Efficacy of Multiple Strain Probiotics Reduces the Neurobehavioral Disorder in Premature Very Low Birth Weight Infants

• ClinicalTrials.gov Identifier: NCT03858816
• Recruitment Status: Recruiting
• First Posted: March 1, 2019
• Last Update Posted: March 6, 2019
• Sponsor: China Medical University Hospital
• Information provided by (Responsible Party): Hung-Chih Lin, China Medical University Hospital

Study Description

Brief Summary:

The management protocols, clinical practices, equipment, infrastructure, and key personnel in NICU are unchanged during the study period. The data collected by each center are transmitted to the office of the principal investigator (Dr Lin) at China Medical University Hospital. Primary outcome is death or attention deficit and hyperactivity disorder (ADHD) and ASD.

Condition or disease	Intervention/treatment	Phase
Very Low Birth Weight Infants	Other: Mixture probiotics; Other: Placebo	Not Applicable

Detailed Description:

Over the years, preterm very low birth weight (PVLBW) infants (<32 weeks gestation) have better survival rates and improved outcomes. Nonetheless, It is of concern that there are increased risk of psychiatric problems reported in PVLBW infants, 11.5% to 31% of them are reported to be at increased risk of attention deficit and hyperactivity disorder (ADHD) and 25 % of them would develop autism spectrum disorder (ASD).

Many VLBWs experience rapid vaginal or Caesarean births that increased relative risk of developing ASD and possibly ADHD when compared to vaginal delivery. Further, PVLBW infants often experience delays in enteral feeding, and many receive little or no mother's own milk, use of antibiotics, invasive procedures and maternal separation can contribute to dysbiosis and dysbiosis in early life may prone to develop ASD and ADHD There is growing body of evidence demonstrates that gut microbiota is involved in communication, and may impact brain development and modulate behavior. Evidences have showed that there were increased intestinal permeability, altered gut microbiota and activity in autism and ADHD. Studies have demonstrated that early postnatal phase of microbial development is a primer for future health. Giving all the evidence, it is reasonable to speculate that probiotics could reduce the ASD and ADHD in preterm VLBW infants.

From Aug 1, 2017 to June 30, 2020, a prospective, double blind, randomized, controlled trial will be conducted in five NICUs at Taiwan. The study protocol will be approved by the institutional review board of each hospital. Preterm infants ≧ 23 weeks and ≦ 32 weeks gestational age and birth weight below 1500 gm and who survive to NICU are eligible for the trial. They will be assigned randomly to either group A: multiple strian probiotics or group B: control group received 1 mL of a 5% glucose solution. Study is continuous until preterm infants grow up to 4 months postnatal age.

The management protocols, clinical practices, equipment, infrastructure, and key personnel in NICU are unchanged during the study period. The data collected by each center are transmitted to the office of the principal investigator (Dr Lin) at China Medical University Hospital. Primary outcome is death or attention deficit and hyperactivity disorder (ADHD) and ASD.

Mortality is defined as death prior to discharge. Secondary outcomes are NEC ≧ stage 2, sepsis, severe (grade 3-4) IVH, BPD, alteration of liver function, and adverse effects or intolerance and neurodevelopment impairment. Objection of the first two years is to enroll cases, ASD and ADHD will be assessed by two independent neurologists at third year of life; no examiner is aware of treatment assigned to any infant.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 320 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy of Multiple Strain Probiotics Reduces the Neurobehavioral Disorder in Premature Very Low Birth Weight Infants
• Actual Study Start Date: June 14, 2018
• Estimated Primary Completion Date: June 30, 2020
• Estimated Study Completion Date: June 30, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Mixture probiotics; The probiotic contain 1 ×10^9 CFU/1 capsule of mixture probiotics, taking 1 probiotic capsule for up to 4 months after birth.	Other: Mixture probiotics; The mixture probiotics capsule
Placebo Comparator: Placebo; Taking 1 placebo capsule for up to 4 months after birth.	Other: Placebo; The placebo contains the same excipient ingredients but without the live bacteria.

Outcome Measures

Primary Outcome Measures :

1. Incidence rate of death or ADHD and ASD [ Time Frame: Two years ]

Secondary Outcome Measures :

1. Incidence rate of NEC ≧ stage 2, sepsis, severe (grade 3-4) IVH, BPD, liver function and adverse effects or intolerance and neurodevelopment impairment. [ Time Frame: Two years ]

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Preterm infants ≧ 23 weeks and ≦ 32 weeks gestational age.
• Birth weight below 1500 gm and who survive to NICU.

Exclusion Criteria:

• Severe asphyxia (stage III)
• Fetal chromosomal anomalies
• Cyanotic congenital heart disease
• Congenital intestinal atresia
• Gastroschisis
• Omphalocele
• Active upper gastric intestinal bleeding
• Lacking/refused of parental consent
• Early onset sepsis (before the third day of life)
• Liver failure (aspartate aminotransferase, alanine aminotransferase, glutamyl transferase, direct bilirubin serum values 3-fold higher than reference range)
• Fasted for >3 weeks.

Contacts and Locations

Contacts

Contact: Hung-chih Lin; 886-4-22052121 ext 4640; d0373@mail.cmuh.org.tw

Locations

Taiwan

Department of Pediatrics, Children Hospital, China Medical University; Recruiting

Taichung, Taiwan, 404

Contact: Hung-chih Lin 886-4-22052121 ext 4640 d0373@mail.cmuh.org.tw

Sponsors and Collaborators

China Medical University Hospital

More Information

Additional Information:

Related Info 

• Responsible Party: Hung-Chih Lin, Attending physician, China Medical University Hospital
• ClinicalTrials.gov Identifier: NCT03858816
• Other Study ID Numbers: CMUH106-REC2-102
• First Posted: March 1, 2019
• Last Update Posted: March 6, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data for all primary and secondary outcome measures will be made available.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: Data will be available within 6 months of study completion.
• Access Criteria: Data access requests will be reviewed by an external Independent Review Panel. Requestors will be required to sign a Data Access Agreement.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hung-Chih Lin, China Medical University Hospital:

probiotics; neuropsychiatric disorder; very low birth weight infants; attention deficit and hyperactivity disorder (ADHD); autism spectrum disorder (ASD)

Additional relevant MeSH terms:

Body Weight; Birth Weight