Dietary Restriction Efficiency Assessment in CMPA

Cow's milk protein allergy (CMPA) is one of the most common food allergies in infants, with a prevalence of approximately 2.5-3.0% globally and 0.83-3.5% in China. Accurate diagnosis is often challenging due to the non-specific and variable symptoms, which may involve gastrointestinal, dermatologic, or respiratory systems. The current diagnostic gold standard involves an elimination diet followed by an oral food challenge (OFC). However, the choice of formula during the elimination phase may affect both symptom relief and diagnostic accuracy.

This multicenter, randomized, open-label controlled trial (DREAM-CHINA) is designed to evaluate the clinical efficacy of two hypoallergenic formulas-amino acid formula (AAF) and extensively hydrolyzed formula (eHF)-in the diagnostic elimination diet phase for infants suspected of having CMPA. The study also aims to compare the two formulas in terms of symptom improvement rate, economic burden, treatment compliance, and formula acceptance.

A total of 320 infants aged 0-6 months with suspected CMPA will be enrolled and randomized (1:1) to receive either AAF or eHF for at least 2 weeks. Infants whose symptoms significantly improve will undergo an OFC to confirm the diagnosis. Those in the eHF group who do not show improvement may switch to AAF for an additional 2 weeks before undergoing OFC.

Record the speed of symptom improvement after eliminating the diet, and evaluate the diagnosis rate of CMPA through OFC, the time of symptom improvement, safety results, and the effectiveness of symptom-based screening tools for CMPA in Chinese infants.

Throughout the study, data will be collected via electronic diaries (eCOA), clinical assessments, and standardized symptom scoring tools (e.g., CoMiSS). Regular follow-ups will monitor anthropometric growth, symptom progression, and adverse events. This study seeks to provide high-quality evidence for optimizing clinical decision-making and improving the diagnostic process for CMPA in Chinese infants.

• Amino Acid Formula (AAF) (Dietary supplement): A formula composed of 100% free amino acids with no intact cow's milk protein. Participants will be fed AAF ad libitum according to their nutritional needs. Daily intake and symptoms will be recorded through an electronic diary (eCOA).
• Extensively Hydrolyzed Formula (eHF) (Dietary supplement): A formula in which cow's milk proteins are broken down into small peptides through enzymatic hydrolysis, reducing allergenicity. Participants will be fed eHF ad libitum based on their nutritional needs. Intake and symptoms will be tracked through an electronic diary (eCOA).

Primary outcomes

• Symptom Improvement Rate After Elimination Diet Approach (EDA) [2 weeks after enrolled]: The proportion of patients in each group who achieve significant symptom improvement at 2 weeks after starting the diagnostic EDA with different hypoallergenic formulas (amino acid formula \[AAF\] vs. extensively hydrolyzed formula \[eHF\]). Improvement Criteria (must meet at least one of the following for ≥3 consecutive days): * A ≥50% reduction in the Diarrhea and Blood Stool Score (baseline gastrointestinal-dominant symptoms). * A ≥50% reduction in the Cow's Milk-related Symptom Score (CoMiSS) total score. ③ Marked improvement or resolution of original gastrointestinal and/or skin symptoms (e.g., spit-up, vomiting, diarrhea, abdominal distension, abdominal pain, reflux, eczema) as assessed by the attending physician.

Secondary outcomes

• Time to Achieve Significant Symptom Improvement [From enrollment up to 6 weeks (censored at last assessment).]: The number of days from the start of the intervention (EDA) until the child first meets the predefined criteria for significant symptom improvement (as defined in the primary outcome). For children who do not achieve improvement within the study period, data will be censored at the last assessment.

Other outcomes

• Cow's Milk Protein Allergy (CMPA) Diagnosis Rate (Oral Food Challenge [OFC] Positivity Rate) [Assessed at OFC completion (typically 2-6 weeks after enrollment).]: The proportion of children with positive EDA response who subsequently have a positive OFC, confirming CMPA diagnosis. Children who are directly diagnosed due to high-risk allergic reactions (without OFC) are also included in the numerator as positive cases.
• Sensitivity and Validity of the CMPA Symptom Scoring System [Baseline and at each follow-up visit (up to 6 weeks).]: Diagnostic performance (sensitivity, specificity) of the newly developed CMPA symptom scoring system (including CoMiSS, Diarrhea and Blood Stool Score, and Fask Score) compared against the OFC gold standard. The scoring system is used to differentiate CMPA-positive from CMPA-negative cases.

Sex: All, ages: 0 Months to 6 Months

Inclusion Criteria:

* Infants aged 0-6 months;
* Diagnosed with suspected CMPA at the time of presentation;
* Artificially or mixed-feeding;
* Parents willing to sign a written informed consent and comply with the study - protocol.

Exclusion Criteria:

* Infants currently receiving eHF or AAF formula;
* Mixed-feeding infants whose current daily formula intake is less than 50% of their total milk intake or less than 200 ml;
* Infants who have already started adding complementary foods;
* Infants who have experienced severe food allergy symptoms such as shock, severe vomiting, etc. after taking cow's milk protein;
* Infants with clinical manifestations of systemic allergic reaction or respiratory difficulties such as acute laryngeal edema or bronchial obstruction;
* Infants who have used prednisolone or anti-allergic drugs in the past 2 weeks;
* Infants with contraindications to eHF or AAF formula;
* Infants whose parents are unable to fully report the occurrence of possible symptoms (e.g., insufficient language skills);
* Infants with other serious diseases, including but not limited to growth retardation, metabolic disorders, kidney disease, congenital heart disease, medical conditions requiring hospitalization for more than 2 weeks, etc.;
* Infants whose mothers are unable to avoid necessary foods when mixed-feeding.

• Chundi Xu, Principal investigator, Ruijin Hospital