Cow's Milk Allergy
Conditions
Keywords
food allergy, oral immunotherapy
Brief summary
The purpose of this study is to determine whether baked milk oral immunotherapy is safe in the treatment of cow's milk allergy.
Detailed description
This study is designed to assess the safety of baked milk oral immunotherapy among patients who are milk allergic and who do not pass a baked milk challenge.
Interventions
DRUGBaked non-fat cow's milk powder
Oral immunotherapy with increasing quantities of baked milk.
DRUGPlacebo: Tapioca Powder
Placebo control.
Sponsors
Myra Reinhardt Foundation
La Jolla Institute for Allergy & Immunology
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Placebo controlled
Eligibility
Sex/Gender
ALL
Age
3 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Patients who meet all of the following criteria are eligible for enrollment as study participants, including participants who: * Are age 3-18 years, either sex, any ethnicity or race * Provide signed informed consent by parent or legal guardian and informed assent if applicable * Have a history of symptomatic reactivity to cow's milk (i.e. eczema, urticarial, upper or lower respiratory symptoms, gastrointestinal disturbances, rash, oral symptoms) * Have a skin prick test positive to milk (diameter of wheal 3 mm ≥ negative control) and serum milk-specific immunoglobulin E (IgE) level \>5 kilo Units (kU)/L within the past 6-12 months * Have a positive reaction to a cumulative dose of ≤444 mg of baked milk powder in the initial qualifying double blind placebo-controlled food challenge. * Use an effective method of contraception by females of childbearing potential to prevent pregnancy and agree to continue to practice an acceptable method of contraception for the duration of their participation in the study. * Have self-injectable epinephrine available at all times
Exclusion criteria
* Patients who meet any of these criteria are not eligible for enrollment as study participants, including participants who: * Have a history of severe anaphylaxis resulting in hypotension, neurological compromise, or mechanical ventilation * Have a history of intubation related to asthma * Tolerate more than 444 mg of baked milk powder at the initial qualifying double blind placebo controlled food challenge. * Allergy to placebo ingredients or reacts to any dose of placebo during the qualifying oral food challenge. * Poor control of atopic dermatitis * Are unable to tolerate at least 3 mg of baked milk protein on dose escalation day * Are pregnant or lactating * Have severe asthma defined by 2007 National Heart Lung and Blood Institute (NHLBI) Criteria Steps 5 or 6 * Have severe or poorly controlled asthma defined by with any of the following criteria: 1. Forced expiratory volume in 1 second (FEV1) \<80% of predicted 2. Inhaled corticosteroid dosing dosing of \>500 mcg daily of fluticasone (or equivalent inhaled corticosteroids based on NHLBI dosing chart) or 3. ≥ 1 hospitalization in the past year for asthma or 4. \> 1 emergency department visit in the past 6 months for asthma * Use of steroid medications (oral steroids, such as prednisone or Medrol, steroid injections, such as Kenalog, or intravenous or oral corticosteroid burst) in the following manners: History of daily oral steroid dosing within 4 weeks prior to baseline visit or for \> 1 month during the past year or \>2 burst oral steroid courses in the past 6 months. * Are unable to discontinue antihistamines for 5 days for long acting and 3 days for short acting prior to skin testing or food challenges * Are receiving omalizumab, mepolizumab, beta- blocker, angiotensin-converting-enzyme inhibitor (ACE-I), angiotensin-receptor blockers, calcium channel blockers, or tricyclic antidepressant therapy * Have used immunomodulatory therapy (not including corticosteroids) or biologic therapy