<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03261466</url>
  </required_header>
  <id_info>
    <org_study_id>CE 165/13</org_study_id>
    <nct_id>NCT03261466</nct_id>
  </id_info>
  <brief_title>BIFI-OBESE: Clinical Trial in Paediatric Obesity</brief_title>
  <acronym>BIFI-OBESE</acronym>
  <official_title>BIFI-OBESE: Effect of Probiotic Bifidobacterium Breve BR03 and Bifidobacterium Breve B632 in Paediatric Obesity</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Ospedaliero Universitaria Maggiore della Carita</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Azienda Ospedaliero Universitaria Maggiore della Carita</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Obesity is a major, public health concern that affects at least 400 million individuals and&#xD;
      is associated with severe disorders including diabetes and cancers. Worldwide, the prevalence&#xD;
      of overweight and obesity combined in children, adolescents and youth, between 1980 and 2013,&#xD;
      increased to 47.1%, with alarming data also in developing countries. Obesity is often caused&#xD;
      by imbalance between excessive caloric intake and reduced physical activity.&#xD;
&#xD;
      Recently, microbial changes in the human gut was proposed to be another possible cause of&#xD;
      obesity and it was found that the gut microbes from fecal samples contained 3.3 million&#xD;
      non-redundant microbial genes. However, it is still poorly understood how the dynamics and&#xD;
      composition of the intestinal microbiota are affected by diet or other lifestyle factors.&#xD;
      Moreover it has been difficult to characterize the composition of the human gut microbiota&#xD;
      due to large variations between individuals.&#xD;
&#xD;
      The role of the digestive microbiota in the human body is still largely unknown, but the&#xD;
      bacteria of the gut flora do contribute enzymes that are absent in humans for food digestion.&#xD;
      Moreover, the link between obesity and the microbiota is likely to be more sophisticated than&#xD;
      the simple phylum-level Bacteroidetes: Firmicutes ratio that was initially identified, and it&#xD;
      is likely to involve a microbiota-diet interaction.&#xD;
&#xD;
      Obese and lean subjects presented increased levels of different bacterial populations. It is&#xD;
      hypothesized that the obese microbiome is set up to extract more calories from the daily&#xD;
      intake when compared to the microbiome of lean counterparts. In addition, a caloric diet&#xD;
      restriction impacted the composition of the gut microbiota in obese/overweight individuals&#xD;
      and weight loss.&#xD;
&#xD;
      In lean subjects there are Coriobacteriaceae, Lactobacillus, Enterococcus, Faecalibacterium&#xD;
      prausnitzii, Prevotella, Clostridium Eubacterium, E. coli and Staphilococcus. By contrast,&#xD;
      Bifidobacterium, Methanobrevibacter, Xylanibacter, Bacteroides characterize the composition&#xD;
      of lean gut microbiota.&#xD;
&#xD;
      For this reason, in a cohort of obese paediatric subjects with visceral adiposity, the aim of&#xD;
      the study is to assess the efficacy of a supplementation with probiotic bifidobacteria with&#xD;
      respect to a conventional treatment on weight loss and improvement of cardio-metabolic risk&#xD;
      factors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study design: A single-center pilot open-label randomized control trial. Population: The&#xD;
      study will comprise a total of 100 subjects of both sexes, between 6 and 18 years of age,&#xD;
      obese, according to the IOTF criteria and with visceral adiposity, as waist circumference ≥&#xD;
      90th percentile, pubertal stage ≥ 2 according to the Tanner stage, HOMA-IR &gt; 2,5 or insulin &gt;&#xD;
      15 µU/ml, diet naïve or with failure of weight loss (defined as -1 kg/m2 BMI in 1 year).&#xD;
&#xD;
      Inclusion/ Exclusion criteria (see Eligibility Criteria). Intervention: In the first part of&#xD;
      the study (Study 1, V0-V1) patients will be randomized in a open-label, into two groups&#xD;
      homogeneous for number and sex of the subjects. One group will receive a supplementation of&#xD;
      probiotic containing Bifidobacterium breve B632 and Bifidobacterium breve BR03, 15 gtt/die&#xD;
