Clinical trial NCT04487834
Conditions: Infantile Colic
Sponsor: The President Stanisław Wojciechowski State University of Applied Sciences in Kalisz
Start date: 2020-04-16; Completion date: 2020-06-30
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Open trial with two parallel arms, assessing the effects of Simethicone and Vivatlac Baby in babies diagnosed for infantile colic.

Detailed description:
Babies aged 3 to 6 weeks will be diagnosed for infantile colic using the Wessel's criteria. Study design will be open label with two parallel arms (Simethicone and Vivatlac Baby). Vivatlac Baby is a synbiotic product containing probiotic bacteria (six lactobacilli and 3 bifidobacteria). Effects of treatments on crying behavior will be assessed by using parental 24h paper diaries.

Arms: arm 1: Treatment with simethicone (Espumisan®, 100 mg/ml, Berlin-Chemie / Menarini Polska Sp z o.o., Warsaw, Poland) for four weeks. Simethicone was administered 3-6 times per day with each treatment comprising 6 drops of the 100 mg/ml emulsion. arm 2: Treatment with one stick pack of the multi-strain synbiotic (Vivatlac® Baby, Vivatrex GmbH, Rees, Germany) per day for four weeks. Each stick pack of Vivatlac® Baby contains a total of 10\^9 colony forming units (CFU) with equal CFU amounts of the following probiotic bacteria: L. acidophilus LA-14, L. casei R0215; L. paracasei Lpc-3; L. plantarum Lp-115; L. rhamnosus GG, L. salivarius Ls-33, B. lactis Bl-04, B. bifidum R0071, B. longum R0175 and 1.43 g of the prebiotic fructooligosaccharides.
Interventions: intervention 1: Simethicone Solution intervention 2: Vivatlac Baby
Intervention descriptions: intervention 1: Oral daily treatment for four weeks intervention 2: Oral daily treatment for four weeks

Protocol documents:
Prot_002.pdf: 
Effects of Simethicone and Multilac Baby in Infantile Colic
24-hours Parents Day Report
Name:
Date:
Night
Morning
Afternoon
Evenning
24
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Sleeping
Restlessness / 
whining
- Duration (min)
Crying
- Duration (min)
Breastfeeding
Formula feeding
Administration of 
treatment
Comments
…………………………………………………….
…………………………………………………….
………………..
………………………………….
Date of birth:
Page-No.:
2020 03 02 24 Hour Parental Diary Form PL & EN
Document date: March 02, 2020 

SAP_003.pdf: 
Effects of Simethicone and Multilac Baby in Infantile Colic 
Statistical Analysis Plan 
Document Date: March 02, 2020 
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Cover page 
 
 


Effects of Simethicone and Multilac Baby in Infantile Colic 
Statistical Analysis Plan 
Document Date: March 02, 2020 
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The statistical analyses will be  conducted with GraphPad Prism software version 8.2 
(GraphPad Software, Dan Diego, California, USA) or MedCalc Statistical Software 
version 19.2.1 (MedCalc Software Ltd., Ostend, Belgium). The Student t-test will be 
used to compare mean values of continuous variables approximating a normal 
distribution. For non-normally distributed variables, the Mann-Whitney U test will be 
used. The X2 test or Fisher exact test will be used, as appropriate, to compare 
percentages. The MedCalc Statistical Software version 19.2.1 will be used to 
calculate the relative risk (RR) and number needed to treat (NNT), all with a 95% 
confidence interval (CI). The difference between the treatment groups will be 
considered significant when the p-value will be less than 0.05, when the 95% CI for 
RR will not include 1.0, or when the 95% CI for mean difference will not include 1.0, 
or when the 95% CI for mean difference will not include 0. One-way ANOVA followed 
by Dunnett’s multiple comparisons test as well as Cochran-Armitage Chi-squared test 
for trend will be performed using GraphPad Prism software. All statistical tests will be 
two-tailed and will be performed at the 5% level of significance. All analyses will be 
conducted on an intention-to-treat basis, including all patients in the groups to which 
they will be allocated. 

