Treatment of Gastroesophageal Reflux Disease in Infants

Treatment of Gastroesophageal Reflux Disease in Infants- a Randomized Controlled Trial

Gastroesophageal reflux disease in infants is not fully understood. Infants are prescribed medical treatments that may not be effective or that contribute to adverse side effects and lead to concerns and expenses for the parents and healthcare system. Current guidelines recommend cow-milk-protein free diet as a first-line treatment, but these recommendations are based on weak evidence. This study investigate the efficacy of a cow-milk-protein free diet compared to treatment with a proton pump inhibitor (omeprazole)

Study Overview

• Status: Recruiting
• Conditions: Infant, Newborn, Diseases; Gastroesophageal Reflux
• Intervention / Treatment: Behavioral: Mother or infant diet; Drug: Placebo; Drug: Protein pump inhibitor.

Detailed Description

An increasing number of infants less than one year of age have been referred to the pediatric departments with gastroesophageal reflux in the past decade. Gastroesophageal reflux is a common condition in infants defined as the passage of gastric contents into the esophagus with regurgitation or vomiting. Around 50% of infants younger than four months regurgitate or vomit regularly. In most cases, it is a harmless, self-limiting condition; in 90% of cases, the symptoms diminish before 12 months. However, if reflux leads to troublesome symptoms or complications, it is defined as gastroesophageal reflux disease. Troublesome symptoms may include failure to thrive, back arching, food refusal, regurgitation, and irritability. The prevalence of gastroesophageal reflux disease varies between studies. Infants can be treated medically, and proton pump Inhibitors have been recommended as the first choice. However, within the last few years, there has been concern among pediatricians that too many infants are unnecessarily treated with this medication. There are only a few randomized studies on proton pump inhibitor treatment in children under one year, and most studies do not show a significant effect on symptoms. Side effects of treatment with proton pump inhibitors include symptoms related to the gastrointestinal tract or airways, increased susceptibility to infections, and increased risk of developing allergy later in life. Within the past years, there has been attention to the overlapping of symptoms between gastroesophageal reflux disease and allergy to cow milk protein. Cow-milk-protein allergy is the most common food allergy in early childhood, with an estimated prevalence of 2-3%, and presents with various symptoms predominantly from the skin and gastrointestinal tract. Consequently, cow-milk-protein allergy can be challenging to differentiate from gastroesophageal reflux disease. Cow-milk-protein-allergy is an immune reaction and can be either immunoglobulin E-mediated, presenting with immediate reaction including anaphylaxis, or non-immunoglobulin E-mediated, presenting with delayed symptoms. In addition, it is possible that cow's milk can aggravate gastroesophageal reflux disease with a non-immunologic mechanism. As there is no biomarker to differentiate non-immunoglobulin E-mediated cow-milk allergy from gastroesophageal reflux disease, the diagnosis of non-immunoglobulin E-mediated cow-milk allergy can only be verified by an oral food challenge test preceded by a cow-milk-protein-elimination period. Therefore, in the updated international guidelines, all children with gastroesophageal reflux disease should start with a 2-4-week cow-milk-protein-elimination diet before a proton pump inhibitor is prescribed. However, evidence is scarce on the effect of a cow-milk-protein-free diet in infants diagnosed with gastroesophageal reflux disease.

• Study Type: Interventional
• Enrollment (Estimated): 96
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Gitte Zachariassen, Professor; Phone Number: +4565413809; Email: Gitte.Zachariassen@rsyd.dk
• Study Contact Backup: Name: Natalia K Barkholt, MD; Phone Number: +4521787136; Email: Natalia.Barkholt@rsyd.dk

Study Locations

• Denmark
  • Region Syddanmark
    • Aabenraa, Region Syddanmark, Denmark, 6200
      • Recruiting
      • Paediatric Department, Hospital of Southern Jutland
      • Contact: Natalia K Barkholt; Phone Number: +46 21787136; Email: natalia.barkholt@rsyd.dk
      • Contact: Gitte Zachariassen; Email: gitte.zachariassen@rsyd.dk
      • Principal Investigator: Natalia K Barkholt, Dr
    • Odense, Region Syddanmark, Denmark, 5000
      • Not yet recruiting
      • Børnelægecentret v/Kasper Dalby
      • Contact: Kasper Dalby; Phone Number: +45 65 90 80 60; Email: blcfyn@gmail.com
      • Contact: Natalia Barkholt; Email: natalia.barkholt@rsyd.dk
      • Principal Investigator: Kasper Dalby
    • Odense, Region Syddanmark, Denmark, 5000
      • Not yet recruiting
      • H.C Andersen Childrens' Hospital
      • Contact: Natalia Barkholt; Email: natalia.barkholt@rsyd.dk
      • Contact: Josefine Gradman; Phone Number: +45 29241375; Email: Josefine.Gradman@rsyd.dk
      • Principal Investigator: Josefine Gradman

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Infants diagnosed with gastroesophageal reflux disease (GERD)
• Age < 1 year at the time of referral
• Age >1 month at start of treatment
• At least 3 reflux episodes/daily in average
• At least one of following troublesome symptoms are present: Crying of unknown reason, discomfort/irritability, problems gaining weight/ weightloss, rejects the breast or bottle, apnea, back-arching.

