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Randomized Trial of Milk Oral Immunotherapy: Fixed Low-Dose vs Escalation to Medium-Dose.

  • 2026-04
  • The journal of allergy and clinical immunology. In practice 14(4)
    • Ken-Ichi Nagakura
    • Kyohei Takahashi
    • Yoko Miura
    • Kaito Goto
    • Akira Kawai
    • Naoko Fusayasu
    • Kiyotake Ogura
    • Sakura Sato
    • Motohiro Ebisawa
    • Noriyuki Yanagida

Study Design

Type
Randomized Controlled Trial (RCT)
Sample size
n = 32
Population
children who had a positive oral food challenge (OFC) to 3 mL of milk before initiating OIT, had continued low-dose OIT targeting 3 mL for a minimum of 1 year, and subsequently failed OFC with 25 mL (32 children each group)
Methods
randomized into fixed-dose group (3-mL target) or dose-escalation group (25-mL target); short-term unresponsiveness to 25 mL assessed via OFC at 1 and 2 years after 2-week avoidance
Blinding
Open-label
Duration
2 years
Funding
Unclear

Background

The optimal oral immunotherapy (OIT) protocol following low-dose desensitization remains unclear.

Objective

To compare the efficacy and safety of fixed low-dose versus escalation to medium dose for severe cow's milk allergy.

Methods

This study included children who had a positive oral food challenge (OFC) to 3 mL of milk before initiating OIT, had continued low-dose OIT targeting 3 mL for a minimum of 1 year, and subsequently failed OFC with 25 mL. They were randomized (32 children each) into "fixed-dose group; 3-mL target (99-mg protein)" or "dose-escalation group; 25-mL target (825-mg protein)." Short-term unresponsiveness to 25 mL was assessed using the OFC at 1 and 2 years after the 2-week avoidance.

Results

The fixed-dose group versus the dose-escalation group had the following characteristics, respectively: median age (9.2 vs 9.1 years), history of anaphylaxis (94% vs 100%), milk-specific IgE level (19.9 vs 27.0 kUA/L), and period from OIT initiation (2.0 vs 1.8 years). The rates of achieving 25 mL short-term unresponsiveness were 31% and 28% at 1 year and 47% and 44% at 2 years, respectively (P > .99). The total symptom frequency per OIT dose was 0.9% versus 3.8% in the first year, and 0.8% versus 2.0% in the second year (P < .001), and anaphylaxis was 0.01% versus 0.06% in the first year. Milk-, casein-, α-lactalbumin-, and β-lactoglobulin-specific IgE levels decreased from baseline at 2 years in both groups (P < .001).

Conclusions

The fixed low-dose OIT protocol following low-dose desensitization provides comparable efficacy and improved safety compared with dose escalation.

Research Insights

  • Milk→Improved Milk Tolerance

    The rates of achieving 25 mL short-term unresponsiveness were 31% and 28% at 1 year and 47% and 44% at 2 years, respectively (P > .99).

    Effect
    Neutral
    Effect size
    Small
    Dose
    3-mL target (99-mg protein) or 25-mL target (825-mg protein)
  • Milk→Reduced Casein-Specific IgE Level

    Milk-, casein-, α-lactalbumin-, and β-lactoglobulin-specific IgE levels decreased from baseline at 2 years in both groups (P < .001).

    Effect
    Beneficial
    Effect size
    Small
    Dose
    3-mL target (99-mg protein) or 25-mL target (825-mg protein)
  • Milk→Reduced Milk-Specific Immunoglobulin E Level

    Milk-, casein-, α-lactalbumin-, and β-lactoglobulin-specific IgE levels decreased from baseline at 2 years in both groups (P < .001).

    Effect
    Beneficial
    Effect size
    Small
    Dose
    3-mL target (99-mg protein) or 25-mL target (825-mg protein)
  • Milk→Reduced α-Lactalbumin-Specific IgE Level

    Milk-, casein-, α-lactalbumin-, and β-lactoglobulin-specific IgE levels decreased from baseline at 2 years in both groups (P < .001).

    Effect
    Beneficial
    Effect size
    Small
    Dose
    3-mL target (99-mg protein) or 25-mL target (825-mg protein)
  • Milk→Reduced β-Lactoglobulin-Specific IgE Level

    Milk-, casein-, α-lactalbumin-, and β-lactoglobulin-specific IgE levels decreased from baseline at 2 years in both groups (P < .001).

    Effect
    Beneficial
    Effect size
    Small
    Dose
    3-mL target (99-mg protein) or 25-mL target (825-mg protein)

Adverse Events Reported

  • Milk→anaphylaxis

    and anaphylaxis was 0.01% versus 0.06% in the first year

    Finding
    Increased risk
    Severity
    Serious adverse event
    Magnitude
    0.01% versus 0.06% in the first year
    Significant
    Yes
  • Milk→symptom

    The total symptom frequency per OIT dose was 0.9% versus 3.8% in the first year, and 0.8% versus 2.0% in the second year (P < .001)

    Finding
    Increased risk
    Magnitude
    total symptom frequency per OIT dose was 0.9% versus 3.8% in the first year, and 0.8% versus 2.0% in the second year (P < .001)
    Significant
    Yes
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