Trial Outcomes & Findings for Prophylactic Probiotics to Extremely Low Birth Weight Prematures (NCT NCT01603368)

Results Overview

The age of the infants in days when the infant receive 150 ml/kg/day via enteral feeding for the first time.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

134 participants

Primary outcome timeframe

Birth to gestational week 36+0

Results posted on

2024-08-13

Participant Flow

Extremely preterm infants with a birth weight \<1000 g were recruited within 72 hours after birth in two level 3 NICUs .

Inclusion should be completed to allow first dose of study product to be administered within 72 hours from birth.

Participant milestones

Participant milestones
Measure	Lactobacillus Reuteri Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Overall Study STARTED	68	66
Overall Study COMPLETED	68	66
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Prophylactic Probiotics to Extremely Low Birth Weight Prematures

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Probiotic n=68 Participants Lactobacillus reuteri	Placebo n=66 Participants	Total n=134 Participants Total of all reporting groups
Age, Continuous	25.5 age in postmenstrual weeks at birth STANDARD_DEVIATION 1.2 • n=5 Participants	25.5 age in postmenstrual weeks at birth STANDARD_DEVIATION 1.3 • n=7 Participants	25.5 age in postmenstrual weeks at birth STANDARD_DEVIATION 1.2 • n=5 Participants
Sex: Female, Male Female	36 Participants n=5 Participants	24 Participants n=7 Participants	60 Participants n=5 Participants
Sex: Female, Male Male	32 Participants n=5 Participants	42 Participants n=7 Participants	74 Participants n=5 Participants
Birth weight	731 gram STANDARD_DEVIATION 129 • n=5 Participants	740 gram STANDARD_DEVIATION 148 • n=7 Participants	735 gram STANDARD_DEVIATION 138 • n=5 Participants

PRIMARY outcome

Timeframe: Birth to gestational week 36+0

Population: Six infants - Four allocated to receive L. reuteri and two allocated to the placebo group died before reaching full enteral feeding and were not included in the analyses.

The age of the infants in days when the infant receive 150 ml/kg/day via enteral feeding for the first time.

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=64 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=64 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Time to Establish Full Enteral Feeds	15 days Interval 11.0 to 23.0	15 days Interval 10.0 to 20.0

SECONDARY outcome

Timeframe: Birth to gestational week 36

Episode with food intolerance. Retention volume\> food volume given the last 2 hours (retention checked routinely every 4 hours) and/or clinical signs consistent with necrotizing enterocolitis (reduced general condition and inflated abdomen). The number of such events will also be indicated.

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=68 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=66 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Days With Halted Feeding Due to Food Intolerance	5.5 days Interval 3.0 to 9.5	6 days Interval 4.0 to 10.0

SECONDARY outcome

Timeframe: Recorded over the first four weeks

Population: Only infants with complete records of stools during the first four weeks are included

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=47 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=44 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Number of Stools	69.6 number of stools Interval 64.1 to 75.1	69.9 number of stools Interval 63.8 to 75.9

SECONDARY outcome

Timeframe: Birth to gw 36+0

Specifies the number of full days the child has lived.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At 14th day of life

In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict.

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=64 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=62 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Weight Gain (SD)	-0.88 change in standard deviations Standard Deviation 0.81	-0.88 change in standard deviations Standard Deviation 0.81

SECONDARY outcome

Timeframe: Birth to gw 36+0

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=68 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=66 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Mortality	5 participants	5 participants

SECONDARY outcome

Timeframe: Birth to gw 36+0

Bell´s criteria II-III

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=68 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=66 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Necrotizing Enterocolitis	7 participants	8 participants

SECONDARY outcome

Timeframe: Birth to gw 36+0

Blood culture positive sepsis

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=68 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=66 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Sepsis	25 participants	23 participants

SECONDARY outcome

Timeframe: Gw 36+0

Population: Only patients surviving to gestational week 36+0 could be assessed for the diagnosis.

Need of oxygen or CPAP/ventilator at gw 36+0

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=63 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=61 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Bronchopulmonary Dysplasia	40 participants	39 participants

SECONDARY outcome

Timeframe: At 28th day of life

In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict.