within the past year * Have participated in any interventional study for treatment of a food allergy in the past 6 months * Are on 'build up phase' of environmental allergen immunotherapy. Subjects tolerating maintenance allergen immunotherapy can be enrolled. * Have a history of eosinophilic esophagitis in the past 3 years * Have a chronic disease (other than asthma, atopic dermatitis, rhinitis) requiring therapy (e.g., heart disease, diabetes) * Have used an investigational drug within 90 days or plan to use an investigational drug during the study period * Severe reaction at initial double blind placebo controlled food challenge, defined as: * Life-threatening anaphylaxis * Requiring overnight hospitalization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | 1 year | Adverse events will be recorded per CTCAE version 4.0. Events per dose on baked milk oral immunotherapy will be compared to adverse events per dose on placebo. Data will be collected over the first year of treatment. Analysis of cumulative adverse reactions per dose of oral immunotherapy or placebo will be performed at the end of year 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Are Able to Tolerate 2 Grams of Unheated Milk Protein After 2 Years of Treatment | 2 years | The investigators will perform unheated milk challenges to up to 8000 mg of unheated milk protein and calculate the proportion of subjects who tolerate 2 grams of unheated milk protein after 2 years of treatment. This measure reports the number of participants that were able to tolerate 2 grams of unheated milk protein. |
| Change in Maximum Tolerated Dose of Baked Milk | Baseline, 1 year and 2 years | Change in maximum tolerated dose (milligrams) of baked milk from baseline to end of year 1 and end of year 2. |
| Change in Milk-specific IgE Level | Baseline and up to year 2 | Change in milk-specific immunoglobulin E (IgE) level measured in kU/L. |
| Proportion of Subjects Who Are Able to Tolerate 4 Grams of Baked Milk Protein After One Year of Treatment | 1 year | The investigators will perform baked milk challenges to 4044 mg of baked milk protein and calculate the proportion of subjects who tolerate 4 grams of baked milk protein after one year of baked milk oral immunotherapy. This measure reports the number of participants that were able to tolerate 4 grams of baked milk protein. |
| Change in Milk Skin Prick Test Responses | Baseline and up to year 2 | Change in milk skin prick test responses measured as a change in wheal size in millimeters. |
| Change in Quality of Life as Assessed by the Food Allergy Questionnaire | Baseline and up to year 2 | The food allergy questionnaire has an overall score range of 0-6 with 6 indicating the worst quality of life. |
| Change in Milk-specific IgG4 Level | Baseline and up to year 2 | Change in milk-specific immunoglobulin G4 (IgG4) level measured in mg/L. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the Johns Hopkins (JH) Pediatric Allergy Clinic, Baltimore, MD from March 2018 to October 2019.
Pre-assignment details
41 subjects were consented and screened. Eleven (27%) did not have dose-limiting symptoms in their screening food challenge to 444mg of baked milk protein and were therefore ineligible for the study. 30 subjects were randomized 1:1.
Participants by arm
| Arm | Count |
|---|---|
| Baked Milk Immunotherapy Subjects will receive baked milk oral immunotherapy with baked non-fat cow's milk powder as the intervention. Subjects will undergo an initial dose escalation, build-up, and then a maintenance period.
Baked non-fat cow's milk powder: Oral immunotherapy with increasing quantities of baked milk. | 15 |
| Placebo Subjects will receive oral immunotherapy with the placebo control (tapioca powder). Subjects will undergo an initial dose escalation, build-up, and then a maintenance period.
