Milk AllergyPhase 2NCT02719405
Impact of Infant Formula on Resolution of Cow's Milk Allergy
A Phase 2 study testing Lactobacillus GG, Extensively Hydrolyzed Casein Formula and Amino Acid Formula in people with Milk Allergy, run by Massachusetts General Hospital at 2 sites in United States.
Trial summary
Primary Endpoint -The percentage of subjects who develop tolerance to cow's milk protein by 12 months post randomization to study formula. Secondary Endpoints Tolerance The transcriptional profile of milk-specific T cells by clinical outcome. Read more about this study
- Who is it for?
- Ages Up to 120 days
- Conditions the study is for
- Milk Allergy
- What is being tested?
- Lactobacillus GG, Extensively Hydrolyzed Casein Formula and Amino Acid Formula
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 49 participants
- Where
- 2 sitesUnited States
- Study dates
- Feb 2016to Feb 2018
- Phase
- Phase 2
- Are there results?
- None posted in the registry
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 Up to 120 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Infants 0-120 days of age with suspected CMA, as determined by the pediatrician or specialist, will be referred to the study. A Standard Operating Procedures (SOP) document will be provided for the clinicians to help guide their referral to the study. Physician diagnosis of CMA will be based on the following:
- Physician documented, gross or persistent microscopic blood in stool (3 positive guaiac cards on three separate stools) in the absence of other explanation (e.g., fissure, moderate-to-severe constipation) AND / OR
- Infant with at least one gastrointestinal, dermatological, or respiratory allergic manifestation suggestive of CMA:
- Gastrointestinal: Chronic Diarrhea, Constipation or Vomiting/Gastro-esophageal reflux
- Dermatologic: Atopic Dermatitis or Urticaria
- Respiratory: Cough, Allergic rhinitis or Recurrent Wheezing
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- General:Colic / Irritability
- No change in treatment with medications during the 7 days preceding the elimination diet and no expected change in medications during the DBPCFCs (unless otherwise medically necessary)
- Signed informed consent obtained for infants participation in the study
- Signed authorization obtained to use and/or disclose Protected Health Information for infant from birth through the length of the study period
- Willingness to comply with following inclusion criteria if found to have a positive DBPCFC screen:
- Caregiver(s) agree to comply with the infant elimination diet given to them by the investigator for the duration of the study
- Mother agrees to follow an elimination diet throughout duration of breast feeding
- Parent(s) or legally authorized representative agrees not to enroll infant in another interventional clinical study while participating in this study
- Positive Double Blind Placebo Controlled Food Challenge (DBPCFC).
Who cannot join
- History of anaphylaxis to milk
- Use of probiotics
- Use in the previous 4 weeks of systemic steroids
- Use of systemic immunomodulatory treatment, including biologics with an immune target such as Xolair
- Known eosinophilic GI disorders
- Episode(s) of severe repetitive vomiting and lethargy prompting an emergency room visit and occurring within 4 hours of ingesting a milk protein (i.e. consistent with FPIES)
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- Co-existing autoimmune or other chronic disease or serious health problem, including celiac disease, inflammatory bowel disease, malignancy, congenital, metabolic or genetic disorders or malformations
- Intention to exclusively breast feed
- Infants born at less than 36 weeks gestation (35 weeks + 6 days is considered 35 weeks gestation)
- Severe reaction to Milk Protein during the DBPCFC
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114
Woburn Pediatric Associates
Woburn, Massachusetts, 01801
About this study
Official title: A Prospective Randomized Controlled Trial to Evaluate the Effect of Infant Formula on the Resolution of Cow's Milk Allergy of Infancy
Primary Endpoint
-The percentage of subjects who develop tolerance to cow's milk protein by 12 months post randomization to study formula.
Secondary Endpoints
- Tolerance
- The transcriptional profile of milk-specific T cells by clinical outcome.
- Growth and Weight Velocity
- Stool Consistency and Frequency
- The estimated frequency of milk-specific T cells by clinical outcome.
