Colic, Infantile, Infantile Colic
Conditions
Keywords
Bifidobacterium
Brief summary
This is a single-center, randomized, double blind controlled study to investigate the effects of Bifidobacterium, BB-12® versus placebo in a study group of pediatric patients with infantile colic.
Interventions
DIETARY_SUPPLEMENTBifidobacterium, BB-12® (Bifidolactis Infant)
DIETARY_SUPPLEMENTBifidolactis Infant Placebo
Sponsors
SOFAR S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This is a prospective randomized double blind placebo controlled clinical trial
Eligibility
Sex/Gender
ALL
Age
No minimum to 7 Weeks
Healthy volunteers
No
Inclusion criteria
Patients are included in the study if they meet all the following criteria: * Exclusively breastfed healthy infants of both sexes, aged ≤ 7 weeks. * Diagnosis of IC according to Rome III criteria. * Written informed consent of the parent/tutor.
Exclusion criteria
Patients are excluded from this study if they meet any of the following criteria: * Birth weight \< 2500 g. * Gestational age \< 37 weeks. * APGAR 5 minutes \< 7. * Formula feeding. * Stunting/loss of weight (\< 100 g/weeks from birth to the last reported weight). * Neurological diseases. * Known or suspected food allergy. * Gastroesophageal reflux disease. * Use of substances that alter gut microbiota (probiotics, prebiotics, antibiotics, gastric acidity inhibitors) in the last 2 weeks prior the enrollment. * History of fever and/or infectious diseases in the last 2 weeks prior to enrollment. * Ongoing systemic infections. * History of congenital infections. * Chronic intestinal diseases (cystic fibrosis or other forms of primitive pancreatic insufficiency) * Primitive or secondary malformations of the gastrointestinal tract (such as esophageal atresia, intestinal atresia, short bowel syndrome, malrotation). * Metabolic diseases. * Genetic diseases and chromosomal abnormalities. * Primary or secondary immunodeficiencies. * Not sufficient reliability or presence of conditions that may result in non-compliance/adherence of the patient to the Protocol. * Previous participation in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With >=50% Reduction in Mean Weekly Crying Duration | at 28 days from the baseline (Visit T5) | Treatment success rate was evaluated in terms of reduction of crying duration, comparing mean weekly duration of the last Week (from T4 to T5) and mean weekly duration of Week 1 (from T0 to T1). The daily number and duration of crying episodes has been collected in the 'Evaluation of crying' section of the patient diary. Weekly mean is defined as the mean of the calculated average daily durations during the selected week and is described by means of descriptive statistics for continuous data. Mean changes from baseline (i.e. mean of the first Week) to the mean of the selected week will be computed as well. The following categories of patients has been defined: Success = patients who meet the criteria for the treatment success rate No Success = patients who do not meet the criteria for the treatment success rate Missing = patients who did not do the last visit (Visit T5 - at 28 days from baseline) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Crying Episodes | at 7 days (Visit T1 - baseline) and 28 days from the baseline (Visit T5) | Weekly mean of cries will be defined as the mean number of cries reported in the Evaluation of behavior section during the week (i.e. number of episodes/number of days with episodes) and will be described by means of descriptive statistics for continuous data. Mean changes from baseline (i.e. mean of the first Week) to the mean of the selected week will be analyzed too. |
| Infectious Diseases Incidence | at each visit, for 5 weeks starting from the enrollment in the study (Visit T0, T1, T2, T3, T4 and T5) | Number of infections in respiratory system, gastrointestinal system, urinary tract and skin. An infection was defined as an Adverse Event with SOC equal to Infections and Infestations. |