Placebo: Tapioca Powder: Placebo control. | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Baked Milk Immunotherapy | Total |
|---|---|---|---|
| Age at Milk Allergy Diagnosis | 9 months | 8 months | 8.5 months |
| Age, Categorical <=18 years | 15 Participants | 12 Participants | 27 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 3 Participants | 3 Participants |
| Age, Continuous | 7 years | 13 years | 11 years |
| Alpha lactalbumin IgE (kU/L) | 19.7 kU/L | 20.4 kU/L | 20 kU/L |
| Beta lactoglobulin igE (kU/L) | 18.8 kU/L | 28.2 kU/L | 24.5 kU/L |
| Casein IgE (kU/L) | 52.8 kU/L | 75.8 kU/L | 64.8 kU/L |
| Cow's Milk IgE | 87 kU/L | 114 kU/L | 88 kU/L |
| Current Atopic History Allergic rhinitis | 11 Participants | 10 Participants | 21 Participants |
| Current Atopic History Asthma | 9 Participants | 11 Participants | 20 Participants |
| Current Atopic History Atopic dermatitis | 8 Participants | 8 Participants | 16 Participants |
| Current Atopic History Non-milk food allergies | 14 Participants | 12 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 15 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Milk IgG4 (mg/L) | 9.4 mg/L | 8.6 mg/L | 9.2 mg/L |
| Milk skin prick test | 10 mm | 14 mm | 13 mm |
| Participants with a History of milk reaction Baked Milk Only | 0 Participants | 3 Participants | 3 Participants |
| Participants with a History of milk reaction Both Unheated and Baked Milk | 10 Participants | 9 Participants | 19 Participants |
| Participants with a History of milk reaction Unheated Milk Only | 5 Participants | 3 Participants | 8 Participants |
| Participants with Prior Baked Milk Exposure | 10 Participants | 12 Participants | 22 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 12 Participants | 21 Participants |
| Region of Enrollment United States | 15 Participants | 15 Participants | 30 Participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 14 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 15 / 15 | 14 / 15 |
| serious Total, serious adverse events | 0 / 15 | 3 / 15 |
Outcome results
Primary
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
Adverse events will be recorded per CTCAE version 4.0. Events per dose on baked milk oral immunotherapy will be compared to adverse events per dose on placebo. Data will be collected over the first year of treatment. Analysis of cumulative adverse reactions per dose of oral immunotherapy or placebo will be performed at the end of year 1.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Baked Milk Immunotherapy | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | 15 Participants |
| Placebo | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | 11 Participants |
Secondary
Change in Maximum Tolerated Dose of Baked Milk
Change in maximum tolerated dose (milligrams) of baked milk from baseline to end of year 1 and end of year 2.
Time frame: Baseline, 1 year and 2 years
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Baked Milk Immunotherapy | Change in Maximum Tolerated Dose of Baked Milk | Change from baseline to 1 year | 3900 miligrams |
| Baked Milk Immunotherapy | Change in Maximum Tolerated Dose of Baked Milk | Change from baseline to 2 years | 3900 miligrams |
| Placebo | Change in Maximum Tolerated Dose of Baked Milk | Change from baseline to 1 year | 0 miligrams |
| Placebo | Change in Maximum Tolerated Dose of Baked Milk | Change from baseline to 2 years | 3900 miligrams |
Secondary
Change in Milk Skin Prick Test Responses
Change in milk skin prick test responses measured as a change in wheal size in millimeters.
Time frame: Baseline and up to year 2
Population: For change from baseline to year 1, 1 participant dropped out in each group so SPT results only were available for 14 participants in each group. 4 participants dropped out in year 2 so SPT results was available for 12 in each group for change from baseline to year 2.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Baked Milk Immunotherapy | Change in Milk Skin Prick Test Responses | Change from baseline to year 1 | -2.5 millimeters |
| Baked Milk Immunotherapy | Change in Milk Skin Prick Test Responses | Change from baseline to 2 years | -4 millimeters |
| Placebo | Change in Milk Skin Prick Test Responses | Change from baseline to year 1 | 3.5 millimeters |
| Placebo | Change in Milk Skin Prick Test Responses | Change from baseline to 2 years | 1.5 millimeters |
Secondary
Change in Milk-specific IgE Level
Change in milk-specific immunoglobulin E (IgE) level measured in kU/L.
