Evaluation of the Efficacy of a New Specific Infant Formula in Case of Functional Constipation

Evaluation of the Efficacy of a New Specific Infant Formula With a Prebiotic and Probiotics in Case of Functional Constipation

This study aims to assess the clinical efficacy, safety and tolerance of a new formula containing a prebiotic and a mix of probiotics in the specific population of infants suffering from functional constipation through a superiority, double-blind, randomized, placebo-controlled trial.

Study Overview

• Status: Recruiting
• Conditions: Functional Constipation
• Intervention / Treatment: Dietary supplement: new infant formula; Dietary supplement: Standard formula

Detailed Description

The study comprises a selection period of 1 week where the eligibility of the infant to participate in the study will be evaluated. Once his/her participation is confirmed, the tested formula will be compared to a standard formula during a 2-month study period followed by an optional follow-up period of 2 months where only the tested formula will be used.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anne-Sophie Garreau; Phone Number: 0033-155372222; Email: as.garreau@novalac.com
• Study Contact Backup: Name: Caroline Thevret, Dr.; Phone Number: 0033-155372222; Email: c.thevret@novalac.com

Study Locations

• Italy
  • Napoli, Italy, 80131
    • Recruiting
    • University of Naples "Federico II"
    • Contact: Annamaria Staiano, Prof.; Phone Number: 0039 0817462679; Email: staiano@unina.it
    • Principal Investigator: Annamaria Staiano, Prof.
  • Napoli, Italy, 80138
    • Not yet recruiting
    • University of Campania Luigi Vanvitelli
    • Contact: Caterina Strisciuglio, Prof.; Email: caterinastrisciuglio@hotmail.it
    • Principal Investigator: Caterina Strisciuglio, Prof.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 1 year (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Selection Criteria:

Infants presenting with constipation according to modified Rome IV criteria, i.e. they must present with 1 month the following:

• Infants without spontaneous stools or with at least one painful or hard spontaneous bowel movement per week AND

• At least one of the following:

  • Two and fewer spontaneous defecations per week
  • History of excessive stool retention
  • History of large-diameter stools

Non-selection Criteria (non-exhaustive list):

• Preterm birth (<34 weeks of gestational age)
• Exclusively or partially breastfed infants within 3 days prior to visit V-1
• Infants with organic causes of constipation (e.g. coeliac disease, paediatric intestinal pseudo-obstruction, hypothyroidism, spina bifida, anorectal malformation or Hirschsprung's disease) or constipation secondary to endocrine, metabolic, neurologic or autoimmune disorders, surgery or drugs.
• Infants on laxative treatment
• Infants taking drugs that are known to affect gastrointestinal motility as well as any probiotic supplements
• Infants treated with antibiotics
• Infants with a known allergy to one of the formula ingredients (e.g. cow's milk proteins…)
• Infants with anaemia who have been prescribed an oral iron supplement as treatment
• Infants participating in another trial
• Infants presenting with any other situation which, according to the investigator, may interfere with the study participation, or lead to a particular risk for the infant

Inclusion Criteria:

• Infants having completed the selection period and still compliant with non-selection criteria
• Infants being constipated according to modified Rome IV criteria based on information recorded in parents' diary during the week preceding visit V0 (inclusion visit)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: IT formula; The test product (IT formula) is an infant formula based on cow's milk proteins containing a high level of lactose, a prebiotic, a high concentration of magnesium and a mix of probiotics.	Dietary supplement: new infant formula; New formula containing a prebiotic and a mix of probiotics, randomly assigned to infants during a 2-month period and allocated to all infants during the optional open-label follow-up period of 2 months.
PLACEBO_COMPARATOR: Standard formula; The control product is a standard infant formula based on cow's milk proteins containing usual lactose and magnesium content, no prebiotic nor probiotic.	Dietary supplement: Standard formula; Standard infant formula containing no prebiotic nor probiotic, randomly assigned to infants during a 2-month period followed by an optional open-label follow-up period of 2 months with the new infant formula; Other Names: Novalac 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hard stool consistency or painful defecation	Proportion of hard or painful stools per total number of spontaneous bowel movements by participant. A spontaneous bowel movement is defined as described in outcome 2. Stool consistency will be evaluated based on the Brussels Infant and Toddler Stool Scale (BITSS). BITSS is a reliable instrument to assess stools of non-toilet trained children. It consists of color photographs of nappies containing stools from infants and toddlers categorized as hard, formed, loose, or watery (Huysentruyt et al., 2019). The consistency and painful defecation of each stool will be assessed by parents at Day 30.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total and spontaneous defecation frequency	Spontaneous bowel movement is defined as a bowel movement not produced by the use of rescue medication. Stools occurring within 24h after the use of rescue medication will not be considered spontaneous. If 2 stools occur within less than 1 hour, only 1 stool will be considered (Koppen et al., 2018). Defecation frequency will be assessed by parents by recording the time of each stool during the week preceding each visit.	30, 60, 90 and 120 days
Stool consistency	Parents will record the consistency of every stool the week preceding each visit as described in the outcome 1 using the BITSS scale (Brussels Infant and Toddler Stool Scale) which consists of 4 stools consistency categories (hard, formed, loose, or watery ; Huysentruyt et al., 2019)	30, 60, 90 and 120 days
Painful defecation	Painful defecation will be evaluated by parents for each stool during the week preceding each visit (Yes/No).	30, 60, 90 and 120 days
Excessive stool retention	"Excessive stool retention" is defined as "the infant withholding stools". It will be evaluated by parents at each visit (presence/absence).	30, 60, 90 and 120 days
Large diameter stools	Large diameter stools will be assessed by parents at each visit using the picture of the largest stool in the BITSS as an example of the large diameter stool (presence/absence).	30, 60, 90 and 120 days
Treatment success	Treatment success is defined as no longer meeting the modified Rome IV criteria for functional constipation, i.e. the treatment will be considered as a success if the infant does not meet more than one of the following criteria per week during the week preceding each visit: At least one painful or hard spontaneous bowel movement (Yes/No); Two or fewer spontaneous defecations per week (Yes/No); Excessive stool retention (Yes/No); Large-diameter stools (assessed using the BITSS as described in the outcome 6) (Yes/No)	30, 60, 90 and 120 days
Rescue medication use	The frequency of use, type and dosage of rescue medication will be assessed by parents during the whole study.	30, 60, 90 and 120 days
Weight	Weight will be expressed in kg and in z scores according to the World Health Organization (WHO) Child Growth Standards.	30, 60, 90 and 120 days
Height	Height will be expressed in cm and in z scores according to the WHO Child Growth Standards.	30, 60, 90 and 120 days
Head circumference	Head circumference will be expressed in cm and in z scores according to the WHO Child Growth Standards.	30, 60, 90 and 120 days
BMI	BMI will be expressed in value and z scores according to the WHO Child Growth Standards.	30, 60, 90 and 120 days
Adverse events	Any untoward medical condition occurring during the study in an infant receiving study products regardless of a causal relationship with the product or not will be considered an adverse event and reported as such. This definition includes events occurring from the moment the parents have signed the Informed Consent form (day -7) up until the study end (or early termination).	Through study completion, i.e. 67 days or 127 days if participation to the optional follow-up period
Nutritional status	Nutritional status will be assessed based on the evaluation of specific blood biological markers (albumin, creatinine, urea, hemoglobin, sodium, potassium, chloride).	0 and 60 days
Crying time	Daily crying duration will be assessed by parents on 3 days in the week preceding each visit.	30, 60, 90 and 120 days
Regurgitations	The number of regurgitation episodes, the volume of regurgitation and regurgitation severity will be assessed by parents on 3 days in the week preceding each visit. Regurgitation severity will be assessed through the Vandenplas score ranging from 0 (=less than 2 regurgitation episodes / day) to 6 (=regurgitation of the complete volume after each feeding).	30, 60, 90 and 120 days
Sleep quality	Sleep quality will be evaluated by parents at each visit by asking them if their child's sleep was quiet or agitated.	30, 60, 90 and 120 days
Sleep time satisfaction	Sleep time satisfaction will be evaluated by parents at each visit (Yes/No).	30, 60, 90 and 120 days
Parents' quality of life (QoL)	Parents' QoL will be assessed based on a questionnaire adapted from the Parental Opinions of Pediatric Constipation (POOPC) scale (Silverman et al., 2015). Questions from this scale were chosen based on their relevance to constipated infants. This questionnaire is composed of 4 items, i.e. Burden/Worry, Family, Treatment and Social. Each question is scored on a scale of 1 (=Strongly Disagree) to 5 (=Strongly Agree) with higher scores indicating that infant's constipation greatly affects parents' QoL. The total score is calculated by summing the scores of all individual question, ranging from 15 to 75 where a score of 15 indicates that infant's constipation does not affect parents' QoL whereas a score of 75 indicates that parents' QoL is extremely affected by infant's constipation.	30, 60, 90 and 120 days
Parents' satisfaction	Parents' adequate relief will be assessed at each visit (Yes/No).	30, 60, 90 and 120 days
Gut microbiota composition	Gut microbiota composition will be analyzed by 16S rRNA gene sequencing from stool samples.	0 and 60 days
Short-chain fatty acids (SCFAs)	SCFAs will be measured in stool samples by gas chromatography/mass spectrometry (GC/MS).	0 and 60 days