| Bowel Evacuation - Stool Frequency | at each weekly visit from baseline (Visit T1, T2, T3, T4 and T5) | Daily frequency of bowel evacuation. The frequency of stools were collected daily in the diary. Stool frequency was evaluated as the mean of total daily stools reported per week. |
| Bowel Evacuation - Stool Consistency | at each weekly visit from baseline (Visit T1, T2, T3, T4 and T5) | Stool consistency was evaluated as the number and the proportion of patients who reported at least one stool sample of each type per week, according to Bristol scale as follows: Type A = separate hard lumps, like nuts (hard to pass) Type B = sausage-shaped, but lumpy Type C = Like a sausage but with cracks on its surface Type D = like a sausage or snake, smooth and soft Only a descriptive statistics Type E = soft blobs with clear-cut edges (passed easily) Type F = fluffy pieces with ragged edges, a mushy stool Type G = watery, no solid pieces (entirely liquid). Patients could report more than one stool consistency per day then the sum of the Count of Participants for each group at each visit could be Greater then the Overall Number of Participants Analyzed |
| Infant's Mood | at each weekly visit from baseline (Visit T1, T2, T3, T4 and T5) | The infant's mood (calm, asleep, agitated, irritable) was collected daily in the diary and was evaluated as the number and the proportion of infants who reported at least one mood of each type per week. Patients could report more than one mood per day then the sum of the Count of Participants for each group at each visit could be greater then the Overall Number of Participants Analyzed. |
| Infant's Sleep | at each weekly visit from baseline (Visit T1, T2, T3, T4 and T5) | Duration of sleep (in minutes) was collected daily in the diary during the entire study period. Mean daily duration of sleep by week was defined as the mean of the daily durations during the selected week and was described by means of descriptive statistics for continuous data. |
| Infant's Temper | at each weekly visit from baseline (Visit T1, T2, T3, T4 and T5) | Duration of temper episodes (in minutes) was collected daily in the diary during the entire study period. Mean daily duration of temper episodes by week was defined as the mean of the daily durations during the selected week and was described by means of descriptive statistics for continuous data. |
| Infant's Feeding | at each weekly visit from baseline (Visit T1, T2, T3, T4 and T5) | Duration of feeding (in minutes) was collected daily in the diary during the entire study period. Mean daily feeding time by week was defined as the mean of the daily durations during the selected week and was described by means of descriptive statistics for continuous data. |
| Calprotectin | at 7 days (Visit T1 - baseline) and 28 days from the baseline (Visit T5) | Evaluation of calprotectin levels in fecal samples |
| Beta-defensin Type 2 | at 7 days (Visit T1 - baseline) and 28 days from the baseline (Visit T5) | Evaluation of Beta-defensin type 2 levels in fecal samples |
| LL37 Peptide | at 7 days (Visit T1 - baseline) and 28 days from the baseline (Visit T5) | Evaluation of LL37 peptide levels in fecal samples |
| Short Chain Fatty Acids - Butyrate | at 7 days (Visit T1 - baseline) and 28 days from the baseline (Visit T5) | Evaluation of Butyrate levels in fecal samples |
| Secretory Immunoglobulin A (SIgA) | at 7 days (Visit T1 - baseline) and 28 days from the baseline (Visit T5) | Secretory immunoglobulin A (SIgA) levels in fecal samples |
Countries
Italy
Participant flow
Recruitment details
The study was a randomized, double-blind, placebo-controlled parallel-group study. Eighty (80) infants were screened and all were enrolled in the study and randomized (40 to Bifidobacteriium BB-12® and 40 to Placebo). The enrollment period started on 11-Nov-2016 and closed on 6-Nov-2017.
Participants by arm
| Arm | Count |
|---|---|
| Bifidobacterium BB-12® patients who take Bifidobacterium BB-12® (Bifidolactis Infant), 6 drops a day (guaranteeing a billion of living cells) for 28 consecutive days;
Bifidobacterium, BB-12® (Bifidolactis Infant) | 40 |
| Placebo patients who take Bifidolactis Infant Placebo 6 drops a day for 28 consecutive days.