Time frame: Baseline and up to year 2
Population: For change from baseline to year 1, 1 participant dropped out in each group so blood/results only available for 14 participants in each group. 4 participants dropped out in year 2 so blood/results was available for 12 in each group for change from baseline to year 2.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Baked Milk Immunotherapy | Change in Milk-specific IgE Level | change from baseline to 1 year | -21.35 KU/L |
| Baked Milk Immunotherapy | Change in Milk-specific IgE Level | change from baseline to 2 years | -77.45 KU/L |
| Placebo | Change in Milk-specific IgE Level | change from baseline to 1 year | -14.75 KU/L |
| Placebo | Change in Milk-specific IgE Level | change from baseline to 2 years | -46.65 KU/L |
Secondary
Change in Milk-specific IgG4 Level
Change in milk-specific immunoglobulin G4 (IgG4) level measured in mg/L.
Time frame: Baseline and up to year 2
Population: For change from baseline to year 1, 1 participant dropped out in each group so blood/results only available for 14 participants in each group. 4 participants dropped out in year 2 so blood/results was available for 12 in each group for change from baseline to year 2.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Baked Milk Immunotherapy | Change in Milk-specific IgG4 Level | change from baseline to 1 year | 8.88 mg/L |
| Baked Milk Immunotherapy | Change in Milk-specific IgG4 Level | Change from baseline to 2 years | 5.5 mg/L |
| Placebo | Change in Milk-specific IgG4 Level | change from baseline to 1 year | 3.79 mg/L |
| Placebo | Change in Milk-specific IgG4 Level | Change from baseline to 2 years | 3.55 mg/L |
Secondary
Change in Quality of Life as Assessed by the Food Allergy Questionnaire
The food allergy questionnaire has an overall score range of 0-6 with 6 indicating the worst quality of life.
Time frame: Baseline and up to year 2
Population: For change from baseline to year 1, 1 participant dropped out in each group so questionnaire results only were available for 14 participants in each group. 4 participants dropped out in year 2 so questionnaire results was available for 12 in each group for change from baseline to year 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baked Milk Immunotherapy | Change in Quality of Life as Assessed by the Food Allergy Questionnaire | change from baseline to 1 year | 0.04 score on a scale | Standard Deviation 0.79 |
| Baked Milk Immunotherapy | Change in Quality of Life as Assessed by the Food Allergy Questionnaire | change from baseline to 2 years | -0.07 score on a scale | Standard Deviation 0.94 |
| Placebo | Change in Quality of Life as Assessed by the Food Allergy Questionnaire | change from baseline to 1 year | 0.37 score on a scale | Standard Deviation 1.08 |
| Placebo | Change in Quality of Life as Assessed by the Food Allergy Questionnaire | change from baseline to 2 years | -0.3 score on a scale | Standard Deviation 1.16 |
Secondary
Number of Subjects Who Are Able to Tolerate 2 Grams of Unheated Milk Protein After 2 Years of Treatment
The investigators will perform unheated milk challenges to up to 8000 mg of unheated milk protein and calculate the proportion of subjects who tolerate 2 grams of unheated milk protein after 2 years of treatment. This measure reports the number of participants that were able to tolerate 2 grams of unheated milk protein.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Baked Milk Immunotherapy | Number of Subjects Who Are Able to Tolerate 2 Grams of Unheated Milk Protein After 2 Years of Treatment | 8 Participants |
| Placebo | Number of Subjects Who Are Able to Tolerate 2 Grams of Unheated Milk Protein After 2 Years of Treatment | 5 Participants |
Secondary
Proportion of Subjects Who Are Able to Tolerate 4 Grams of Baked Milk Protein After One Year of Treatment
The investigators will perform baked milk challenges to 4044 mg of baked milk protein and calculate the proportion of subjects who tolerate 4 grams of baked milk protein after one year of baked milk oral immunotherapy. This measure reports the number of participants that were able to tolerate 4 grams of baked milk protein.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Baked Milk Immunotherapy | Proportion of Subjects Who Are Able to Tolerate 4 Grams of Baked Milk Protein After One Year of Treatment | 11 Participants |
| Placebo | Proportion of Subjects Who Are Able to Tolerate 4 Grams of Baked Milk Protein After One Year of Treatment | 0 Participants |