Preliminary Efficacy, Safety and Pharmacokinetics Study of Nepadutant in Infant With Feeding Intolerance

Study Overview
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Brief Summary
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The present pilot study is aimed to obtain preliminary data on the effect of three ascending oral dose levels of nepadutant on the relief of symptoms associated with feeding intolerance. In addition, the assessment of drug exposure (PK assessment) will provide additional information on the dose-effect relationship, thus supporting the dose selection and dosing schedule in the future studies.

Detailed Description
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Feeding intolerance is a transient neuro-developmental phenomenon affecting 25% to 40% of infant and toddler, with a peak at 6 weeks of age. Feeding problems include mainly vomiting, slow feeding, refusal to eat and colic. Current non pharmacological interventions (e.g. message, restriction in maternal diet in breast-feeding infants) and pharmacological treatments (simethicone, antimuscarinic drugs and antiacids) are largely unsatisfactory. Nepadutant is postulated to have a therapeutic effect in infant colic since it reverts exaggerated intestinal motility and sensitivity induced by different stimuli through the activation of neurokinin-2 receptors, without interferring on the on physiological gastrointestinal transit. This phase IIa study is designed to test in each participant infant two out of three oral doses of nepadutant in order to measure its blood levels, safety and efficacy with each dose level to be given for 7 concecutive days. The experimental clinical phase encompasses the following periods: Screening period (no study medication), lasting approximately 7 days prior to randomization Treatment period, lasting fourteen days (7 days fore each dose)with once daily administration A safety follow-up visit, approximately four weeks after start of treatment.

Official Title
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A Multicenter, Open Label, Ascending 7 Day-Repeated Dose Study to Investigate Efficacy, Safety and Pharmacokinetics of Nepadutant In Infants With Feeding Intolerance

Conditions
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Colic

Intervention / Treatment
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* Drug: Nepadutant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants with a clinical diagnosis of feeding intolerance. Age ≤ 6 months at the enrolment. Normal growth. Infants who can refrain from use of erythromycin, metoclopramide, antihistaminic drug, proton pump inhibitors (PPIs), antacids, antimuscarinic drugs, simethicone and dimethicone from 1 week prior randomization until end of study. Exclusion Criteria: Any clinically relevant event (excluding those relevant to the condition under study) which has occurred within one week prior to randomization. Any pharmacological treatment starting within one week prior to randomization. Infants for whom a change in the diet (i.e. weaning) has been performed within one week prior to randomization or is planned during the study period.