Bifidolactis Infant Placebo | 40 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Difficulties in completing daily diary | 2 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliance of family | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo | Bifidobacterium BB-12® | Total |
|---|---|---|---|
| Age, Continuous | 32.73 days STANDARD_DEVIATION 5.69 | 33.05 days STANDARD_DEVIATION 5.03 | 32.89 days STANDARD_DEVIATION 5.34 |
| Apgar 5 minutes score | 8.83 scores on a scale STANDARD_DEVIATION 0.38 | 8.95 scores on a scale STANDARD_DEVIATION 0.39 | 8.89 scores on a scale STANDARD_DEVIATION 0.39 |
| Birth weight | 3412.00 grams STANDARD_DEVIATION 442.75 | 3280.75 grams STANDARD_DEVIATION 367.54 | 3346.38 grams STANDARD_DEVIATION 409.66 |
| Clinical/surgical history No prior clinical/surgical events were reported | 40 Participants | 40 Participants | 80 Participants |
| Clinical/surgical history Prior clinical/surgical events were reported | 0 Participants | 0 Participants | 0 Participants |
| Exposure to second-hand tobacco smoke within the home environment No | 29 Participants | 29 Participants | 58 Participants |
| Exposure to second-hand tobacco smoke within the home environment Yes | 11 Participants | 11 Participants | 22 Participants |
| Gestational age | 38.53 weeks STANDARD_DEVIATION 1.2 | 38.43 weeks STANDARD_DEVIATION 0.93 | 38.48 weeks STANDARD_DEVIATION 1.07 |
| Positive family history of allergic disease No | 22 Participants | 21 Participants | 43 Participants |
| Positive family history of allergic disease Yes | 18 Participants | 19 Participants | 37 Participants |
| Positive family history of functional gastrointestinal diseases No | 33 Participants | 37 Participants | 70 Participants |
| Positive family history of functional gastrointestinal diseases Yes | 7 Participants | 3 Participants | 10 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Italy | 40 participants | 40 participants | 80 participants |
| Sex: Female, Male Female | 19 Participants | 18 Participants | 37 Participants |
| Sex: Female, Male Male | 21 Participants | 22 Participants | 43 Participants |
| Smoking habits Father | 6 Participants | 5 Participants | 11 Participants |
| Smoking habits Mother | 4 Participants | 6 Participants | 10 Participants |
| Smoking habits Mother, Father | 1 Participants | 3 Participants | 4 Participants |
| Smoking habits No one | 29 Participants | 26 Participants | 55 Participants |
| Type of childbirth Caesarean section | 19 Participants | 25 Participants | 44 Participants |
| Type of childbirth Natural childbirth | 21 Participants | 15 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 40 |
| other Total, other adverse events | 0 / 40 | 0 / 40 |
| serious Total, serious adverse events | 1 / 40 | 0 / 40 |
Outcome results
Primary
Number of Participants With >=50% Reduction in Mean Weekly Crying Duration
Treatment success rate was evaluated in terms of reduction of crying duration, comparing mean weekly duration of the last Week (from T4 to T5) and mean weekly duration of Week 1 (from T0 to T1). The daily number and duration of crying episodes has been collected in the 'Evaluation of crying' section of the patient diary. Weekly mean is defined as the mean of the calculated average daily durations during the selected week and is described by means of descriptive statistics for continuous data. Mean changes from baseline (i.e. mean of the first Week) to the mean of the selected week will be computed as well. The following categories of patients has been defined: Success = patients who meet the criteria for the treatment success rate No Success = patients who do not meet the criteria for the treatment success rate Missing = patients who did not do the last visit (Visit T5 - at 28 days from baseline)
Time frame: at 28 days from the baseline (Visit T5)
Population: Intention to Treat Set (ITT): all randomized patients who received at least one dose of study treatment. Following the intent-to-treat (ITT) principle, patients were analyzed according to the treatment they were assigned to at the randomization visit.~Patients drop-out were also considered and classified as Treatment success rate = Missing.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bifidobacterium BB-12® | Number of Participants With >=50% Reduction in Mean Weekly Crying Duration | Visit T5 - No Success | 3 Participants |
| Bifidobacterium BB-12® | Number of Participants With >=50% Reduction in Mean Weekly Crying Duration | Visit T5 - Missing | 5 Participants |
| Bifidobacterium BB-12® | Number of Participants With >=50% Reduction in Mean Weekly Crying Duration | Visit T5 - Success | 32 Participants |
| Placebo | Number of Participants With >=50% Reduction in Mean Weekly Crying Duration | Visit T5 - No Success | 24 Participants |
| Placebo | Number of Participants With >=50% Reduction in Mean Weekly Crying Duration | Visit T5 - Missing | 3 Participants |
| Placebo | Number of Participants With >=50% Reduction in Mean Weekly Crying Duration | Visit T5 - Success | 13 Participants |
Comparison: According to the results of a previous trial that looked at a probiotic's effect on infants with CI, it was estimated that when the sample size in each group is 33, the study has 80% power to detect an absolute difference of 35% in the treatment success rate (15% in the Placebo group and 50% in the treatment group) with a 0,05 alpha level.~The number of infants that was included in the study was 80, with an expected maximum dropout rate of 20%.p-value: 0.0001Chi-squared
Secondary
Beta-defensin Type 2
Evaluation of Beta-defensin type 2 levels in fecal samples
Time frame: at 7 days (Visit T1 - baseline) and 28 days from the baseline (Visit T5)
Population: The analysis Population includes all participants for wich an evaluable fecal sample was available at Visit T1 and Visit T5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bifidobacterium BB-12® | Beta-defensin Type 2 | Visit T1 - baseline | 73.50 ng/g | Standard Deviation 10.92 |
| Bifidobacterium BB-12® | Beta-defensin Type 2 | Visit T5 | 166.34 ng/g | Standard Deviation 43.79 |
| Placebo | Beta-defensin Type 2 | Visit T1 - baseline | 69.41 ng/g | Standard Deviation 7.03 |
| Placebo | Beta-defensin Type 2 | Visit T5 | 127.97 ng/g | Standard Deviation 35.41 |
Secondary
Bowel Evacuation - Stool Consistency