      (3x108 CFU/die) and one group will receive a placebo for a total of 2 months of treatment.&#xD;
      Both group receives a Standard Diet according to routine care and practice. For patients who&#xD;
      wants to continue the study there will be a cross-over study (study 2, V2-V3) after one month&#xD;
      of wash-out.&#xD;
&#xD;
      Dietary restriction: The standard diet will be distributed with 55-60% of carbohydrates&#xD;
      (45-50% complex and no more than 10% refined and processed sugars), 25-30% lipids and 15%&#xD;
      proteins, and will be performed in accordance with the calories of an isocaloric balanced&#xD;
      diet calculated throughout the Italian LARN Guidelines for age and gender.&#xD;
&#xD;
      Physical activity: all subjects will receive general recommendations about performing&#xD;
      physical activity. Exercise will be conducted daily and will consist of 30 minutes of aerobic&#xD;
      physical activity.&#xD;
&#xD;
      Randomization: Participants will be randomly assigned in a 1:1 to probiotic intervention&#xD;
      group or placebo group.&#xD;
&#xD;
      Timing: Patients will be evaluated firstly at time of enrollment (V0) and, at the end of the&#xD;
      first part of study (Study 1, V1), biochemical evaluations will be completed. Next there will&#xD;
      be one month of wash-out when the patients don't take any probiotic or placebo. In the second&#xD;
      part of the study 2, patients will be evaluated at V2 and, after 2 months of treatment (Study&#xD;
      2, V3). The following anthropometric measures, biochemical and ultrasound evaluations and&#xD;
      questionnaires will be obtained:&#xD;
&#xD;
        1. Anthropometric measures:&#xD;
&#xD;
             -  height (V0, V1, V2, V3);&#xD;
&#xD;
             -  weight (V0, V1, V2, V3);&#xD;
&#xD;
             -  body mass index (BMI; Kg/m2) (V0, V1, V2, V3);&#xD;
&#xD;
             -  waist and hip circumferences (V0, V1, V2, V3) for the calculation of the following&#xD;
                ratios: waist/hip, waist/height;&#xD;
&#xD;
             -  Tanner stage (V0, V1, V2, V3);&#xD;
&#xD;
             -  blood pressure and heart rate (V0, V1, V2, V3). Biochemical evaluations (after a&#xD;
                12-h overnight fast): CBC with formula, serum insulin-like growth factor 1 (IGF1,&#xD;
                ng/mL), 25-hydroxy (OH) vitamin D (ng/mL), uric acid (mg/dL), alkaline phosphatase&#xD;
                (U/L), ACTH (pg/mL), cortisol (microg/dL), TSH (uuI/mL), fT4 (ng/dL) (V0, V1, V2,&#xD;
                V3); aspartate aminotransferase (AST, IU/L), alanine aminotransferase (ALT, IU/L);&#xD;
                AST-to-ALT ratio will be calculated as the ratio of AST (IU/L) and ALT(IU/L) (V0,&#xD;
                V1, V2, V3); serum creatinine concentration (mg/dL) will be measured with the&#xD;
                enzymatic method; according to the NKF-K/DOQI Guidelines for CKD in children and&#xD;
                adolescents, the eGFR will be calculated using updated Schwartz's formula: eGFR&#xD;
                (mL/min/1.73 m2) = [0.413 x patient's height (cm)] / serum creatinine (mg/dL) (V0,&#xD;
                V1, V2, V3); glucose (mg/dL), insulin (μUI/mL); insulin-resistance (IR) will be&#xD;
                calculated using the formula of Homeostasis Model Assessment (HOMA)-IR: (insulin&#xD;
                [mU/L] x glucose [mmol/lL) / 22.5) (V0, V1, V2, V3); lipid profile: total&#xD;
                cholesterol (mg/dL), High-Density Lipoprotein (HDL)-cholesterol (mg/dL),&#xD;
                triglycerides (mg/dL); Low-Density Lipoprotein (LDL)-cholesterol will be calculated&#xD;
                by the Friedwald formula and non-HDL (nHDL)-cholesterol will be also calculated(V0,&#xD;
                V1, V2, V3); oral glucose tolerance test (OGTT: 1.75 g of glucose solution per kg,&#xD;
                maximum 75 g) and samples willbe collected for the determination of glucose and&#xD;
                insulin every 30 min. The area under the curve (AUC) for parameters after OGTT will&#xD;
                be calculated according to the trapezoidal rule. Insulin sensitivity at fasting and&#xD;
                during OGTT will be calculated as the formula of the Quantitative&#xD;
                Insulin-Sensitivity Check Index (QUICKI) and Matsuda index (ISI). The stimulus for&#xD;