- The TCR diversity of milk-specific T cells by clinical outcome.
- The milk allergen component-specific IgE, IgG4 and IgA by clinical outcome.
- Safety
- The rate of reported adverse events by treatment group.
Read the detailed description
Cow's Milk Allergy (CMA) is prevalent and most often presents during infancy. Disease manifestations vary through a range of immediate and delayed inflammatory responses to milk protein from anaphylaxis to enterocolitis. The natural history is also highly variable; most children will achieve clinical tolerance early in life, while a minority will have disease persisting to adulthood for reasons that are not known. Most presentations are mild and are managed by restriction or reduction of immunologically intact milk protein with reintroduction sometime after a year of age; however, there are data to suggest that some level of antigenic stimulation may be beneficial. Furthermore, recent data suggest that oral probiotic exposure may also promote tolerance, though the kinetics of tolerance acquisition, the interaction between these two factors (probiotics and milk antigen exposure) and their relationship to regulatory T cell responses are all poorly defined. Therefore, there is an unmet need to identify dietary interventions, along with corresponding immune responses, that favor the promotion of tolerance.
A major objective will be to measure the effect probiotics have on the development of tolerance to milk antigen over time. By following these infants during the first year of life, and repeatedly collecting blood and stool samples from them, we will be poised to analyze their stool microbiome signatures, and we will estimate the frequency, phenotype and TCR diversity of milk-specific T cells over time. By repeatedly challenging them with more immunologically intact milk protein, we will better define the kinetics of CMA resolution and its association to these variables. This information is likely to further elucidate CMA disease mechanisms and identify possible biomarkers of disease resolution versus persistence. It will be directly useful for evaluating the efficacy of probiotics and hydrolyzed formula for promoting milk tolerance.
- Conditions
- Milk Allergy
- Being tested
- Lactobacillus GG, Extensively Hydrolyzed Casein Formula, Amino Acid Formula
- Keywords
- milk, allergy, tolerance
- Medical subject headings
- Milk Hypersensitivity, Hypersensitivity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lactobacillus GGDietary supplement
Lactobacillus GG
Extensively Hydrolyzed Casein FormulaDietary supplement
Extensively Hydrolyzed Casein Formula
Amino Acid FormulaDietary supplement
Amino Acid Formula
| Study group | Role | What they receive |
|---|---|---|
| Amino Acid Formula | Placebo comparator | Not described Receives: Dietary Supplement: Amino Acid Formula |
| EHCF | Active comparator | Extensively Hydrolyzed Casein Formula Receives: Dietary Supplement: Extensively Hydrolyzed Casein Formula |
| EHCF + LGG | Active comparator | Extensively Hydrolyzed Casein Formula + Lactobacillus GG Receives: Dietary Supplement: Lactobacillus GG; Dietary Supplement: Extensively Hydrolyzed Casein Formula |
What is being measured
The primary outcome is the main question the study is designed to answer.
The percentage of subjects who develop tolerance to cow's milk protein by 12 months post randomization to study formula.
Measured: 12 months post randomization
Secondary outcomes (11)
Safety as assessed by adverse events graded using the NCI-CTCAE scale by treatment group.
The rate of reported adverse events by treatment group.
Measured: 36 months
Tolerance as assessed by the transcriptional profile of milk-specific T cells by clinical outcome.
Measured: 36 months
Tolerance as assessed by weight for age Z-scores.
Measured: 36 months
Tolerance as assessed by length for age Z-scores.
Measured: 36 months
Tolerance as assessed by weight for length Z-scores.
Measured: 36 months
Tolerance as assessed by stool consistency using the Bristol Stool Chart.
Measured: 36 months
Tolerance as assessed by stool frequency.
Measured: 36 months
Tolerance as assessed by changes in the stool microbiome.
Measured: 36 months
Tolerance as assessed by the estimated frequency of milk-specific T cells by clinical outcome.
Measured: 36 months
Tolerance as assessed by the TCR diversity of milk-specific T cells by clinical outcome.