Stool consistency was evaluated as the number and the proportion of patients who reported at least one stool sample of each type per week, according to Bristol scale as follows: Type A = separate hard lumps, like nuts (hard to pass) Type B = sausage-shaped, but lumpy Type C = Like a sausage but with cracks on its surface Type D = like a sausage or snake, smooth and soft Only a descriptive statistics Type E = soft blobs with clear-cut edges (passed easily) Type F = fluffy pieces with ragged edges, a mushy stool Type G = watery, no solid pieces (entirely liquid). Patients could report more than one stool consistency per day then the sum of the Count of Participants for each group at each visit could be Greater then the Overall Number of Participants Analyzed
Time frame: at each weekly visit from baseline (Visit T1, T2, T3, T4 and T5)
Population: Intention to Treat Set (ITT): all randomized patients who received at least one dose of study treatment.~The number of participants analyzed in Visit T5 is less then Visit T1 since 8 participants dropped from the study before Visit T5.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T1: Patients with at least one stool of type E | 21 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T3: Patients with at least one stool of type E | 24 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T2: Patients with at least one stool of type E | 25 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T3: Patients with at least one stool of type F | 27 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T1: Patients with at least one stool of type G | 12 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T3: Patients with at least one stool of type G | 8 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T2: Patients with at least one stool of type F | 30 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T4: Patients with at least one stool of type C | 0 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T1: Patients with at least one stool of type D | 14 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T4: Patients with at least one stool of type D | 18 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T2: Patients with at least one stool of type G | 12 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T4: Patients with at least one stool of type E | 27 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T2: Patients with at least one stool of type C | 0 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T4: Patients with at least one stool of type F | 23 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T3: Patients with at least one stool of type C | 0 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T4: Patients with at least one stool of type G | 8 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T1: Patients with at least one stool of type F | 27 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T5: Patients with at least one stool of type C | 0 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T1: Patients with at least 1 stool of type C | 0 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T5: Patients with at least one stool of type D | 17 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T3: Patients with at least one stool of type D | 16 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T5: Patients with at least one stool of type E | 26 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T2: Patients with at least one stool of type D | 14 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T5: Patients with at least one stool of type F | 19 participants |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Consistency | T5: Patients with at least one stool of type G | 6 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T5: Patients with at least one stool of type C | 0 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T1: Patients with at least 1 stool of type C | 1 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T1: Patients with at least one stool of type D | 10 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T1: Patients with at least one stool of type E | 15 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T1: Patients with at least one stool of type F | 34 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T1: Patients with at least one stool of type G | 21 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T2: Patients with at least one stool of type C | 1 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T2: Patients with at least one stool of type D | 8 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T2: Patients with at least one stool of type E | 19 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T2: Patients with at least one stool of type F | 34 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T2: Patients with at least one stool of type G | 20 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T3: Patients with at least one stool of type C | 0 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T5: Patients with at least one stool of type G | 3 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T3: Patients with at least one stool of type D | 8 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T3: Patients with at least one stool of type E | 26 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T3: Patients with at least one stool of type F | 30 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T3: Patients with at least one stool of type G | 8 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T4: Patients with at least one stool of type C | 0 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T4: Patients with at least one stool of type D | 15 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T4: Patients with at least one stool of type E | 30 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T4: Patients with at least one stool of type F | 27 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T4: Patients with at least one stool of type G | 5 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T5: Patients with at least one stool of type D | 25 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T5: Patients with at least one stool of type E | 29 participants |
| Placebo | Bowel Evacuation - Stool Consistency | T5: Patients with at least one stool of type F | 16 participants |
Secondary
Bowel Evacuation - Stool Frequency
Daily frequency of bowel evacuation. The frequency of stools were collected daily in the diary. Stool frequency was evaluated as the mean of total daily stools reported per week.
