Safety and Efficacy of Rabeprazole in Infants With Gastroesophageal Erosive Reflux Disease (GERD)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the effectiveness and safety of rabeprazole sodium, an inhibitor of gastric acid secretion of the protein pump inhibitor (PPI) class, compared with placebo in the treatment of gastrointestinal esophageal reflux disease (GERD) in infants 1 to 11 months of age.

Detailed Description
-----------------
Rabeprazole sodium belongs to the class of drugs known as proton pump inhibitors, which suppress gastric acid secretion. The drug is approved in the United States for the treatment of adults with GERD and other acid-related gastrointestinal disorders, and has been studied in adolescents (older than 12 years of age) with results similar to those in adults. However, the drug has not been studied in children under the age of 12 years. This study focuses on the efficacy and safety of rabeprazole sodium in infants aged 1 to 11 months, the pediatric group in which the prevalence of GERD-related symptoms is the greatest. This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group withdrawal study to compare the efficacy and safety of 2 doses (0.5 mg/kg or 1.0 mg/kg daily) of rabeprazole with placebo in the treatment of infants aged 1 to 11 months who have a diagnosis of suspected GERD, symptomatic GERD, or endoscopically or histologically proven GERD. The study consists of 3 study periods: a screening period of up to 10 days, an open-label treatment period of up to 3 weeks, and a 5-week double-blind treatment period. Patients who have been receiving GERD therapy before screening will have their GERD therapy discontinued for 3 days before entering the open-label treatment period. Patients who have a positive clinical response according to the Clinical Global Impressions - Improvement (CGI-I) scale at the end of the first or second week of the open-label treatment period will enter the double-blind treatment period; those who do not will be withdrawn from the study. A parent, legal guardian, or other individual experienced in the care of the infant will be the primary caregiver, who is responsible for the daily and weekly assessments and study drug administration. Efficacy assessments consist of the Infant Gastroesophageal Reflux Questionnaire Revised (I GERQ-R) total score, the Infant Gastroesophageal Reflux Questionnaire-Daily Diary (I GERQ-DD) total score, the CGI-I, the Global Treatment Satisfaction Score, and the weight-for-age Z-score. Safety assessments include monitoring of concomitant therapies and adverse events throughout the study; clinical laboratory testing (hematology, clinical chemistry, urinalysis), measurement of vital signs (pulse and respiratory rate, blood pressure, temperature); and physical examination including length and weight. The study hypothesis is that rabeprazole sodium is superior to placebo in the treatment of GERD in infants aged 1 to 11 months. Rabeprazole sodium capsule(s) by mouth once a day, 10.0 milligram (mg)/kilogram (kg) for up to 3 weeks during the open-label treatment period and either 5.0 mg/kg or 10.0 mg/kg during the 5-week double-blind treatment period. To give the study drug to the infants, the contents of the capsule(s) are sprinkled onto a small amount of soft food or, as needed, the contents of the capsule(s) may be given in a small amount (5 milliliter [mL]) of infant formula or expressed breast milk.

Official Title
-----------------
A Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Parallel Group, Withdrawal Study to Evaluate the Safety and Efficacy of Delayed Release Rabeprazole in 1- to 11-Month-Old Pediatric Subjects With Symptomatic/Gastroesophageal Erosive Reflux Disease (GERD)

Conditions
-----------------
Gastroesophageal Reflux

Intervention / Treatment
-----------------
* Drug: Rabeprazole sodium 5 mg
* Drug: Rabeprazole sodium 10 mg
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of suspected GERD, symptomatic GERD, or endoscopically or histologically proven GERD, based on frequent vomiting or regurgitation, with at least 1 of the following: a) poor weight gain, or b) irritability, excessive crying or disturbed sleep that both the parent(s) and the doctor consider abnormal (but not due to colic) or c) refusal to eat even if hungry or arching of the back during meals weight 2.5 kg to 15.0 kg I-GERQ-R score >16 Have only 1 caregiver in addition to the parent(s) Exclusion Criteria: History of confirmed acute life-threatening events due to GERD Known narrowing of the opening from the stomach to the small intestines Confirmed diagnosis of cow's milk allergy Have taken PPIs or H2-blockers (a class of drugs that inhibit stomach acid production) or any of several drugs that affect the normal movement of the digestive tract (caffeine, theophylline, antacids, erythromycin, and others) within 3 days before entering the study Have blood or urine test results that are well above or below the normal range for the infant

