Gastroesophageal RefluxPhase 4NCT06255886
Treatment of Gastroesophageal Reflux Disease in Infants
A Phase 4 study testing Protein pump inhibitor. and Mother or infant diet in people with Gastroesophageal Reflux and Infant, Newborn, Diseases, run by Odense University Hospital at 3 sites in Denmark.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 1 month to 1 year
- Conditions the study is for
- Gastroesophageal Reflux, Infant, Newborn, Diseases
- What is being tested?
- Protein pump inhibitor. and Mother or infant diet
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 96 participants
- Where
- 3 sitesDenmark
- Study dates
- 27 Oct 2025to 26 Dec 2026
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month to 1 year
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Denmark3 sites, 3 recruiting
- Recruiting
Paediatric Department, Hospital of Southern Jutland
Aabenraa, Region Syddanmark, 6200
Natalia K Barkholt, +46 21787136, natalia.barkholt@rsyd.dk
Gitte Zachariassen, gitte.zachariassen@rsyd.dk
- Not yet recruiting
Børnelægecentret v/Kasper Dalby
Odense, Region Syddanmark, 5000
Kasper Dalby, +45 65 90 80 60, blcfyn@gmail.com
Natalia Barkholt, natalia.barkholt@rsyd.dk
- Not yet recruiting
H.C Andersen Childrens' Hospital
Odense, Region Syddanmark, 5000
Josefine Gradman, +45 29241375, Josefine.Gradman@rsyd.dk
Natalia Barkholt, natalia.barkholt@rsyd.dk
About this study
Official title: 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)
Read the 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.
- Conditions
- Gastroesophageal Reflux, Infant, Newborn, Diseases
- Being tested
- Protein pump inhibitor., Mother or infant diet, Placebo
- Keywords
- Reflux, Infants, GERD, GER, GORD, GOR, Cow milk protein, Bovine milk protein, CMP, Proton pump inhibitor, PPI, Omeprazole
- Medical subject headings
- Gastroesophageal Reflux, Infant, Newborn, Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Protein pump inhibitor.Drug
Also called Omeprazole
1 mg/kg /day
Mother or infant dietBehavioural
Also called Cow milk protein free diet
Mother on cow milk protein diet or infant on hypoallergenic formula in case of bottle fed
PlaceboDrug
Placebo medicine (appearing substantially like Omeprazole) 1mg/ ml, and continuing nutrition containing cows' milk protein
| Study group | Role | What they receive |
|---|---|---|
| Proton pump inhibitor | Active comparator | Omeprazole 1 mg/ kg and continuing nutrition containing cow's milk protein Receives: Drug: Protein pump inhibitor. |
| Mother or infant diet | Active comparator | Mother on cow milk-protein-free diet if breastfeeding and infant on a hypoallergenic formula if bottle-fed. Receives: Behavioral: Mother or infant diet |
| Placebo | Placebo comparator | Placebo medicine (appearing substantially like Omeprazole) 1mg/kg and continuing nutrition containing cow's milk protein Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline and daily in 4 weeks.
Secondary outcomes (10)
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
Measured: Baseline and 4 weeks
Change from baseline in weight
A nurse or physician will perform the measurement on a weight in the clinic/hospital. Measurement unit: gram.
Measured: 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.
Measured: 1,2,3,4 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 1,2,3,4 weeks
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.
Measured: 4 weeks after treatment is started
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Feb 2024
- Study start27 Oct 2025
- Primary completion26 Dec 2026 (estimated)
- Study completion26 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Gastroesophageal RefluxStudies of the same condition, open and under way.
- More trials run by Odense University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 96 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Odense University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Gitte Zachariassen, Professor, Study director, H.C Andersen Childrens Hospital, Odense University Hospital and Syddansk University (SDU)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06255886
- Sponsor's protocol ID
- OUH-HCA006
- Status last verified
- Aug 2025
- First submitted
- 5 Feb 2024
- Last updated
- 20 Nov 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Raw data can not be shared, but the study protocol and the Statistical Analysis plan will be shared.