Time frame: at each weekly visit from baseline (Visit T1, T2, T3, T4 and T5)
Population: Intention to Treat Set (ITT): all randomized patients who received at least one dose of study treatment.~The number of participants analyzed in Visit T5 is less then Visit T1 since 8 participants dropped from the study before Visit T5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Frequency | Visit T5 | 4.34 daily number of bowel evacuations | Standard Deviation 1.45 |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Frequency | Visti T1 - Baseline | 5.30 daily number of bowel evacuations | Standard Deviation 1.49 |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Frequency | Visit T2 | 5.15 daily number of bowel evacuations | Standard Deviation 1.63 |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Frequency | Visit T3 | 4.92 daily number of bowel evacuations | Standard Deviation 1.53 |
| Bifidobacterium BB-12® | Bowel Evacuation - Stool Frequency | Visit T4 | 4.51 daily number of bowel evacuations | Standard Deviation 1.51 |
| Placebo | Bowel Evacuation - Stool Frequency | Visit T4 | 5.10 daily number of bowel evacuations | Standard Deviation 1.24 |
| Placebo | Bowel Evacuation - Stool Frequency | Visit T3 | 5.35 daily number of bowel evacuations | Standard Deviation 1.45 |
| Placebo | Bowel Evacuation - Stool Frequency | Visti T1 - Baseline | 5.61 daily number of bowel evacuations | Standard Deviation 1.6 |
| Placebo | Bowel Evacuation - Stool Frequency | Visit T5 | 4.64 daily number of bowel evacuations | Standard Deviation 1.23 |
| Placebo | Bowel Evacuation - Stool Frequency | Visit T2 | 5.50 daily number of bowel evacuations | Standard Deviation 1.54 |
p-value: 0.001Wilcoxon (Mann-Whitney)
Secondary
Calprotectin
Evaluation of calprotectin levels in fecal samples
Time frame: at 7 days (Visit T1 - baseline) and 28 days from the baseline (Visit T5)
Population: The analysis Population includes all participants for wich an evaluable fecal sample was available at Visit T1 and Visit T5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bifidobacterium BB-12® | Calprotectin | Visit T1 - Baseline | 667.76 mM/Kg | Standard Deviation 162.06 |
| Bifidobacterium BB-12® | Calprotectin | Visit T5 | 802.64 mM/Kg | Standard Deviation 131.33 |
| Placebo | Calprotectin | Visit T1 - Baseline | 658.47 mM/Kg | Standard Deviation 112.61 |
| Placebo | Calprotectin | Visit T5 | 915.41 mM/Kg | Standard Deviation 106.47 |
Secondary
Infant's Feeding
Duration of feeding (in minutes) was collected daily in the diary during the entire study period. Mean daily feeding time by week was defined as the mean of the daily durations during the selected week and was described by means of descriptive statistics for continuous data.
Time frame: at each weekly visit from baseline (Visit T1, T2, T3, T4 and T5)
Population: Intention to Treat Set (ITT): all randomized patients who received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bifidobacterium BB-12® | Infant's Feeding | Visit T2 | 186.13 minutes | Standard Deviation 63.37 |
| Bifidobacterium BB-12® | Infant's Feeding | Visit T4 | 180.31 minutes | Standard Deviation 47.85 |
| Bifidobacterium BB-12® | Infant's Feeding | Visit T3 | 179.80 minutes | Standard Deviation 55.16 |
| Bifidobacterium BB-12® | Infant's Feeding | Visit T5 | 176.47 minutes | Standard Deviation 38.55 |
| Bifidobacterium BB-12® | Infant's Feeding | Visit T1 - Baseline | 187.72 minutes | Standard Deviation 35.95 |
| Placebo | Infant's Feeding | Visit T5 | 182.26 minutes | Standard Deviation 27.2 |
| Placebo | Infant's Feeding | Visit T1 - Baseline | 177.72 minutes | Standard Deviation 34.66 |
| Placebo | Infant's Feeding | Visit T2 | 188.98 minutes | Standard Deviation 32.75 |
| Placebo | Infant's Feeding | Visit T3 | 185.98 minutes | Standard Deviation 30.98 |
| Placebo | Infant's Feeding | Visit T4 | 182.22 minutes | Standard Deviation 28.7 |
Secondary
Infant's Mood
The infant's mood (calm, asleep, agitated, irritable) was collected daily in the diary and was evaluated as the number and the proportion of infants who reported at least one mood of each type per week. Patients could report more than one mood per day then the sum of the Count of Participants for each group at each visit could be greater then the Overall Number of Participants Analyzed.