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 11 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rabeprazole sodium 5 mg<br> | Drug: Rabeprazole sodium 5 mg<br>* Rabeprazole Sodium 5 mg capsules once daily in the morning.<br>|
| Experimental: Rabeprazole sodium 10 mg<br> | Drug: Rabeprazole sodium 10 mg<br>* Rabeprazole Sodium 10 mg capsules once daily in the morning.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Matching placebo capsules once daily in the morning.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Average Daily Frequency of Regurgitation (Double-blind Phase/ Baseline Observation Carried Forward) |  | Baseline, Week 8 | 
| Change From Baseline in Weight-for-Age Z-Score (Double-blind Phase/ Baseline Observation Carried Forward) | Body weight was measured with the participant unclothed and before a feeding during each office visit. In the analysis of weight data, weight will be transformed to the weight-for-age Z-score using World Health Organization Child Growth Standards, taking into account the infant's age and gender (Borghi E, 2006). | Baseline, Week 8 | 
| Change From Baseline in I-GERQ-R Total Score (Double-blind Phase/ Baseline Observation Carried Forward) | The Infant Gastroesophageal Reflux Questionnaire-Revised (I-GERQ-R) is a 12-item questionnaire that is completed by the primary caregiver at every office or telephonic visit. It has a weekly recall and the items cover the frequency, amount and discomfort attributed to spit-up, refusal or stopping feeding, crying and fussing, hiccups, arching back and stopping breathing or changing color. The total score is calculated as the sum of all 12 scores for the individual questions, and ranges from 0 to 42. A higher value indicates a worse outcome. | Baseline, Week 8 | 
| Change From Baseline in in Weekly Average I-GERQ-DD Total Score (Double-blind Phase/ Baseline Observation Carried Forward) | The Infant Gastroesophageal Reflux Questionnaire-Daily Diary (I-GERQ-DD) is a 9-item daily diary that the primary caregiver will be instructed to complete every evening at the same time interval after the participant has gone to sleep for the night. The I-GERQ-DD contains 3 subscales: the Regurgitation subscale, the Eating Behavior subscale and the Discomfort subscale. Each of the 9 items will be assigned a numeric score. The total score will be calculated as the sum of all 9 items, and ranges from 0 to 37. A higher value indicates a worse outcome. | Baseline, Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Daily Average Number of Episodes Related to Each Volume of Regurgitation During the Double-blind Treatment Period |  | Baseline, Week 8 | 
| Change From Baseline in Weekly Average I-GERQ-DD Regurgitation Subscale Score (Double-blind Phase/ Last Observation Carried Forward) | The Infant Gastroesophageal Reflux Questionnaire-Daily Diary (I-GERQ-DD) is a 9-item daily diary that the primary caregiver will be instructed to complete every evening at the same time interval after the participant has gone to sleep for the night. The I-GERQ-DD contains 3 subscales: the Regurgitation subscale, the Eating Behavior subscale and the Discomfort subscale. The Regurgitation subscale will be calculated as the sum of the 3 questions regarding regurgitation (Questions 1, 2, 3) and will range from 0 to 13. For each subscale score, a higher value indicates a worse outcome. | Baseline, Week 8 | 
| Change From Baseline in Weekly Average I-GERQ-DD Discomfort Subscale Score (Double-blind Phase/ Last Observation Carried Forward) | The Infant Gastroesophageal Reflux Questionnaire-Daily Diary (I-GERQ-DD) is a 9-item daily diary that the primary caregiver will be instructed to complete every evening at the same time interval after the subject has gone to sleep for the night. The I-GERQ-DD contains 3 subscales: the Regurgitation subscale, the Eating Behavior subscale and the Discomfort subscale. The Discomfort subscale score will be calculated as the sum of the 3 questions regarding discomfort (Questions, 7, 8, 9) and will range from 0 to 12. For each subscale score, a higher value indicates a worse outcome. | Baseline, Week 8 | 
| Change From Baseline in Weekly Average I-GERQ-DD Eating Behavior Subscale Score (Double-blind Phase/ Last Observation Carried Forward) | The Infant Gastroesophageal Reflux Questionnaire-Daily Diary (I-GERQ-DD) is a 9-item daily diary that the primary caregiver will be instructed to complete every evening at the same time interval after the subject has gone to sleep for the night. The I-GERQ-DD contains 3 subscales: the Regurgitation subscale, the Eating Behavior subscale and the Discomfort subscale. The Eating Behavior subscale score will be calculated as the sum of the 3 questions regarding eating behavior (Questions 4, 5, 6) and will range from 0 to 12. For each subscale score, a higher value indicates a worse outcome. | Baseline, Week 8 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Gastroesophageal Reflux, Gastroesophageal Reflux Disease, GERD, Proton Pump Inhibitor, PPI, Regurgitation, Infants, AcipHex, PARIET, ALFENCE