Measured: 36 months
Tolerance as assessed by the milk allergen component-specific IgE, IgG4 and IgA by clinical outcome.
Measured: 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Mar 2016 (estimated)
- Study startFeb 2016
- Primary completionFeb 2018
- Study completionFeb 2018
Why it stopped: Insufficient enrollment
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 Milk AllergyStudies of the same condition, open and under way.
- More trials run by Massachusetts General 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 2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 49 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Mead Johnson Nutrition
- Responsible party
- Principal investigator, Wayne G. Shreffler, MD, PhD, Massachusetts General Hospital
- Investigators
- Wayne G Shreffler, MD, PhD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02719405
- Sponsor's protocol ID
- 2015P000962
- Status last verified
- Jul 2018
- First submitted
- 30 Oct 2015
- Last updated
- 13 Jul 2018
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Amari S, Shahrook S, Namba F, Ota E, Mori R. Branched-chain amino acid supplementation for improving growth and development in term and preterm neonates. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD012273. doi: 10.1002/14651858.CD012273.pub2.
PubMed 33006765
Study at a glance
From the registry record, last updated by the sponsor on 13 Jul 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Prospective Randomized Controlled Trial to Evaluate the Effect of Infant Formula on the Resolution of Cow's Milk Allergy of Infancy
- ClinicalTrials.gov ID
- NCT02719405
- Acronym / sponsor ID
- 2015P000962
- Conditions
- Milk Allergy
- Keywords
- milk, allergy, tolerance
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Insufficient enrollment
- Enrolment
- 49 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Collaborators
- Mead Johnson Nutrition
- Study start
- Feb 2016 (actual)
- Primary completion
- Feb 2018 (actual)
- Study completion
- Feb 2018 (actual)
- First posted
- 25 Mar 2016 (estimated)
- 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.
Primary Endpoint
-The percentage of subjects who develop tolerance to cow's milk protein by 12 months post randomization to study formula.
Secondary Endpoints
- Tolerance
- The transcriptional profile of milk-specific T cells by clinical outcome.
- Growth and Weight Velocity
- Stool Consistency and Frequency
- The estimated frequency of milk-specific T cells by clinical outcome.
- The TCR diversity of milk-specific T cells by clinical outcome.
- The milk allergen component-specific IgE, IgG4 and IgA by clinical outcome.
- Safety
- The rate of reported adverse events by treatment group.
Detailed description
Cow's Milk Allergy (CMA) is prevalent and most often presents during infancy. Disease manifestations vary through a range of immediate and delayed inflammatory responses to milk protein from anaphylaxis to enterocolitis. The natural history is also highly variable; most children will achieve clinical tolerance early in life, while a minority will have disease persisting to adulthood for reasons that are not known. Most presentations are mild and are managed by restriction or reduction of immunologically intact milk protein with reintroduction sometime after a year of age; however, there are data to suggest that some level of antigenic stimulation may be beneficial. Furthermore, recent data suggest that oral probiotic exposure may also promote tolerance, though the kinetics of tolerance acquisition, the interaction between these two factors (probiotics and milk antigen exposure) and their relationship to regulatory T cell responses are all poorly defined. Therefore, there is an unmet need to identify dietary interventions, along with corresponding immune responses, that favor the promotion of tolerance.