Time frame: at each weekly visit from baseline (Visit T1, T2, T3, T4 and T5)
Population: Intention to Treat Set (ITT): all randomized patients who received at least one dose of study treatment. The number of participants analyzed in Visit T5 is less then Visit T1 since 8 participants dropped from the study before Visit T5
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bifidobacterium BB-12® | Infant's Mood | T1: Pts with at least one mood equal to Calm | 4 participants |
| Bifidobacterium BB-12® | Infant's Mood | T1: Pts. with at least one mood equal to Asleep | 5 participants |
| Bifidobacterium BB-12® | Infant's Mood | T1: Pts. with at least one mood equal to Agitated | 38 participants |
| Bifidobacterium BB-12® | Infant's Mood | T1: Pts. with at least one mood equal to Irritable | 36 participants |
| Bifidobacterium BB-12® | Infant's Mood | T2: Pts. with at least one mood equal to Calm | 14 participants |
| Bifidobacterium BB-12® | Infant's Mood | T2: Pts. with at least one mood equal to Asleep | 11 participants |
| Bifidobacterium BB-12® | Infant's Mood | T2: Pts. with at least one mood equal to Agitated | 37 participants |
| Bifidobacterium BB-12® | Infant's Mood | T2: Pts. with at least one mood equal to Irritable | 33 participants |
| Bifidobacterium BB-12® | Infant's Mood | T3: Pts. with at least one mood equal to Calm | 28 participants |
| Bifidobacterium BB-12® | Infant's Mood | T3: Pts. with at least one mood equal to Asleep | 12 participants |
| Bifidobacterium BB-12® | Infant's Mood | T3: Pts. with at least one mood equal to Agitated | 34 participants |
| Bifidobacterium BB-12® | Infant's Mood | T3: Pts. with at least one mood equal to Irritable | 25 participants |
| Bifidobacterium BB-12® | Infant's Mood | T4: Pts. with at least one mood equal to Calm | 35 participants |
| Bifidobacterium BB-12® | Infant's Mood | T4: Pts. with at least one mood equal to Asleep | 21 participants |
| Bifidobacterium BB-12® | Infant's Mood | T4: Pts. with at least one mood equal to Agitated | 32 participants |
| Bifidobacterium BB-12® | Infant's Mood | T4: Pts. with at least one mood equal to Irritable | 11 participants |
| Bifidobacterium BB-12® | Infant's Mood | T5: Pts. with at least one mood equal to Calm | 35 participants |
| Bifidobacterium BB-12® | Infant's Mood | T5: Pts. with at least one mood equal to Asleep | 27 participants |
| Bifidobacterium BB-12® | Infant's Mood | T5: Pts. with at least one mood equal to Agitated | 9 participants |
| Bifidobacterium BB-12® | Infant's Mood | T5: Pts. with at least one mood equal to Irritable | 5 participants |
| Placebo | Infant's Mood | T5: Pts. with at least one mood equal to Asleep | 23 participants |
| Placebo | Infant's Mood | T1: Pts with at least one mood equal to Calm | 5 participants |
| Placebo | Infant's Mood | T3: Pts. with at least one mood equal to Agitated | 33 participants |
| Placebo | Infant's Mood | T1: Pts. with at least one mood equal to Asleep | 6 participants |
| Placebo | Infant's Mood | T4: Pts. with at least one mood equal to Irritable | 28 participants |
| Placebo | Infant's Mood | T1: Pts. with at least one mood equal to Agitated | 25 participants |
| Placebo | Infant's Mood | T3: Pts. with at least one mood equal to Irritable | 30 participants |
| Placebo | Infant's Mood | T1: Pts. with at least one mood equal to Irritable | 36 participants |
| Placebo | Infant's Mood | T5: Pts. with at least one mood equal to Irritable | 20 participants |
| Placebo | Infant's Mood | T2: Pts. with at least one mood equal to Calm | 7 participants |
| Placebo | Infant's Mood | T4: Pts. with at least one mood equal to Calm | 15 participants |
| Placebo | Infant's Mood | T2: Pts. with at least one mood equal to Asleep | 8 participants |
| Placebo | Infant's Mood | T5: Pts. with at least one mood equal to Calm | 17 participants |
| Placebo | Infant's Mood | T2: Pts. with at least one mood equal to Agitated | 32 participants |
| Placebo | Infant's Mood | T4: Pts. with at least one mood equal to Asleep | 17 participants |
| Placebo | Infant's Mood | T2: Pts. with at least one mood equal to Irritable | 34 participants |
| Placebo | Infant's Mood | T5: Pts. with at least one mood equal to Agitated | 34 participants |
| Placebo | Infant's Mood | T3: Pts. with at least one mood equal to Calm | 12 participants |
| Placebo | Infant's Mood | T4: Pts. with at least one mood equal to Agitated | 36 participants |
| Placebo | Infant's Mood | T3: Pts. with at least one mood equal to Asleep | 8 participants |
Secondary
Infant's Sleep
Duration of sleep (in minutes) was collected daily in the diary during the entire study period. Mean daily duration of sleep by week was defined as the mean of the daily durations during the selected week and was described by means of descriptive statistics for continuous data.