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=64 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=63 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Weight Gain (SD)	-1.14 change in standard deviations Standard Deviation 1.07	-1.25 change in standard deviations Standard Deviation 0.95

SECONDARY outcome

Timeframe: At gestational week 36+0

In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict.

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=63 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=61 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Weight Gain (SD)	-0.40 change in standard deviations Standard Deviation 1.30	-0.24 change in standard deviations Standard Deviation 1.10

SECONDARY outcome

Timeframe: At 14th day of life

In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict.

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=62 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=63 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Length Gain (SD)	-1.02 change in standard deviations Standard Deviation 1.00	-1.20 change in standard deviations Standard Deviation 1.01

SECONDARY outcome

Timeframe: At 28th day of life

In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict.

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=62 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=62 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Length Gain (SD)	-1.67 change in standard deviations Standard Deviation 1.47	-1.96 change in standard deviations Standard Deviation 1.28

SECONDARY outcome

Timeframe: At gestational week 36+0

In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict.

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=63 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=61 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Length Gain (SD)	-1.44 change in standard deviations Standard Deviation 1.65	-1.34 change in standard deviations Standard Deviation 1.52

SECONDARY outcome

Timeframe: At 14th day of life

In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict.

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=61 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=62 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Head Circumference Growth (SD)	-0.92 change in standard deviations Standard Deviation 0.56	-1.11 change in standard deviations Standard Deviation 0.82

SECONDARY outcome

Timeframe: At 28th day of life

In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict.

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=64 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=63 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Head Circumference Growth (SD)	-1.21 change in standard deviations Standard Deviation 0.85	-1.73 change in standard deviations Standard Deviation 0.91

SECONDARY outcome

Timeframe: At gestational week 36+0

In this analysis, the difference in standard deviation score (delta z-scores) for weight, height and head circumference at birth and 14 and 28 days and gestational week 36+0 will be calculated. At gestational week 36+0 also absolute values will be analyzed. A positive delta z-score indicates faster growth than the growth chart would predict.

Outcome measures

Outcome measures
Measure	Lactobacillus Reuteri n=63 Participants Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=61 Participants The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Head Circumference Growth (SD)	-0.57 change in standard deviations Standard Deviation 1.29	-0.79 change in standard deviations Standard Deviation 1.24

SECONDARY outcome

Timeframe: At 2 years corrected age

Bayleys´s test by psychologist

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At 2 years corrected age

A composite of several outcomes: impaired cognition at the Bayleys´test, cerebral palsy, blindness and deafness, divided into normal, mild, moderate and severe. Mild -1SD to -2SD, Moderate \<-2D to 3 SD and Severe \<3SD

Outcome measures

Outcome data not reported

Adverse Events

Lactobacillus Reuteri

Serious events: 55 serious events

Other events: 0 other events

Deaths: 5 deaths

Placebo

Serious events: 52 serious events

Other events: 0 other events

Deaths: 5 deaths

Serious adverse events

Serious adverse events
Measure	Lactobacillus Reuteri n=68 participants at risk Lactobacillus reuteri DSM 17938, 125 million bacteria/day Lactobacillus reuteri: Oil drops with Lactobacillus reuteri DSM 17938, 125 million bacteria=0.2 ml per day	Placebo n=66 participants at risk The same oil drops as the active study product but without Lactobacillus reuteri Placebo: Oil drops without Lactobacillus reuteri
Infections and infestations Infection by the probiotic bacterium	0.00% 0/68 • From birth until 36+0 weeks corrected postmenstrual age	0.00% 0/66 • From birth until 36+0 weeks corrected postmenstrual age
General disorders Severe morbidity or death	80.9% 55/68 • From birth until 36+0 weeks corrected postmenstrual age	78.8% 52/66 • From birth until 36+0 weeks corrected postmenstrual age

Other adverse events

Adverse event data not reported

Additional Information

Thomas Abrahamsson, MD PhD

University of Linköping

Phone: +46.10.1030000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place