                insulin secretion in the increment in plasma glucose as insulinogenic index will be&#xD;
                calculated as the ratio of the changes in insulin and glucose concentration from 0&#xD;
                to 30 min (InsI). Βeta-cell compensatory capacity will be evaluated by the&#xD;
                disposition index defined as the product of the ISI and InsI (DI) (V0, V1, V2, V3);&#xD;
                a collection at rest of first-morning urine sample. Physical and chemical&#xD;
                urinalysis; urine albumin (mg/L) will be determined by an advanced&#xD;
                immunoturbidimetric assay and urine creatinine (mg/dL) will be measured using the&#xD;
                enzymatic method. Urine albumin to creatinine ratio (u-ACR - mg/g), will be&#xD;
                calculated using the following formula: [urine albumin (mg/dL) / urine creatinine&#xD;
                (mg/dL)] x 1000. For these calculations both albumin and creatinine will be in the&#xD;
                same unit. The subjects whose urine will be found positive, they will undergo a&#xD;
                collection of two more samples and will be considered the u-ACR mean value of these&#xD;
                (V0, V1, V2, V3). A sample of feces will be taken for microbic count (V0, V1, V2,&#xD;
                V3). LPS (V0, V1, V2, V3). LPS will be measured with commercial kits (Limulus&#xD;
                amoebocyte lysate assay) with standard procedures. Citokines IL1, IL1β, IL6, IL10,&#xD;
                TNFα will be evaluated (V0, V1, V2, V3) (ELISA kit).&#xD;
&#xD;
        2. A health diary will be taken during the 2 months of treatment: each patient will&#xD;
           complete the diary with collateral effects or antibiotic treatment ecc.&#xD;
&#xD;
        3. NGS (Next Generation Sequencing) will be analized for fecal analysis (V0, V1, V2, V3)&#xD;
&#xD;
        4. Metabolomic analysis will be taken with mass spectrometry on fecal samples (V0, V1, V2,&#xD;
           V3)&#xD;
&#xD;
        5. SCFA analysis on fecal samples (V0, V1, V2, V3).&#xD;
&#xD;
      Outcomes (see Outcome Measures). Information retrieval: A case report form (CRF) will be&#xD;
      completed for each subject included in the study. The source documents will be the hospital's&#xD;
      or the physician's chart.&#xD;
&#xD;
      Statistical e sample size: A sample of 16 individuals has been estimated to be sufficient to&#xD;
      demonstrate a difference of 10 mg/dl in the basal glucose concentration with 90% power and a&#xD;
      significance level of 95% and a drop-out rate of 10% at the 8th weeks of treatment. A sample&#xD;
      of 34 individuals in each group has been estimated to be sufficient to demonstrate a&#xD;
      difference of 1,4 point in the HOMA-IR index with 90% power and a significance level of 95%&#xD;
      and a drop-out rate of 10% at the 8th weeks of treatment. Statistical significance will be&#xD;
      assumed at P&lt; 0.05. The statistical analysis will be performed with SPSS for Windows version&#xD;
      17.0 (SPSS Inc., Chicago, IL, USA).&#xD;
&#xD;
      Organization characteristics: The study will be conducted at the Pediatric Endocrine Service&#xD;
      of Division of Pediatrics.&#xD;
&#xD;
      All blood samples will be measured evaluated using standardized methods in the Hospital's&#xD;
      Chemistry Laboratory, in Maggiore della Carità hospital, in Novara, previously described.&#xD;
      Fecal analysis will be measured in the Department of Sciences and Technologies, University of&#xD;
      Bologna, in Bologna.&#xD;
&#xD;
      Good Clinical Practice: The protocol will be conducted in accordance with the declaration of&#xD;
      Helsinki. Informed consent will be obtained from all parents prior to the evaluations after&#xD;
      careful explanations to each patient.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 20, 2013</start_date>
  <completion_date type="Actual">October 30, 2017</completion_date>
  <primary_completion_date type="Actual">October 30, 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>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. 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.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The study is a triple blind study in which the treatment or intervention is unknown to the research participant, the individuals who administer the treatment or intervention, and the researchers who assess the outcomes.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in glucose level during oral glucose tolerance test (OGTT)</measure>