Time frame: at each weekly visit from baseline (Visit T1, T2, T3, T4 and T5)
Population: Intention to Treat Set (ITT): all randomized patients who received at least one dose of study treatment. The number of participants analyzed in Visit T5 is less then Visit T1 since 8 participants dropped from the study before Visit T5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bifidobacterium BB-12® | Infant's Sleep | Visit T2 | 687.47 minutes | Standard Deviation 113.41 |
| Bifidobacterium BB-12® | Infant's Sleep | Visit T4 | 725.76 minutes | Standard Deviation 112.54 |
| Bifidobacterium BB-12® | Infant's Sleep | Visit T3 | 722.37 minutes | Standard Deviation 116.3 |
| Bifidobacterium BB-12® | Infant's Sleep | Visit T5 | 713.20 minutes | Standard Deviation 98.97 |
| Bifidobacterium BB-12® | Infant's Sleep | Visit T1 - baseline | 678.14 minutes | Standard Deviation 96.13 |
| Placebo | Infant's Sleep | Visit T5 | 738.61 minutes | Standard Deviation 141.58 |
| Placebo | Infant's Sleep | Visit T1 - baseline | 693.62 minutes | Standard Deviation 121.79 |
| Placebo | Infant's Sleep | Visit T2 | 696.68 minutes | Standard Deviation 121 |
| Placebo | Infant's Sleep | Visit T3 | 711.99 minutes | Standard Deviation 128.87 |
| Placebo | Infant's Sleep | Visit T4 | 725.14 minutes | Standard Deviation 131.74 |
Secondary
Infant's Temper
Duration of temper episodes (in minutes) was collected daily in the diary during the entire study period. Mean daily duration of temper episodes by week was defined as the mean of the daily durations during the selected week and was described by means of descriptive statistics for continuous data.
Time frame: at each weekly visit from baseline (Visit T1, T2, T3, T4 and T5)
Population: Intention to Treat Set (ITT): all randomized patients who received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bifidobacterium BB-12® | Infant's Temper | Visit T2 | 118.61 minutes | Standard Deviation 45.59 |
| Bifidobacterium BB-12® | Infant's Temper | Visit T4 | 71.71 minutes | Standard Deviation 54.79 |
| Bifidobacterium BB-12® | Infant's Temper | Visit T3 | 89.48 minutes | Standard Deviation 47.96 |
| Bifidobacterium BB-12® | Infant's Temper | Visit T5 | 36.79 minutes | Standard Deviation 42.45 |
| Bifidobacterium BB-12® | Infant's Temper | Visit T1 - Baseline | 158.82 minutes | Standard Deviation 36.31 |
| Placebo | Infant's Temper | Visit T5 | 72.96 minutes | Standard Deviation 40.22 |
| Placebo | Infant's Temper | Visit T1 - Baseline | 138 minutes | Standard Deviation 34.71 |
| Placebo | Infant's Temper | Visit T2 | 117.24 minutes | Standard Deviation 58.32 |
| Placebo | Infant's Temper | Visit T3 | 84.33 minutes | Standard Deviation 46.76 |
| Placebo | Infant's Temper | Visit T4 | 84.89 minutes | Standard Deviation 58.04 |
Secondary
Infectious Diseases Incidence
Number of infections in respiratory system, gastrointestinal system, urinary tract and skin. An infection was defined as an Adverse Event with SOC equal to Infections and Infestations.