A major objective will be to measure the effect probiotics have on the development of tolerance to milk antigen over time. By following these infants during the first year of life, and repeatedly collecting blood and stool samples from them, we will be poised to analyze their stool microbiome signatures, and we will estimate the frequency, phenotype and TCR diversity of milk-specific T cells over time. By repeatedly challenging them with more immunologically intact milk protein, we will better define the kinetics of CMA resolution and its association to these variables. This information is likely to further elucidate CMA disease mechanisms and identify possible biomarkers of disease resolution versus persistence. It will be directly useful for evaluating the efficacy of probiotics and hydrolyzed formula for promoting milk tolerance.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Amino Acid Formula | Placebo comparator | Dietary Supplement: Amino Acid Formula |
| EHCF | Active comparator | Dietary Supplement: Extensively Hydrolyzed Casein FormulaExtensively Hydrolyzed Casein Formula |
| EHCF + LGG | Active comparator | Dietary Supplement: Lactobacillus GG, Dietary Supplement: Extensively Hydrolyzed Casein FormulaExtensively Hydrolyzed Casein Formula + Lactobacillus GG |
Who may qualify
- Ages
- Up to 120 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (15 listed)
- Infants 0-120 days of age with suspected CMA, as determined by the pediatrician or specialist, will be referred to the study. A Standard Operating Procedures (SOP) document will be provided for the clinicians to help guide their referral to the study. Physician diagnosis of CMA will be based on the following:
- Physician documented, gross or persistent microscopic blood in stool (3 positive guaiac cards on three separate stools) in the absence of other explanation (e.g., fissure, moderate-to-severe constipation) AND / OR
- Infant with at least one gastrointestinal, dermatological, or respiratory allergic manifestation suggestive of CMA:
- Gastrointestinal: Chronic Diarrhea, Constipation or Vomiting/Gastro-esophageal reflux
- Dermatologic: Atopic Dermatitis or Urticaria
Key exclusion criteria (10 listed)
- History of anaphylaxis to milk
- Use of probiotics
- Use in the previous 4 weeks of systemic steroids
- Use of systemic immunomodulatory treatment, including biologics with an immune target such as Xolair
- Known eosinophilic GI disorders
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 |
|---|---|---|
| Lactobacillus GGLactobacillus GG | Dietary supplement | EHCF + LGG |
| Extensively Hydrolyzed Casein FormulaExtensively Hydrolyzed Casein Formula | Dietary supplement | EHCF, EHCF + LGG |
| Amino Acid FormulaAmino Acid Formula | Dietary supplement | Amino Acid Formula |
Primary outcome
The percentage of subjects who develop tolerance to cow's milk protein by 12 months post randomization to study formula.
Time frame: 12 months post randomization
11 secondary outcomes
Safety as assessed by adverse events graded using the NCI-CTCAE scale by treatment group.
Time frame: 36 months
Tolerance as assessed by the transcriptional profile of milk-specific T cells by clinical outcome.
Time frame: 36 months
Tolerance as assessed by weight for age Z-scores.
Time frame: 36 months
Tolerance as assessed by length for age Z-scores.
Time frame: 36 months
Tolerance as assessed by weight for length Z-scores.
Time frame: 36 months
Tolerance as assessed by stool consistency using the Bristol Stool Chart.
Time frame: 36 months
Tolerance as assessed by stool frequency.
Time frame: 36 months
Tolerance as assessed by changes in the stool microbiome.
Time frame: 36 months
Tolerance as assessed by the estimated frequency of milk-specific T cells by clinical outcome.
Time frame: 36 months
Tolerance as assessed by the TCR diversity of milk-specific T cells by clinical outcome.
Time frame: 36 months
Tolerance as assessed by the milk allergen component-specific IgE, IgG4 and IgA by clinical outcome.
Time frame: 36 months
Results and safety
The study was stopped early (reason given: Insufficient enrollment). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jul 2018.
- Derived from this study: PubMed 33006765Amari S, Shahrook S, Namba F, Ota E, Mori R. Branched-chain amino acid supplementation for improving growth and development in term and preterm neonates. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD012273. doi: 10.1002/14651858.CD012273.pub2.
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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. This study is not recruiting at the moment.
Wayne G Shreffler, MD, PhD principal investigator
Massachusetts General Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Lactobacillus GG, Extensively Hydrolyzed Casein Formula and Amino Acid Formula in people with Milk Allergy, run by Massachusetts General Hospital at 2 sites in United States.
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 15 inclusion and 10 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: stopped early, as of the sponsor's last update on 13 Jul 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Insufficient enrollment). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The percentage of subjects who develop tolerance to cow's milk protein by 12 months post randomization to study formula. (time frame: 12 months post randomization). 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 NCT02719405, 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 13 Jul 2018.