    <time_frame>Change from Baseline OGTT (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in HOMA-IR index</measure>
    <time_frame>Change from baseline HOMA-IR (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)</time_frame>
    <description>Evaluate if after the treatment with probiotic there is a variation of HOMA-IR index.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Metabolic control: Improvement of metabolic risk factors</measure>
    <time_frame>Change from baseline lipid profile, insulin, leptin, adiponectin, GLP1 (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)</time_frame>
    <description>Evaluate any variation of serum lipids, leptin, adiponectin, GLP1 and insulin during OGTT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in fecal microbiome</measure>
    <time_frame>Change from Baseline fecal microbiome (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)</time_frame>
    <description>Evaluate any variation of fecal microbiome</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in SCFA (short-chain fatty acids) in fecal samples</measure>
    <time_frame>Change from Baseline fecal SCFA (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)</time_frame>
    <description>Evaluate any variation of short-chain fatty acids in fecal samples</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in inflammatory cytokines</measure>
    <time_frame>Change from Baseline cytokines and metabolites (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)</time_frame>
    <description>Evaluate new citokines and metabolites that regulates hormone metabolism.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">100</enrollment>
  <condition>Obesity, Childhood</condition>
  <arm_group>
    <arm_group_label>Active group Bifidobacterium breve BR03 and B632</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>This arm will receive a supplementation with a same product equal to the active product but without bifidobacterium inside.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bifidobacterium breve BR03 and Bifidobacterium breve B632</intervention_name>
    <arm_group_label>Active group Bifidobacterium breve BR03 and B632</arm_group_label>
    <other_name>probiotic</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <arm_group_label>Placebo group</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. both sexes&#xD;
&#xD;
          2. between 6 and 18 years of age&#xD;
&#xD;
          3. obese, according to the IOTF criteria (Cole TJ et al., 2000)&#xD;
&#xD;
          4. pubertal stage ≥ 2 according to the Tanner stage (Tanner et al., 1961)&#xD;
&#xD;
          5. HOMA-IR &gt; 2,5 or insulin &gt; 15 µU/ml&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Adverse reactions to the product or component of the product (allergies…)&#xD;
&#xD;
          2. Genetic obesity (Prader Willi syndrome, Down syndrome), Metabolic obesity&#xD;
             (Laurence-biedl syndrome…), endocrinological obesity (Cushinch syndrome,&#xD;
             hypotiroidism)&#xD;
&#xD;
          3. Chronic diseases, hepatic or gastroenterological diseases&#xD;
&#xD;
          4. Medical treatment for chronic diseases&#xD;
&#xD;
          5. Probiotic or prebiotic therapies and antibiotic treatment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>AOU Maggiore della Carità - Clinica Pediatrica - Ambulatorio di Auxologia ed Endocrinologia Pediatrica</name>
      <address>
        <city>Novara</city>
        <zip>28100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
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    <citation>Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994. Arch Pediatr Adolesc Med. 2003 Aug;157(8):821-7. doi: 10.1001/archpedi.157.8.821.</citation>
    <PMID>12912790</PMID>
  </reference>
  <reference>
    <citation>Cruz ML, Goran MI. The metabolic syndrome in children and adolescents. Curr Diab Rep. 2004 Feb;4(1):53-62. doi: 10.1007/s11892-004-0012-x.</citation>
    <PMID>14764281</PMID>
  </reference>
  <reference>
    <citation>Società Italiana di Nutrizione Umana.(2014).Livelli di assunzione raccomandati di energia e nutrienti per la popolazione italiana (LARN). Milan, Italy: S.I.N.U.</citation>