Exclusion Criteria:

• Children with diagnosed or suspected syndrome /genetic disorder
• Congenital malformations (minor deformities are excepted)
• Abdominal surgery
• Metabolic disease
• Treatment with proton pump inhibitor within the last week
• Allergy for proton pump inhibitors
• Allergy for cow milk protein
• Infants on Cow's milk free diet

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Proton pump inhibitor; Omeprazole 1 mg/ kg and continuing nutrition containing cow's milk protein	Drug: Protein pump inhibitor.; 1 mg/kg /day; Other Names: Omeprazole
Active Comparator: Mother or infant diet; Mother on cow milk-protein-free diet if breastfeeding and infant on a hypoallergenic formula if bottle-fed.	Behavioral: Mother or infant diet; Mother on cow milk protein diet or infant on hypoallergenic formula in case of bottle fed; Other Names: Cow milk protein free diet
Placebo Comparator: Placebo; Placebo medicine (appearing substantially like Omeprazole) 1mg/kg and continuing nutrition containing cow's milk protein	Drug: Placebo; Placebo medicine (appearing substantially like Omeprazole) 1mg/ ml, and continuing nutrition containing cows' milk protein

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in reflux episodes in the fourth week of active treatment, compared to placebo	Parent-reported reduction in the weekly number of reflux-episodes in the fourth week of active treatment with either PPI or diet, compared to placebo. The outcome is registered daily in an App.	Baseline and daily in 4 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunoglobulin E level	Blood positive/negative for specific immunoglobulin E for cows milk protein. Values above 0,35 kU/l are considered positive for cows' milk allergy.	4 weeks after treatment is started
Change from baseline in weight	A nurse or physician will perform the measurement on a weight in the clinic/hospital. Measurement unit: gram.	Baseline and 4 weeks
Change from baseline in the number of reflux episodes with visible blood	Parent reported weekly number of reflux episodes with visible blood. Registered in MyCap App.	1,2,3,4 weeks
Change from baseline in the numbers of episodes with crying	Parent reported weekly numbers of episodes with crying 5 minutes after feeding. Registered in MyCap App	1,2,3,4 weeks
Change from baseline in the number of episodes of refusing breast/ bottle	Parent reported weekly numbers of episodes of refusing breast/bottle. Registered in MyCap App	1,2,3,4 weeks
Change from baseline in the number of episodes with short breathing pauses	Parent-reported weekly numbers of episodes with short breathing pauses. Registered in MyCap App	1,2,3,4 weeks
Change from baseline in the number of episodes with paleness/blue color in face or lips	Parent reported weekly numbers of episodes with paleness/blue color in face. Registered in MyCap App	1,2,3,4 weeks
Change from baseline in the number of episodes with troublesome breathing/cough	Parent reported weekly numbers of episodes with troublesome breathing/cough. Registered in MyCap App	1,2,3,4 weeks
Change from baseline in reflux episodes in the fourth week in the PPI group, compared to the diet group.	Reduction in the number of regurgitation episodes (compared to the run-in period) in the PPI group compared to the diet group	Baseline and 4 weeks
Change from baseline in the number of episodes with discomfort	Parent reported weekly episodes with discomfort 5 minutes after feeding. Registered in MyCap App	1,2,3,4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events to trial medicine in the proton pump inhibitor group and the placebo group	Any parent-reported adverse events to the trial medicine (both Omeprazole and placebo) are registered weekly. There are several well-known side effects; 1-10 % experience symptoms from the gastrointestinal tract (i.e., stomach pain, nausea, and constipation), skin, airways, and increased susceptibility to infections.	1,2,3,4 weeks
Cows milk allergy?	After 4 weeks´ of cows milk protein-free diet, an oral provocation test with cow's milk is conducted on all infants in the diet group, who experienced effect of the diet. The test will be carried out in the hospital. During the test, the infants are given increasing doses of fresh cow's milk every 30 minutes until they reach a maximum of 200 ml. A nurse records any symptoms experienced during the first few hours of the test, and the parents are required to monitor and report any symptoms at home. Additionally, the parents inform the physician of any late symptoms via phone call 48 hours after the test.	4 weeks

Collaborators and Investigators

• Sponsor: Odense University Hospital
• Collaborators: Hospital of Southern Jutland
• Investigators: Study Director: Gitte Zachariassen, Professor, H.C Andersen Childrens Hospital, Odense University Hospital and Syddansk University (SDU)

Study record dates

Study Major Dates

• Study Start (Actual): October 27, 2025
• Primary Completion (Estimated): December 26, 2026
• Study Completion (Estimated): December 26, 2026

Study Registration Dates

• First Submitted: February 5, 2024
• First Submitted That Met QC Criteria: February 12, 2024
• First Posted (Actual): February 13, 2024

Study Record Updates

• Last Update Posted (Actual): November 20, 2025
• Last Update Submitted That Met QC Criteria: November 17, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: GERD; Reflux; Infants; PPI; Omeprazole; Proton pump inhibitor; GORD; GER; GOR; Cow milk protein; Bovine milk protein; CMP
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Esophageal Diseases; Esophageal Motility Disorders; Deglutition Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Gastroesophageal Reflux; Infant, Newborn, Diseases; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Omeprazole
• Other Study ID Numbers: OUH-HCA006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Raw data can not be shared, but the study protocol and the Statistical Analysis plan will be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No