Oral Challenge Studies: Purpose, Design and Evaluation

Stefano Luccioli, MD

Goals

• Purpose• Design and conduct

– Selection of subjects & materials– Blinding and dosing protocol– Statistics

• Evaluation and interpretation of data– General issues– Sensitivity of subjects– Clinical response and severity

Overview of oral challenge studies

Purpose of challenge studiesConfirm diagnosis of food allergy

– Gold standard: Double-blind, placebo-controlled food challenge (DBPCFC)

Evaluate tolerance

Evaluate allergenic foods/ingredients for certain subpopulations

Purpose of challenge studiesDetermine minimal eliciting doses

Information on individual sensitivityTherapeutic comparisonsLOEL/NOEL data for establishing thresholds

Insufficient animal model and epidemiological (market experience, case reports) data

Evaluate reaction severity- uncommon Current biomarkers not predictive

Assessment of food ingredientsTraditional Tox models

• Genetic Homogeneity• One ingredient in food• Defined endpoints for

severity• NOEL defined• Reproducible• Dose response

Allergen food challenges• Genetic Heterogeneity• Multiple allergens in food• Multiple endpoints;

severity not well defined• LOEL mainly; rare NOEL • May not be reproducible• Dose distribution

Design and Conduct of Oral Challenge Studies

Subjects• Subpopulations: Adults vs children vs infants• Men and women, multiethnic• Particular concerns/issues:

Diagnosis for equivocal IgE or clinical history– Evidence of tolerance– Coexistant allergies (i.e. milk/soy)– Specific ingredients (i.e. hypoallergenic infant formulas)

• Exclusion of individuals:– Elevated food-specific IgE levels– Previous H/O anaphylaxis or unstable asthma– Self exclusion

Test materials• Type of food material

– Various preparations per food• Ex: Peanut flour vs ground peanut vs peanut butter

Increased shelf-life for ease of administration

• Liquid vs solid (dried) food• Fresh vs processed • Raw vs cooked• Dose units (mg food vs mg protein vs mg/kg)

Blinding• Foods – mask taste, smell, and texture

– Vehicles (i.e. Milk shakes, oatmeal, tapioca) GI effects; may not mask taste

– Capsules Delayed absorption; bypass oral cavity

• Protocol – mask subject and/or researcher– Open– Singled-blinded (SB)– Double-blinded (DB)

• Placebos –false positive “nocebo” responses

Dose protocol

• Starting dose (X) varies (usually mg doses)• Time interval varies• Dose escalation of divided doses (usually 6 to 10) w/ placebos • Two to 10-fold dose increments Stop after objective symptom; some also record subjective symptoms Report eliciting discrete and/or cumulative dose

X 2X 4X 8X 16X 32X 64X 108X

15-60min

LOEL NOEL

4X

7X

Negative

Obj.symptom

Subj.symptom

Open Challenge

1-2 hrs

10g solid60g wet

Other issues

• Clinic/office –experimental setting • Medications• Fasting• Clinical history of reactivity

– i.e. exercise, oral allergy syndrome

Statistical endpoints • Sampled population

– Percentage that will react to challenge (i.e. food allergy diagnosis)

– Percentage to have a mild vs severe initial reaction• General allergic population

– Percentage that will or will not react to specific food concentration (s) during challenge

– Confidence levels for incidence of allergic reactions

Incidence Confidence level 95% 99% 99.9%

1/10 = .1 *29 44 661/20 = .05 59 90 1351/50 = .02 149 228 3421/100 = .01 299 459 6881/200 = .005 598 919 13801/500 = .002 1497 2301 34511/1000 = .001 2995 4604 69051/2000 = .0005 5992 9210 138141/5000 = .0002 14978 23030 345401/10000 = .0001 29957 46060 69080

Sample size and confidence levels

*Basis for hypoallergenicity determination for infant formulas

}Number of individuals to be tested

Evaluation/Interpretation of Challenge Study Data

General interpretation • Grouping of data for population statistics

– Most studies not standardized* • Dose, blinding/testing materials, or interpretation of

clinical symptoms– All sensitive populations included?– Statistical power for confidence levels

• Should this include data from individuals nonreactive to oral challenge?