Collaborators and Investigators

• Sponsor: United Pharmaceuticals
• Collaborators: Delta Consultants
• Investigators: Study Director: Annamaria Staiano, Prof., Federico II University; Study Chair: Marc Benninga, Prof., Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Principal Investigator: Caterina Strisciuglio, Prof., University of Campania "Luigi Vanvitelli"

Publications and helpful links

General Publications

• Huysentruyt K, Koppen I, Benninga M, Cattaert T, Cheng J, De Geyter C, Faure C, Gottrand F, Hegar B, Hojsak I, Miqdady M, Osatakul S, Ribes-Koninckx C, Salvatore S, Saps M, Shamir R, Staiano A, Szajewska H, Vieira M, Vandenplas Y; BITSS working group. The Brussels Infant and Toddler Stool Scale: A Study on Interobserver Reliability. J Pediatr Gastroenterol Nutr. 2019 Feb;68(2):207-213. doi: 10.1097/MPG.0000000000002153.
• Koppen IJN, Saps M, Lavigne JV, Nurko S, Taminiau JAJM, Di Lorenzo C, Benninga MA. Recommendations for pharmacological clinical trials in children with functional constipation: The Rome foundation pediatric subcommittee on clinical trials. Neurogastroenterol Motil. 2018 Apr;30(4):e13294. doi: 10.1111/nmo.13294. Epub 2018 Jan 30.
• Silverman AH, Berlin KS, Di Lorenzo C, Nurko S, Kamody RC, Ponnambalam A, Mugie S, Gorges C, Sanghavi R, Sood MR. Measuring Health-Related Quality of Life With the Parental Opinions of Pediatric Constipation Questionnaire. J Pediatr Psychol. 2015 Sep;40(8):814-24. doi: 10.1093/jpepsy/jsv028. Epub 2015 Apr 2.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 20, 2022
• Primary Completion (ANTICIPATED): December 1, 2023
• Study Completion (ANTICIPATED): September 1, 2024

Study Registration Dates

• First Submitted: April 8, 2022
• First Submitted That Met QC Criteria: April 15, 2022
• First Posted (ACTUAL): April 22, 2022

Study Record Updates

• Last Update Posted (ACTUAL): November 7, 2022
• Last Update Submitted That Met QC Criteria: November 4, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Constipation; Infant formula; Probiotics; Prebiotic; Nutrition; Infants; Defecation
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Constipation
• Other Study ID Numbers: UP2021-02-FALCON

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No