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

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

Conditions
-----------------
Functional Constipation

Intervention / Treatment
-----------------
* Dietary Supplement: new infant formula
* Dietary Supplement: Standard formula


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 12 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Superiority, double-blind, randomized, placebo-controlled trial of 60 days followed by an optional 60 day, open-label follow-up period with the tested formula only
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IT formula<br>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<br>* 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.<br>|
| Placebo Comparator: Standard formula<br>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<br>* 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<br>* 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Constipation, Infants, Infant formula, Nutrition, Defecation, Prebiotic, Probiotics