Modulation of the Intestinal Flora With the Probiotic VIVOMIXX™ in Pregnant Women at Risk of Metabolic Complications

The investigators aimed at evaluating the effectiveness of probiotics ingestion in changing maternal microbiota and preventing gestational diabetes in overweight and obese women.

To achieve these goals, obese (BMI> 30 kg/m^2) or overweight (BMI> 25 kg/m^2) pregnant women with risk factors were enrolled in the study and randomized to the supplementation with the probiotic VIVOMIXX® or with placebo.

The endpoints of this study are to evaluate if the dietary supplementation with the probiotic VIVOMIXX® modifies the maternal fecal microbiota (bifidobacteria and lactobacilli) and related enzymatic activity (alkaline sphingomyelinase and alkaline phosphatase), and if this if this is linked to an improvement of the intermediate metabolism (positive Oral Glucose Tolerance Test at 24-26 weeks).

Study Overview

• Status: Unknown
• Conditions: Exercise Addiction; Dietary Modification; High-Risk Pregnancy; Gestational Diabetes Mellitus in Pregnancy, Diet- Controlled
• Intervention / Treatment: Dietary supplement: Probiotic VIVOMIXX™; Dietary supplement: Placebo

Detailed Description

This is a prospective, multicenter, randomized, double-blind, placebo-controlled trial.

208 pregnant women from the recruiting centers will be enrolled as follow: Women eligible to participate, prior informed consent, will be randomized to 2 capsules twice daily before breakfast and before dinner from randomization until delivery. The boxes will be given to the patients coded and blinded to investigators and participants, and will contain either the active ingredient (VIVOMIXX®, a mixture of 112 billion of eight strains for each capsule, namely Streptococcus thermophilus, bifidobacteria (B. breve, B. longum, B. infantis) and lactobacilli (L. paracasei, L. acidophilus, L. delbrueckii subsp bulgaricus, L. plantarum) or placebo.

The protocol includes a screening visit (Visit 1) at 10-12 weeks, two visits during pregnancy (at 26-28 weeks= Visit 2, and at 36-38 weeks=Visit 3) and a postnatal visit (2-3 days after delivery=Visit 4).

Eligible women should take two capsules twice daily (2 in the morning and 2 in the evening). Patients will be randomly assigned to the control or the VIVOMIXX® group.

The study agent VIVOMIXX® as well as the placebo will be supplied by "Mendes SA" for the whole study period.

During Visit 1 (at 10-12 weeks) written consent will be obtained, after information on expected benefits and possible inconveniences related to participation in the trial. Furthermore, eligible women will be asked to complete two questionnaires, one on dietary habits and one on gastrointestinal symptoms. The questionnaire on gastrointestinal symptoms will be submitted to the patients at each visit.

Height will be assessed at Visit 1, while the following parameters will be measured at each visit: weight, waits/hip circumference ratio, arterial blood pressure, plasma hemoglobin (Hb), hematocrit (Ht), fasting glycemia, fasting insulin and fasting glycated hemoglobin (HbA1c1).

A blood sample for the evaluation of homocysteine will be taken as well as urine and a faeces sample will be collected for nuclear-magnetic-resonance (NMR)-based metabolomics and intestinal microbiota analysis.

Furthermore, an Arm-band will be positioned for monitoring sleep and physical activities for one week at each visit.

At Visit 2 and 3 data regarding ultrasound examinations (Amniotic fluid index, abdominal circumference, cephalic circumference ratio) will be also collected.

Two-three days after delivery (Visit 4) data regarding the delivery (mode of delivery, gestational age at delivery) as well as the newborn (Apgar score, glycemia and serum bilirubin) were collected.

Moreover, a sample of colostrum (for NMR-based metabolomics, microbiota and high performance liquid chromatography-mass spectrometry -HPLC/MS- of vitamins analysis) and newborn faeces (for NMR-based metabolomics and microbiota analysis) sample will be collected.

