60% of carbohydrates (45-50% complex and no more than 10% refined and processed sugars), 25-30% lipids and 15% proteins, and will be performed in accordance with the calories of an isocaloric balanced diet calculated throughout the Italian LARN Guidelines for age and gender.

Physical activity: all subjects will receive general recommendations about performing physical activity. Exercise will be conducted daily and will consist of 30 minutes of aerobic physical activity.

Randomization: Participants will be randomly assigned in a 1:1 to probiotic intervention group or placebo group.

Timing: Patients will be evaluated firstly at time of enrollment (V0) and, at the end of the first part of study (Study 1, V1), biochemical evaluations will be completed. Next there will be one month of wash-out when the patients don't take any probiotic or placebo. In the second part of the study 2, patients will be evaluated at V2 and, after 2 months of treatment (Study 2, V3). The following anthropometric measures, biochemical and ultrasound evaluations and questionnaires will be obtained:

  1. Anthropometric measures:

    • height (V0, V1, V2, V3);
    • weight (V0, V1, V2, V3);
    • body mass index (BMI; Kg/m2) (V0, V1, V2, V3);
    • waist and hip circumferences (V0, V1, V2, V3) for the calculation of the following ratios: waist/hip, waist/height;
    • Tanner stage (V0, V1, V2, V3);
    • blood pressure and heart rate (V0, V1, V2, V3). Biochemical evaluations (after a 12-h overnight fast): CBC with formula, serum insulin-like growth factor 1 (IGF1, ng/mL), 25-hydroxy (OH) vitamin D (ng/mL), uric acid (mg/dL), alkaline phosphatase (U/L), ACTH (pg/mL), cortisol (microg/dL), TSH (uuI/mL), fT4 (ng/dL) (V0, V1, V2, V3); aspartate aminotransferase (AST, IU/L), alanine aminotransferase (ALT, IU/L); AST-to-ALT ratio will be calculated as the ratio of AST (IU/L) and ALT(IU/L) (V0, V1, V2, V3); serum creatinine concentration (mg/dL) will be measured with the enzymatic method; according to the NKF-K/DOQI Guidelines for CKD in children and adolescents, the eGFR will be calculated using updated Schwartz's formula: eGFR (mL/min/1.73 m2) = [0.413 x patient's height (cm)] / serum creatinine (mg/dL) (V0, V1, V2, V3); glucose (mg/dL), insulin (μUI/mL); insulin-resistance (IR) will be calculated using the formula of Homeostasis Model Assessment (HOMA)-IR: (insulin [mU/L] x glucose [mmol/lL) / 22.5) (V0, V1, V2, V3); lipid profile: total cholesterol (mg/dL), High-Density Lipoprotein (HDL)-cholesterol (mg/dL), triglycerides (mg/dL); Low-Density Lipoprotein (LDL)-cholesterol will be calculated by the Friedwald formula and non-HDL (nHDL)-cholesterol will be also calculated(V0, V1, V2, V3); oral glucose tolerance test (OGTT: 1.75 g of glucose solution per kg, maximum 75 g) and samples willbe collected for the determination of glucose and insulin every 30 min. The area under the curve (AUC) for parameters after OGTT will be calculated according to the trapezoidal rule. Insulin sensitivity at fasting and during OGTT will be calculated as the formula of the Quantitative Insulin-Sensitivity Check Index (QUICKI) and Matsuda index (ISI). The stimulus for insulin secretion in the increment in plasma glucose as insulinogenic index will be calculated as the ratio of the changes in insulin and glucose concentration from 0 to 30 min (InsI). Βeta-cell compensatory capacity will be evaluated by the disposition index defined as the product of the ISI and InsI (DI) (V0, V1, V2, V3); a collection at rest of first-morning urine sample. Physical and chemical urinalysis; urine albumin (mg/L) will be determined by an advanced immunoturbidimetric assay and urine creatinine (mg/dL) will be measured using the enzymatic method. Urine albumin to creatinine ratio (u-ACR - mg/g), will be calculated using the following formula: [urine albumin (mg/dL) / urine creatinine (mg/dL)] x 1000. For these calculations both albumin and creatinine will be in the same unit. The subjects whose urine will be found positive, they will undergo a collection of two more samples and will be considered the u-ACR mean value of these (V0, V1, V2, V3). A sample of feces will be taken for microbic count (V0, V1, V2, V3). LPS (V0, V1, V2, V3). LPS will be measured with commercial kits (Limulus amoebocyte lysate assay) with standard procedures. Citokines IL1, IL1β, IL6, IL10, TNFα will be evaluated (V0, V1, V2, V3) (ELISA kit).
  2. A health diary will be taken during the 2 months of treatment: each patient will complete the diary with collateral effects or antibiotic treatment ecc.
  3. NGS (Next Generation Sequencing) will be analized for fecal analysis (V0, V1, V2, V3)
  4. Metabolomic analysis will be taken with mass spectrometry on fecal samples (V0, V1, V2, V3)
  5. SCFA analysis on fecal samples (V0, V1, V2, V3).