  </reference>
  <reference>
    <citation>Tanner JM. (1961). Growth at adolescence. 2 edn. Oxford: Blackwell Scientific Publications.</citation>
  </reference>
  <reference>
    <citation>de Ferranti SD, Gauvreau K, Ludwig DS, Neufeld EJ, Newburger JW, Rifai N. Prevalence of the metabolic syndrome in American adolescents: findings from the Third National Health and Nutrition Examination Survey. Circulation. 2004 Oct 19;110(16):2494-7. doi: 10.1161/01.CIR.0000145117.40114.C7. Epub 2004 Oct 11.</citation>
    <PMID>15477412</PMID>
  </reference>
  <reference>
    <citation>Cacciari E, Milani S, Balsamo A, Spada E, Bona G, Cavallo L, Cerutti F, Gargantini L, Greggio N, Tonini G, Cicognani A. Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest. 2006 Jul-Aug;29(7):581-93. doi: 10.1007/BF03344156.</citation>
    <PMID>16957405</PMID>
  </reference>
  <reference>
    <citation>Prodam F, Ricotti R, Agarla V, Parlamento S, Genoni G, Balossini C, Walker GE, Aimaretti G, Bona G, Bellone S. High-end normal adrenocorticotropic hormone and cortisol levels are associated with specific cardiovascular risk factors in pediatric obesity: a cross-sectional study. BMC Med. 2013 Feb 20;11:44. doi: 10.1186/1741-7015-11-44.</citation>
    <PMID>23425018</PMID>
  </reference>
  <reference>
    <citation>Prodam F, Savastio S, Genoni G, Babu D, Giordano M, Ricotti R, Aimaretti G, Bona G, Bellone S. Effects of growth hormone (GH) therapy withdrawal on glucose metabolism in not confirmed GH deficient adolescents at final height. PLoS One. 2014 Jan 30;9(1):e87157. doi: 10.1371/journal.pone.0087157. eCollection 2014.</citation>
    <PMID>24498035</PMID>
  </reference>
  <reference>
    <citation>Prodam F, Zanetta S, Ricotti R, Marolda A, Giglione E, Monzani A, Walker GE, Rampone S, Castagno M, Bellone S, Petri A, Aimaretti G, Bona G. Influence of Ultraviolet Radiation on the Association between 25-Hydroxy Vitamin D Levels and Cardiovascular Risk Factors in Obesity. J Pediatr. 2016 Apr;171:83-9.e1. doi: 10.1016/j.jpeds.2015.12.032. Epub 2016 Jan 12.</citation>
    <PMID>26794470</PMID>
  </reference>
  <reference>
    <citation>Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993 Nov;42(11):1663-72. doi: 10.2337/diab.42.11.1663.</citation>
    <PMID>8405710</PMID>
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  <reference>
    <citation>Hogg RJ, Furth S, Lemley KV, Portman R, Schwartz GJ, Coresh J, Balk E, Lau J, Levin A, Kausz AT, Eknoyan G, Levey AS; National Kidney Foundation's Kidney Disease Outcomes Quality Initiative. National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification. Pediatrics. 2003 Jun;111(6 Pt 1):1416-21. doi: 10.1542/peds.111.6.1416.</citation>
    <PMID>12777562</PMID>
  </reference>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>July 14, 2017</study_first_submitted>
  <study_first_submitted_qc>August 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 25, 2017</study_first_posted>
  <last_update_submitted>January 10, 2018</last_update_submitted>
  <last_update_submitted_qc>January 10, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 11, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Azienda Ospedaliero Universitaria Maggiore della Carita</investigator_affiliation>
    <investigator_full_name>Flavia Prodam</investigator_full_name>
    <investigator_title>Assoc. Professor in Clinical Nutrition</investigator_title>
  </responsible_party>
  <keyword>obesity</keyword>
  <keyword>paediatric</keyword>
  <keyword>probiotic</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Obesity</mesh_term>
    <mesh_term>Pediatric Obesity</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03261466
org study id: CE 165/13
nct id: NCT03261466
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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 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.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: 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. 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.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: The study is a triple blind study in which the treatment or intervention is unknown to the research participant, the individuals who administer the treatment or intervention, and the researchers who assess the outcomes.