Ages Eligible for Study
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Maximum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 3<br>Nepadutant low dose (0.1mg/kg) for 7 days followed by Nepadutant high dose (1mg/kg) for additional 7 days | Drug: Nepadutant<br>* Nepadutant oral solution<br>* Other names: MEN 11420;|
| Experimental: Cohort 2<br>Nepadutant medium dose (0.5mg/kg) for 7 days followed by Nepadutant high dose (1mg/kg) for additional 7 days | Drug: Nepadutant<br>* Nepadutant oral solution<br>* Other names: MEN 11420;|
| Experimental: Cohort 1<br>Nepadutant low dose (0.1mg/kg) for 7 days followed by Nepadutant medium dose (0.5mg/kg) for additional 7 days | Drug: Nepadutant<br>* Nepadutant oral solution<br>* Other names: MEN 11420;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Absolute Differences of I-GERQ-R Total Score at V3 (End of First Week of Treatment) Respect to the Baseline (V2). | Results obtained at V2 serve as baseline values for the assessment of effects at V3 (i.e. end of first week of treatment). Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R ), with a minimum-maximum score of 0-42 (minimum for diagnosis >15). The higher values reflect worse outcome. The questionnaire comprised 12 items as questions quantifying aspects of regurgitation (3 questions), crying (3 questions), feeding refusal (2 questions), apnea/cyanosis (2 questions), hiccups and arching. Questions with 4 possible options have a score ranging from 0 to 3; questions with 5 possible options have a score ranging from 0 to 4. The scores of each item are summed, so the total score is presented. | Baseline (V2) and end of first week of treatment (V3) | 
| The Absolute Differences of I-GERQ-R Total Score at V4 (End of 2nd Week of Treatment) Respect to V3 (End of 1st Week of Treatment). | The results obtained at V3 are used as baseline for the second week treatment period (V4). Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R ), with a minimum-maximum score of 0-42 (minimum for diagnosis >15). The higher values reflect worse outcome. The questionnaire comprised 12 items as questions quantifying aspects of regurgitation (3 questions), crying (3 questions), feeding refusal (2 questions), apnea/cyanosis (2 questions), hiccups and arching. Questions with 4 possible options have a score ranging from 0 to 3; questions with 5 possible options have a score ranging from 0 to 4. The scores of each item are summed, so the total score is presented. | V3 (end of 1st week of treatment) and V4 (end of 2nd week of treatment) | 
| The Absolute Differences of I-GERQ-R Total Score at V5 (Follow-up) Respect to V2 (Baseline). | Results obtained at V2 serve as baseline values for follow-up assessment 2 weeks after the last administered dose (V5) Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R ), with a minimum-maximum score of 0-42 (minimum for diagnosis >15). The higher values reflect worse outcome. The questionnaire comprised 12 items as questions quantifying aspects of regurgitation (3 questions), crying (3 questions), feeding refusal (2 questions), apnea/cyanosis (2 questions), hiccups and arching. Questions with 4 possible options have a score ranging from 0 to 3; questions with 5 possible options have a score ranging from 0 to 4. The scores of each item are summed, so the total score is presented. | Baseline (V2) and follow up 2 weeks after the last administered dose (V5) | 
| I-GERQ-R Score Changes vs Baseline (Visit 2) by First Dose Level (0.1mg/kg and 0.5mg/kg). | Change in Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R) Score. Assessing the I-GERQ-R score changes vs baseline (Visit 2) by first dose level (0.1mg/kg and 0.5mg/kg). Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R ), with a minimum-maximum score of 0-42 (minimum for diagnosis >15). The higher values reflect worse outcome. The questionnaire comprised 12 items as questions quantifying aspects of regurgitation (3 questions), crying (3 questions), feeding refusal (2 questions), apnea/cyanosis (2 questions), hiccups and arching. Questions with 4 possible options have a score ranging from 0 to 3; questions with 5 possible options have a score ranging from 0 to 4. The scores of each item are summed, so the total score is presented. | Baseline (V2) and end of 1st week of treatment(V3) | 
| I-GERQ-R Score Changes vs Visit 3 by Second Dose Level (0.5mg/kg and 1mg/kg). | Change in Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R) Score. Assessing the I-GERQ-R score changes vs Visit 3 by second dose level (0.5mg/kg and 1mg/kg). Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R ), with a minimum-maximum score of 0-42 (minimum for diagnosis >15). The higher values reflect worse outcome. The questionnaire comprised 12 items as questions quantifying aspects of regurgitation (3 questions), crying (3 questions), feeding refusal (2 questions), apnea/cyanosis (2 questions), hiccups and arching. Questions with 4 possible options have a score ranging from 0 to 3; questions with 5 possible options have a score ranging from 0 to 4. The scores of each item are summed, so the total score is presented. | end of first week of treatment (V3) and end of second week of treatment (V4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of AEs_ Number of Adverse Events by Treatment Dose Level | The analysis is by treatment - Each infant was treated with two out of three ascending dose (0.1, 0.5 or 1.0 mg/kg), therefore counted in more than one dose level. | up to 4 weeks | 
| A Population Pharmacokinetic Analysis to Characterize the Plasma Concentration-time Course for Nepadutant in Infant With Colics From NIC-04 | The population pharmacokinetic analyses is presented. PopPK Clearance estimated with a one compartment model with first order absorption and elimination. | 0.5, 1, 2, 3 hours post Single Dose and 24 hours post Repeated Dose | 
| A Population Pharmacokinetic Analysis to Characterize the Plasma Concentration-time Course for Nepadutant in Infant With Colics From NIC-04 | PopPK Volume estimated with a one compartment model with first order absorption and elimination. NOTE: for this measure, no inter-individual variability was estimated, therefore the value for each cohort corresponds to the typical value. | 0.5, 1, 2, 3 hours post Single Dose and 24 hours post Repeated Dose | 
| A Population Pharmacokinetic Analysis to Characterize the Plasma Concentration-time Course for Nepadutant in Infant With Colics From NIC-04 | The population pharmacokinetic analyses is presented. PopPK Ka estimated with a one compartment model with first order absorption and elimination. NOTE: for this measure, no inter-individual variability was estimated, therefore the value for each cohort corresponds to the typical value. | 0.5, 1, 2, 3 hours post Single Dose and 24 hours post Repeated Dose | 
| A Population Pharmacokinetic Analysis to Characterize the Plasma Concentration-time Course for Nepadutant in Infant With Colics From NIC-04 | The population pharmacokinetic analyses is presented. The PopPK parameter fraction of the dose absorbed (F1) is estimated with a one compartment model with first order absorption and elimination.The results are presented fraction of the absorbed dose with 95% CI of the parameter estimate value | 0.5, 1, 2, 3 hours post Single Dose and 24 hours post Repeated Dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Feeding intolerance, Infant, tachykinin antagonist, Infant colic, Nepadutant