Outcomes (see Outcome Measures). Information retrieval: A case report form (CRF) will be completed for each subject included in the study. The source documents will be the hospital's or the physician's chart.

Statistical e sample size: A sample of 16 individuals has been estimated to be sufficient to demonstrate a difference of 10 mg/dl in the basal glucose concentration with 90% power and a significance level of 95% and a drop-out rate of 10% at the 8th weeks of treatment. A sample of 34 individuals in each group has been estimated to be sufficient to demonstrate a difference of 1,4 point in the HOMA-IR index with 90% power and a significance level of 95% and a drop-out rate of 10% at the 8th weeks of treatment. Statistical significance will be assumed at P< 0.05. The statistical analysis will be performed with SPSS for Windows version 17.0 (SPSS Inc., Chicago, IL, USA).

Organization characteristics: The study will be conducted at the Pediatric Endocrine Service of Division of Pediatrics.

All blood samples will be measured evaluated using standardized methods in the Hospital's Chemistry Laboratory, in Maggiore della Carità hospital, in Novara, previously described. Fecal analysis will be measured in the Department of Sciences and Technologies, University of Bologna, in Bologna.

Good Clinical Practice: The protocol will be conducted in accordance with the declaration of Helsinki. Informed consent will be obtained from all parents prior to the evaluations after careful explanations to each patient.

Study Type

Interventional

Enrollment (Actual)

100

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Novara, Italy, 28100
        • AOU Maggiore della Carità - Clinica Pediatrica - Ambulatorio di Auxologia ed Endocrinologia Pediatrica

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 years to 16 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. both sexes
  2. between 6 and 18 years of age
  3. obese, according to the IOTF criteria (Cole TJ et al., 2000)
  4. pubertal stage ≥ 2 according to the Tanner stage (Tanner et al., 1961)
  5. HOMA-IR > 2,5 or insulin > 15 µU/ml

Exclusion Criteria:

  1. Adverse reactions to the product or component of the product (allergies…)
  2. Genetic obesity (Prader Willi syndrome, Down syndrome), Metabolic obesity (Laurence-biedl syndrome…), endocrinological obesity (Cushinch syndrome, hypotiroidism)
  3. Chronic diseases, hepatic or gastroenterological diseases
  4. Medical treatment for chronic diseases
  5. Probiotic or prebiotic therapies and antibiotic treatment

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Active group Bifidobacterium breve BR03 and B632
This arm will receive a supplementation of probiotic containing Bifidobacterium breve B632 and Bifidobacterium breve BR03, 15 gtt/die (3x108 CFU/die) once a day.
Drug: Bifidobacterium breve BR03 and Bifidobacterium breve B632
Other Names:
  • probiotic
Placebo Comparator: Placebo group
This arm will receive a supplementation with a same product equal to the active product but without bifidobacterium inside.
Drug: Placebos
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in glucose level during oral glucose tolerance test (OGTT)
Time Frame: Change from Baseline OGTT (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)
Evaluate if after the treatment with probiotic there is a reduction of glucose values during the OGTT at time 0' e 120' after oral glucose tolerance test.
Change from Baseline OGTT (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)
Change in HOMA-IR index
Time Frame: Change from baseline HOMA-IR (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)
Evaluate if after the treatment with probiotic there is a variation of HOMA-IR index.
Change from baseline HOMA-IR (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Metabolic control: Improvement of metabolic risk factors
Time Frame: Change from baseline lipid profile, insulin, leptin, adiponectin, GLP1 (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)
Evaluate any variation of serum lipids, leptin, adiponectin, GLP1 and insulin during OGTT.
Change from baseline lipid profile, insulin, leptin, adiponectin, GLP1 (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)
Change in fecal microbiome
Time Frame: Change from Baseline fecal microbiome (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)
Evaluate any variation of fecal microbiome
Change from Baseline fecal microbiome (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)
Change in SCFA (short-chain fatty acids) in fecal samples
Time Frame: Change from Baseline fecal SCFA (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)
Evaluate any variation of short-chain fatty acids in fecal samples
Change from Baseline fecal SCFA (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in inflammatory cytokines
Time Frame: Change from Baseline cytokines and metabolites (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)
Evaluate new citokines and metabolites that regulates hormone metabolism.
Change from Baseline cytokines and metabolites (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Ospedaliero Universitaria Maggiore della Carita

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 20, 2013

Primary Completion (Actual)

October 30, 2017

Study Completion (Actual)

October 30, 2017

Study Registration Dates

First Submitted

July 14, 2017

First Submitted That Met QC Criteria

August 24, 2017

First Posted (Actual)

August 25, 2017

Study Record Updates

Last Update Posted (Actual)

January 11, 2018

Last Update Submitted That Met QC Criteria

January 10, 2018

Last Verified

January 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CE 165/13

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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