– What about foreign challenge study data?

*Standardization of protocols has been proposed; however, the bulk of currently available data is from non-standardized studies

General interpretation

• Experimental exposure – non real-life

– False positives/ negatives– Difficult to predict reactions to future

exposures

Subject sensitivity• Genetic heterogeneity of individuals

– Sensitization to different allergens within food– High variability in dose (million-fold) from least sensitive to most

sensitive

• Potential link with severity– Some studies suggest that the individuals most sensitive to low

doses also appear to have the most severe reactions– Sensitivity/severity may vary with food type

• Individual sensitivities may vary over time– Influenced by H/O asthma– Eating behaviors and other factors (exercise, alcohol, medications)

Hypothetical Dose Response Curve* *Model adapted from J. Hourihane

Dose of Allergenic protein

Severe

Moderate

Mild

2 1 3 4

1- “Normal”

2- ?Unstable asthma, alcohol, exercise

3- ?Food matrix, antihistamines

4- ?Unidentified factors

Evaluation of Clinical Responses

• Interpretation of eliciting dose– Subjective vs objective symptoms

• Reaction severity– Dose-response endpoints

Allergic Response EndpointsSubjective Symptoms Objective Symptoms

Skin pruritus (Itching) Urticaria (hives), Eczema,Angioedema (swelling)

Nausea Vomiting, diarrhea Throat dryness/tightness Laryngeal swelling, Voice hoarseness,

stridor (inspiratory wheeze), CoughShortness of breath, chest pain Respiratory distress (i.e., breathing

rate), Wheezing

Feeling of faintness, dizziness Syncope (fainting), Hypotension (low blood pressure)

“Sense of impending doom” Shock (very low blood pressure), dysrhythmia (abnormal heart rhythm)

?Interpretation of: Fussiness/ behavior change (infants); Abdominal pain (infants); Skin flushing; Shortness of breath

Subjective vs objective symptomsObjective symptoms

– Measurable indicator of allergic response– Many different endpoints possible, including anaphylaxis– Interpretation may vary among investigators

Subjective symptoms– May result from nonallergic causes; often not recorded– Often occur prior to objective signs– Early adverse events/ LOELs?

• Need to review challenge and placebo data

Other eliciting dose considerations• Starting dose

– If response at this dose, cannot derive NOEL Common finding with many diagnostic challenges

– Is this the lowest eliciting dose?• Dose increments – 2 vs 10-fold • Time interval between doses

Some adverse reactions may be delayed > 60 min (i.e. eczema)

• Discrete vs cumulative dose How does this mimic true exposure?

B cell T cell

Food /Protein

IgEAntibody

Mast cell/ Basophil

Sensitization

Elicitation

ALLERGY

Release of mediators, cytokines (Amplification mechanism)Rapidly progresses in severity

Unique toxicological

response

Severity of allergic response is on a continuum

Subjective Objective Anaphylaxis Death

• Not a fixed response - early observed objective symptom may rapidly progress to something worse

• Degree of amplification varies - symptoms may not be reproducible on subsequent rechallenge

Reaction Severity• Most studies only report actual symptom• Few document severity of challenge response

– Mild vs moderate vs severe– Should severe responses be interpreted differently?– Anxiety/stress; medications; asthma

• Potentiating/ mitigating factors for severity• Challenge stops after initial positive response• Not a true dose-response study for severity

– What is dose interval from mild to severe reaction?

Conclusions• Oral food challenges provide data on:

– Clinical sensitivity to minimal eliciting doses– Reaction severity to initial dose

• Challenge data currently available for interpretation is not standardized among studies

• Current data pool may not include extremely sensitive population (with regards to severity)

• Challenges have proven value as a diagnostic tool but not as a tool for predicting reaction severity to future exposures