Prot_001.pdf: 
Effects of Simethicone and Multilac Baby in Infantile Colic
Doctor Information
Doctor
Date
Patient Data
General Patient Data
Patient Initials
Gender:
male
female
Date of birth:
Delivery type:
Normal
Ceasarian section
Birth in pregnancy week:
Weight at time of birth:
Breast feeding:
yes
no
Formula feeding:
yes
no
Antibiotics therapies:
yes
no
Details of antibiotics therapy:
Pro-/Synbiotics
yes
no
Details of Pro-/Syn-Therapy
Primary Diagnostics (before treatment start) 
Days of crying during last 3 weeks?
Average duration of crying?
Number of crying phases per day?
Can the child be calmed during crying?
yes
no
Bloated belly?
yes
no
Retracted legs?
yes
no
Red face?
yes
no
Problems to fall asleep?
yes
no
Short (<30 min) sleeping periodes during the day?
yes
no
Short  (<16h) total sleeping time per day?
yes
no
Number of sleeping periodes per day?
Comments
2020 03 02 Patient Assessment Sheet Day 0 PL & EN
Docuemnt date: March 02, 2020

Prot_000.pdf: 
Effects of Simethicone and Multilac Baby in Infantile Colic  
Study Protocol 
Document Date: March 02, 2020 
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Cover page 
 
 


Effects of Simethicone and Multilac Baby in Infantile Colic  
Study Protocol 
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1. General Information 
Infantile colic or extensive crying is a major burden for newborns, their parents and 
healthcare providers [1]. In most of the cases infantile colic will disappear after the 
first three to five months of life [2]. Nevertheless, due to its stressful nature for 
parents, infant colic is among the leading causes to consult a health care 
professional during early infancy [3]. The parental burden associated with infantile 
colic finally results in enormous pressure on pediatricians to prescribe at least some 
kind of remedy. Diagnosis of infantile colic can be based on the Wessel’s criteria, 
defined by crying and restlessness for more than three hours a day for more than 
three days per week for more than three weeks [4]. Depending on diagnostic details, 
occurrence rates between 3 to 40% of all infants have been found [5,6]. 
2. Background Information 
The etiology of infant colic remains unclear [7], with a variety of potential causes 
(gastrointestinal, hormonal, neurodevelopmental, and psychosocial) discussed. This 
has resulted in a broad range of therapeutic approaches aiming to address the 
problem [3,8]. 
Simethicone [9], a mixture of dimethicone and SiO2, is a rather old product that, it is 
claimed, acts as a topical barrier for protecting the gut mucosa against irritants. It is 
not absorbed and is virtually non-toxic. While its use in diagnostic procedures is well-
established, the therapeutic effects in a number of gastroenterological indications are 
contradictory [10]. In infantile colic, a number of smaller simethicone trials [11-13] 
have been published, but evidence did not reach the threshold of significance. 
Despite the absence of evidence for beneficial effects, simethicone is widely used for 
the treatment of infantile colic in some countries. 
There is growing evidence that the gut microbiotas of colicky infants significantly 
differ from those of non-colicky babies [14-16]. In the gut microbiota of colicky babies 
a lower level of commensal bacteria like lactobacilli and bifidobacteria and higher 
numbers of proteobacteria have been found. Among these proteobacteria were 
Escherichia and Klebsiella bacteria [17], which are well known for their gas-producing 
properties, as well as the potential production of inflammatory lipopolysaccharides 
(LPS). In addition, it has been described that the gut microbiota of colicky infants 
exhibits a slower bacterial colonization, a reduced microbiota diversity and a lower 
microbiota stability [18]. These findings have triggered a number of studies 
investigating the effect of supplementation of the gut microbiota of colicky babies with 
products containing probiotic bacteria without a prebiotic component (probiotics), or 
with (synbiotics). 
Although infantile colic is in most cases a self-limiting condition, pediatricians are 
writing a prescription for most of the affected infants. Unpublished results from 


Effects of Simethicone and Multilac Baby in Infantile Colic  
Study Protocol 
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surveys, performed by our research team among German and Polish pediatricians, 
revealed that in these two countries simethicone and pro-/synbiotics were the most 
frequently prescribed products for infantile colic. In our study we want to evaluate the 
effects of simethicone and of a food supplement multi-strain synbiotic (Multilac® 
Baby), which is frequently used by German and Polish pediatricians. The multi-strain 
synbiotic preparation contains six lactobacilli (L. acidophilus, L. casei, L. paracasei, L. 
plantarum, L. rhamnosus GG, L. salivarius), three bifidobacteria (B. lactis, B. bifidum, 
B. longum) and the prebiotic fructooligosaccharides (FOS). In a study, recently 
published by us [19], it was found that this multi-strain synbiotic antagonizes the in-
vitro growth of the pathogenic bacteria Escherichia coli EPEC, Shigella sonnei, 
Salmonella typhimurium, Klebsiella pneumoniae and Clostridioides difficile.  
During the preparation phase of this study, we learned that pediatricians willing to 
participate were not ready to treat colicky babies with a placebo, as this would not be 
acceptable for the majority of parents of the colicky babies. In addition, placebo 
preparations are neither available for us for simethicone nor for the multi-strain 
synbiotic. Consequently, our study has to be performed as an open trial, comparing 
the two products. Effects of simethicone in infantile colic have been shown not to 
differ significantly from treatment with a placebo [11-13], therefore the simethicone 
treatment group in our study has to be considered as the control group against which 
the effect of the multi-strain synbiotic has to be evaluated. 
3. Objectives/Purpose 
The objective of the study is to compare the effects of simethicone and a multi-strain 
synbiotic (Multilac Baby) on the crying behavior of colicky babies. 
4. Study Design 
Open label comparing treatment with simethicone (Arm 1) versus treatment with 
Multilac Baby (Arm 2). Treatment duration of four weeks. Assessment of crying 
behavior with parental daily diary during the last three weeks before enrollment and 
during last three weeks before the end of treatment. 
5. Selection and Exclusion of Subjects 
Inclusion criteria 
The study is aiming to recruit babies aged 3 to 6 weeks of aged diagnosed for 
infantile colic based on Wessels criteria. Wessel’s criteria for infantile colic diagnosis 
(Rule of Three) [4]: extensive evening crying for at least three hours per day, during 
at least three days per week, during the last three weeks. 
 