Time frame: at each visit, for 5 weeks starting from the enrollment in the study (Visit T0, T1, T2, T3, T4 and T5)
Population: Intention to Treat Set (ITT): all randomized patients who received at least one dose of study treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bifidobacterium BB-12® | Infectious Diseases Incidence | 0 Number of infections | Standard Deviation 0 |
| Placebo | Infectious Diseases Incidence | 0 Number of infections | Standard Deviation 0 |
Secondary
LL37 Peptide
Evaluation of LL37 peptide levels in fecal samples
Time frame: at 7 days (Visit T1 - baseline) and 28 days from the baseline (Visit T5)
Population: The analysis Population includes all participants for wich an evaluable fecal sample was available at Visit T1 and Visit T5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bifidobacterium BB-12® | LL37 Peptide | Visit T5 | 7.65 ng/g | Standard Deviation 1.15 |
| Bifidobacterium BB-12® | LL37 Peptide | Visit T1 - Baseline | 5.50 ng/g | Standard Deviation 0.82 |
| Placebo | LL37 Peptide | Visit T5 | 6.07 ng/g | Standard Deviation 1.41 |
| Placebo | LL37 Peptide | Visit T1 - Baseline | 5.37 ng/g | Standard Deviation 0.83 |
Secondary
Number of Crying Episodes
Weekly mean of cries will be defined as the mean number of cries reported in the Evaluation of behavior section during the week (i.e. number of episodes/number of days with episodes) and will be described by means of descriptive statistics for continuous data. Mean changes from baseline (i.e. mean of the first Week) to the mean of the selected week will be analyzed too.
Time frame: at 7 days (Visit T1 - baseline) and 28 days from the baseline (Visit T5)
Population: Intention to Treat Set (ITT): all randomized patients who received at least one dose of study treatment.~The number of participants analyzed in Visit T5 is less then Visit T1 since 8 participants dropped from the study before Visit T5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bifidobacterium BB-12® | Number of Crying Episodes | Visit T5 | 3.15 number of episodes | Standard Deviation 1.48 |
| Bifidobacterium BB-12® | Number of Crying Episodes | Visit T1 - Baseline | 7.92 number of episodes | Standard Deviation 2.79 |
| Placebo | Number of Crying Episodes | Visit T1 - Baseline | 8.28 number of episodes | Standard Deviation 3.12 |
| Placebo | Number of Crying Episodes | Visit T5 | 6.04 number of episodes | Standard Deviation 2.42 |
p-value: 0.001Wilcoxon (Mann-Whitney)
Secondary
Secretory Immunoglobulin A (SIgA)
Secretory immunoglobulin A (SIgA) levels in fecal samples
Time frame: at 7 days (Visit T1 - baseline) and 28 days from the baseline (Visit T5)
Population: The analysis Population includes all the participants for wich an evaluable fecal sample was available at Visit T1 and Visit T5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bifidobacterium BB-12® | Secretory Immunoglobulin A (SIgA) | Visit T1 - Baseline | 84.79 microg/g | Standard Deviation 21.71 |
| Bifidobacterium BB-12® | Secretory Immunoglobulin A (SIgA) | Visit T5 | 250.65 microg/g | Standard Deviation 37.95 |
| Placebo | Secretory Immunoglobulin A (SIgA) | Visit T1 - Baseline | 86.55 microg/g | Standard Deviation 12.13 |
| Placebo | Secretory Immunoglobulin A (SIgA) | Visit T5 | 192.01 microg/g | Standard Deviation 27.12 |
Secondary
Short Chain Fatty Acids - Butyrate
Evaluation of Butyrate levels in fecal samples
Time frame: at 7 days (Visit T1 - baseline) and 28 days from the baseline (Visit T5)
Population: The analysis Population includes all participants for wich an evaluable fecal sample was available at Visit T1 and Visit T5
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bifidobacterium BB-12® | Short Chain Fatty Acids - Butyrate | Visit T1 - Baseline | 0.19 mM/Kg | Standard Deviation 0.14 |
| Bifidobacterium BB-12® | Short Chain Fatty Acids - Butyrate | Visit T5 | 0.63 mM/Kg | Standard Deviation 0.49 |
| Placebo | Short Chain Fatty Acids - Butyrate | Visit T1 - Baseline | 0.17 mM/Kg | Standard Deviation 0.16 |
| Placebo | Short Chain Fatty Acids - Butyrate | Visit T5 | 0.32 mM/Kg | Standard Deviation 0.33 |