Publications
Barkholt NK, Dalby K, Mogensen CB, Zachariassen G, Gradman J. Infant Reflux Trial: study protocol for a multicentre randomized controlled trial on the treatment of gastroesophageal reflux disease in infants. Trials. 2026 Jan 29;27(1):169. doi: 10.1186/s13063-026-09477-x.
PubMed 41612404
Study at a glance
From the registry record, last updated by the sponsor on 20 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of Gastroesophageal Reflux Disease in Infants- a Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT06255886
- Acronym / sponsor ID
- OUH-HCA006
- Conditions
- Gastroesophageal Reflux, Infant, Newborn, Diseases
- Keywords
- Reflux, Infants, GERD, GER, GORD, GOR, Cow milk protein, Bovine milk protein
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 96 participants (estimated)
- Lead sponsor
- Odense University HospitalUniversity, hospital or other
- Study start
- 27 Oct 2025 (actual)
- Primary completion
- 26 Dec 2026 (estimated)
- Study completion
- 26 Dec 2026 (estimated)
- First posted
- 13 Feb 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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)
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Proton pump inhibitor | Active comparator | Drug: Protein pump inhibitor.Omeprazole 1 mg/ kg and continuing nutrition containing cow's milk protein |
| Mother or infant diet | Active comparator | Behavioral: Mother or infant dietMother on cow milk-protein-free diet if breastfeeding and infant on a hypoallergenic formula if bottle-fed. |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo medicine (appearing substantially like Omeprazole) 1mg/kg and continuing nutrition containing cow's milk protein |
Who may qualify
- Ages
- 1 month to 1 year
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Protein pump inhibitor.Also: Omeprazole1 mg/kg /day | Drug | Proton pump inhibitor |
| Mother or infant dietAlso: Cow milk protein free dietMother on cow milk protein diet or infant on hypoallergenic formula in case of bottle fed | Behavioural | Mother or infant diet |
| PlaceboPlacebo medicine (appearing substantially like Omeprazole) 1mg/ ml, and continuing nutrition containing cows' milk protein | Drug | Placebo |
Primary outcome
Change from baseline in reflux episodes in the fourth week of active treatment, compared to placebo
Time frame: Baseline and daily in 4 weeks.
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.
10 secondary outcomes
Change from baseline in reflux episodes in the fourth week in the PPI group, compared to the diet group.
Time frame: Baseline and 4 weeks
Change from baseline in weight
Time frame: Baseline and 4 weeks
Change from baseline in the number of reflux episodes with visible blood
Time frame: 1,2,3,4 weeks
Change from baseline in the number of episodes with discomfort
Time frame: 1,2,3,4 weeks
Change from baseline in the numbers of episodes with crying
Time frame: 1,2,3,4 weeks
Change from baseline in the number of episodes of refusing breast/ bottle
Time frame: 1,2,3,4 weeks
Change from baseline in the number of episodes with short breathing pauses
Time frame: 1,2,3,4 weeks
Change from baseline in the number of episodes with paleness/blue color in face or lips
Time frame: 1,2,3,4 weeks
Change from baseline in the number of episodes with troublesome breathing/cough
Time frame: 1,2,3,4 weeks
Immunoglobulin E level
Time frame: 4 weeks after treatment is started
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Nov 2025.
- Derived from this study: PubMed 41612404Barkholt NK, Dalby K, Mogensen CB, Zachariassen G, Gradman J. Infant Reflux Trial: study protocol for a multicentre randomized controlled trial on the treatment of gastroesophageal reflux disease in infants. Trials. 2026 Jan 29;27(1):169. doi: 10.1186/s13063-026-09477-x.
- Individual participant dataSharing planned: No. Raw data can not be shared, but the study protocol and the Statistical Analysis plan will be shared.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Gitte Zachariassen, Professor study director
H.C Andersen Childrens Hospital, Odense University Hospital and Syddansk University (SDU)
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Protein pump inhibitor. and Mother or infant diet in people with Gastroesophageal Reflux and Infant, Newborn, Diseases, run by Odense University Hospital at 3 sites in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 20 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Natalia K Barkholt, MD (+4521787136, Natalia.Barkholt@rsyd.dk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change from baseline in reflux episodes in the fourth week of active treatment, compared to placebo (time frame: Baseline and daily in 4 weeks.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06255886, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Nov 2025.