Effects of Simethicone and Multilac Baby in Infantile Colic  
Study Protocol 
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Exclusion criteria 
- 
Organic causes for crying 
- 
Previous treatment with antibiotics 
- 
Previous treatment with probiotic 
- 
Previous treatment with synbiotic 
6. Treatment of Subjects 
Simethicone (Arm 1) 
Treatment for four weeks with simethicone (Espumisan®, 100 mg/ml, Berlin-Chemie / 
Menarini Polska Sp z o.o., Warsaw, Poland). Simethicone administered 3-6 times per 
day with each treatment comprising 6 drops of the 100 mg/ml emulsion. It is planned 
to include 30 patients to this arm. 
Multilac Baby (Arm 2) 
Treated for four weeks with one stick pack of a multi-strain synbiotic (Multilac® Baby, 
Vivatrex GmbH, Aachen, Germany) per day. Each stick pack of Multilac® Baby 
contains a total of 109 colony forming units (CFU) with equal CFU amounts of the 
following probiotic bacteria: L. acidophilus LA-14, L. casei R0215; L. paracasei Lpc-3; 
L. plantarum Lp-115; L. rhamnosus GG, L. salivarius Ls-33, B. lactis Bl-04, B. bifidum 
R0071, B. longum R0175 and 1.43 g of the prebiotic fructooligosaccharides. It is 
planned to include 50 patients to this arm. 
7. Assessment of Efficacy 
Crying behavior will be assessed by using a parental diary (24-hour Parental Daily 
Report). 
8. Assessment of Safety 
Safety will be assessed by using a parental diary (24-hour Parental Daily Report). 
9. Adverse Events 
Adverse Events will be reported by the standard procedure established to report 
adverse events of pharmaceutical products by physicians. 
10. 
Discontinuation of the Study 
The study will be discontinued in case of: 
- 
occurrence of adverse events, 
- 
failure to recruit patients. 


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11. 
Statistics 
The statistical analyses will be  conducted with GraphPad Prism software version 8.2 
(GraphPad Software, Dan Diego, California, USA) or MedCalc Statistical Software 
version 19.2.1 (MedCalc Software Ltd., Ostend, Belgium). The Student t-test will be 
used to compare mean values of continuous variables approximating a normal 
distribution. For non-normally distributed variables, the Mann-Whitney U test will be 
used. The X2 test or Fisher exact test will be used, as appropriate, to compare 
percentages. The MedCalc Statistical Software version 19.2.1 will be used to 
calculate the relative risk (RR) and number needed to treat (NNT) [20], all with a 95% 
confidence interval (CI). The difference between the treatment groups will be 
considered significant when the p-value will be less than 0.05, when the 95% CI for 
RR will not include 1.0, or when the 95% CI for mean difference will not include 1.0, 
or when the 95% CI for mean difference will not include 0. One-way ANOVA followed 
by Dunnett’s multiple comparisons test as well as Cochran-Armitage Chi-squared test 
for trend will be performed using GraphPad Prism software. All statistical tests will be 
two-tailed and will be performed at the 5% level of significance. All analyses will be 
conducted on an intention-to-treat basis, including all patients in the groups to which 
they will be allocated. 
12. 
Quality Control and Assurance 
According to local GCP SOPs. 
13. 
Ethics 
Study will have to be approved by the Ethics Committee of The President Stanisław 
Wojciechowski State University of Applied Sciences in Kalisz. 
Informed consent of parents of colicky babies will be collected from parents in writing 
before enrolling of the babies into the study. 
14. 
Data handling and Recordkeeping 
Data will be handled by study investigators monitored and supervised by the principle 
investigator of the study (Prof. Dr. Hanna Kraus). Records will be kept at the office of 
the principle investigator applying all local regulations of data protection provisions. 
15. 
Publication Policy 
It is planned to publish the study results in a peer-reviewed scientific/medical journal. 
16. 
Project Timetable/Flowchart 
Start of study immediately after approval by the ethics committee. 