• Study Type: Interventional
• Enrollment (Anticipated): 205
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Modena, Italy, 41124
    • Recruiting
    • Mother-Infant Department, University of Modena and Reggio Emilia, Italy
    • Sub-Investigator: Valeria Tamborrino, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 38 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Women aged between 20 and 40 with singleton pregnancies and BMI at recruitment > 30 kg/m^2 or a BMI> 25 kg/m^2 and the simultaneous presence of at least 1 of the following risk factors: age> 35 years, previous fetal macrosomia (> 4500gr), family history of diabetes (first-degree relative with type 2 diabetes mellitus), previous gestational diabetes mellitus.
• Adherence to lifestyle prescription including dietary counselling and physical activity stimulation

Exclusion Criteria:

• Subjects who require intervention in addition to the lifestyle changes women with diet and habits much different from the Mediterranean area (Central Africa, Asian, etc..). In such subgroup it will be difficult to obtain adherence to diet prescription since their cultural attitudes and dietary habits.
• Pre-pregnancy BMI> 40 kg/m^2
• Chronic hypertension
• Fasting glycemia in the first trimester of> 126 mg / dl or random glycemia > 200 mg/dl

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; Placebo	Dietary supplement: Placebo; The patients will be randomly assigned to the VIVOMIXX™ (intervention) or the control (placebo) group through a randomization list elaborated by a specific software.
Experimental: Intervention; Probiotic VIVOMIXX™	Dietary supplement: Probiotic VIVOMIXX™; The patients will be randomly assigned to the VIVOMIXX™ (intervention) or the control (placebo) group through a randomization list elaborated by a specific software.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal and newborn fecal microbiota changes (bifidobacteria and lactobacilli) and related enzymatic activity (alkaline sphingomyelinase and alkaline phosphatase) modifications	NMR-based metabolomics, microbiota and high performance liquid chromatography-mass spectrometry -HPLC/MS- of vitamins analysis	At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
Glucose metabolism changes	Positive Oral Glucose Tolerance Test	At 24-26 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight changes	Measured in kg	At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
Maternal BMI	Measured in kg/m^2	At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
Waist/hip circumference ratio		At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
Gestational weight gain	Measured in kg	At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
HOMA Index		At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
HbA1c1		At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
glycemia		At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
insulinemia		At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
homocysteine plasmatic levels		At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
Requirement for insulin therapy	Week of onset	At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
Requirement for insulin therapy	Dose of insulin	At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
Quality of sleep	Hours of deep sleep measured through the armband	At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
Duration of sleep	Measured in hours through the armband	At baseline, at 24-26 week, at 36-38 week, 2-3 days after delivery
Onset of hypertension / preeclampsia		At delivery
Time of delivery		At delivery
Mode of delivery		At delivery
Complications during delivery	Surgery and/or hemorrhage >500ml and/or shoulder dystocia	At delivery
Apgar score		Within 1 hour after delivery
Newborn's weight		Within 1 hour after delivery
Newborn's sex		Within 1 hour after delivery
Newborn's abdomen / head ratio		2-3 days after delivery
Newborn's skinfold thickness at birth		2-3 days after delivery
Neonatal hypoglycemia	Neonatal hypoglycemia (measured in mg/dl) that requires therapy	Within 24 hours from delivery
Neonatal bilirubinemia	Measured in mg/dl	At delivery, 2-3 days after delivery
Neonatal complications	Respiratory Distress Syndrome, Necrotizing Enterocolitis, Retinopathy of prematurity, Bronchopulmonary Dysplasia, Neonatal Death	2-3 days after delivery
Admission to Neonatal Intensive Care Unit (NICU)	Admission to NICU	Within 24 hours after delivery
Admission to Neonatal Intensive Care Unit (NICU)	Duration of stay at the NICU	Within 24 hours after delivery

Collaborators and Investigators

• Sponsor: University of Modena and Reggio Emilia

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Anticipated): June 1, 2016
• Study Completion: December 1, 2016

Study Registration Dates

• First Submitted: April 20, 2016
• First Submitted That Met QC Criteria: May 9, 2016
• First Posted (Estimate): May 11, 2016

Study Record Updates

• Last Update Posted (Estimate): May 11, 2016
• Last Update Submitted That Met QC Criteria: May 9, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Maternal Obesity Complicating Pregnancy
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Pregnancy Complications; Diabetes, Gestational; Pregnancy in Diabetics
• Other Study ID Numbers: CE 91/14