measure: 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)
description: 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.
measure: Change in HOMA-IR index
time frame: Change from baseline HOMA-IR (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)
description: Evaluate if after the treatment with probiotic there is a variation of HOMA-IR index.
measure: 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)
description: Evaluate any variation of serum lipids, leptin, adiponectin, GLP1 and insulin during OGTT.
measure: Change in fecal microbiome
time frame: Change from Baseline fecal microbiome (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)
description: Evaluate any variation of fecal microbiome
measure: 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)
description: Evaluate any variation of short-chain fatty acids in fecal samples
measure: Change in inflammatory cytokines
time frame: Change from Baseline cytokines and metabolites (V0) at 2 months (V1), 3 months (V2) and 5 months (V3)
description: Evaluate new citokines and metabolites that regulates hormone metabolism.
arm group label: Active group Bifidobacterium breve BR03 and B632
arm group type: Active Comparator
description: 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.
arm group label: Placebo group
arm group type: Placebo Comparator
description: This arm will receive a supplementation with a same product equal to the active product but without bifidobacterium inside.
intervention type: Drug
intervention name: Bifidobacterium breve BR03 and Bifidobacterium breve B632
arm group label: Active group Bifidobacterium breve BR03 and B632
other name: probiotic
intervention type: Drug
intervention name: Placebos
arm group label: Placebo group
other name: Placebo
criteria: 
gender: All
minimum age: 6 Years
maximum age: 18 Years
healthy volunteers: No
facility: 
country: Italy
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PMID: 23425018
citation: Prodam F, Savastio S, Genoni G, Babu D, Giordano M, Ricotti R, Aimaretti G, Bona G, Bellone S. Effects of growth hormone (GH) therapy withdrawal on glucose metabolism in not confirmed GH deficient adolescents at final height. PLoS One. 2014 Jan 30;9(1):e87157. doi: 10.1371/journal.pone.0087157. eCollection 2014.
PMID: 24498035
citation: Prodam F, Zanetta S, Ricotti R, Marolda A, Giglione E, Monzani A, Walker GE, Rampone S, Castagno M, Bellone S, Petri A, Aimaretti G, Bona G. Influence of Ultraviolet Radiation on the Association between 25-Hydroxy Vitamin D Levels and Cardiovascular Risk Factors in Obesity. J Pediatr. 2016 Apr;171:83-9.e1. doi: 10.1016/j.jpeds.2015.12.032. Epub 2016 Jan 12.
PMID: 26794470
citation: Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993 Nov;42(11):1663-72. doi: 10.2337/diab.42.11.1663.
PMID: 8405710
citation: Hogg RJ, Furth S, Lemley KV, Portman R, Schwartz GJ, Coresh J, Balk E, Lau J, Levin A, Kausz AT, Eknoyan G, Levey AS; National Kidney Foundation's Kidney Disease Outcomes Quality Initiative. National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification. Pediatrics. 2003 Jun;111(6 Pt 1):1416-21. doi: 10.1542/peds.111.6.1416.
PMID: 12777562
responsible party type: Principal Investigator
investigator affiliation: Azienda Ospedaliero Universitaria Maggiore della Carita
investigator full name: Flavia Prodam
investigator title: Assoc. Professor in Clinical Nutrition
mesh term: Obesity
mesh term: Pediatric Obesity
sharing ipd: No