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17. 
References 
[1]  Landgren K, Hallström I. ”Parents′ experience of living with a baby with infantile 
colic – a phenomenological hermeneutic study.” Scandinavian Journal of Caring 
Sciences Vol. 25, 2011, pp 317–24. 
[2]  Sung V. ”Infantile colic.” Australian Prescriber Vol. 41, No. 4, 2018, pp. 105–10. 
[3]  Lucassen P. ”Colic in infants.” British Medical Journal clinical evidence Vol. 
2010, 2010, 0309. 
[4]  Wessel MA, Jackson EB, et al. ”Paroxysmal fussing in infancy, sometimes 
called colic.” Pediatrics Vol. 14, No. 5, 1954, pp. 421-35. 
[5]  Lucassen P, Assendelft W, et al. ”Systematic review of the occurrence of 
infantile colic in the community.” Archives of Disease in Childhood Vol. 84, No. 
5, 2001, pp. 398–403. 
[6]  Helseth S, Begnum S. ”A comprehensive definition of infant colic: parents' and 
nurses' perspectives.” Journal of Clinical Nursing Vol. 11, No. 5, pp. 672-80. 


Effects of Simethicone and Multilac Baby in Infantile Colic  
Study Protocol 
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[7]  Sarasu JM, Narang M, et al. ”Infantile Colic: An Update.” Indian Pediatrics, Vol. 
55, No. 11, 2018, pp. 979-87. 
[8]  Mai T, Fatheree NY, et al. ”Infantile Colic: New Insights into an Old Problem.” 
Gastroenterology Clinics of North America Vol. 47, No. 4, 2018, pp. 829-44. 
[9]  ”Simethicone”. Available online: https://www.drugs.com/mtm/simethicone.html 
(accessed on 28/06/2020). 
[10]  Meier R, Steuerwald M. ”Review of the therapeutic use of simethicone in 
gastroenterology.” Schweizer Zeitschrift für GanzheitsMedizin Vol. 19, No. 7/8, 
2007, pp. 380-87. 
[11]  Metcalf TJ; Irons TG; et al. ”Simethicone in the treatment of infant colic: A 
randomized multicenter trial.” Pediatrics Vol. 94, No. 1, 1994, pp. 29-34. 
[12]  Sethi KS, Sethi JK. ”Simethicone in the management of infant colic.” The 
Practitioner Vol. 232, No. 1448, 1988, p. 508. 
[13]  Danielsson B, Hwang CP. ”Treatment of infantile colic with surface active 
substance (simethicone). ” Acta Paediatrica Scandinavica Vol. 74, No. 3, 1985, 
pp. 446-50. 
[14]  Savino F, Cresi F, et al. ”Intestinal microflora in breastfed colicky and non-
colicky infants.” Acta Paediatrica Vol. 93, No. 6, 2004, pp. 825-29. 
[15]  Savino F, Bailo E, et al. ”Bacterial counts of intestinal Lactobacillus species in 
infants with colic.” Pediatric allergy and immunology Vol. 16, No. 1, 2005, pp. 
72-5. 
[16]  Savino F, Cordisco L, et al. ”Molecular identification of coliform bacteria from 
colicky breastfed infants.” Acta Paediatrica, Vol. 98, No. 10, 2009, pp. 1582-88. 
[17]  Savino F, Cordisco L, et al. ”Antagonistic effect of Lactobacillus strains against 
gas-producing coliforms isolated from colicky infants”. BMC Microbiology Vol. 
11, 2011, p. 157. 
[18]  De Weerth C, Fuentes S, et al. ”Crying in infants. On the possible role of 
intestinal microbiota in the development of colic.” Gut Microbes Vol. 4, No. 5, 
2013, pp. 416-21. 


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[19]  Piatek J, Krauss H, et al. “In-Vitro Growth Inhibition of Bacterial Pathogens by 
Probiotics and a Synbiotic: Product Composition Matters.“ International Journal 
of Environmental Research and Public Health Vol. 17 No. 9, 2020, 3332. 
[20]  Altman DG. ”Confidence intervals for the number needed to treat.” British 
Medical Journal Vol 317, No. 7168, 1998, pp. 1309–12. 
18. 
Supplements/Appendices 
Patient Assessment Sheet Day 0 PL 
24 Hours Parental Diary Form PL