Pharmacokinetics of Intramuscular Adrenaline in Food--Allergic Teenagers

Study Overview
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Brief Summary
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Food allergy affects up to 2% of adults and 8% of children in the United Kingdom (UK), and is a major public health issue. It is the commonest cause of life-threatening allergic reactions (anaphylaxis), which can be fatal. Adrenaline (epinephrine) auto-injector (AAI) devices are the first-line treatment for anaphylaxis, yet in a UK survey, over 80% of 245 teenagers experiencing anaphylaxis did not use their AAI. Delays in, or lack of adrenaline (epinephrine) administration during anaphylaxis are risk factors for fatal anaphylaxis. In 2010, a coroner's investigation into the death of a food-allergic teenager in the UK raised several questions around AAI safety and efficacy, since the teenager died despite administering her auto-injector device. This prompted a review by the Medicines and Healthcare products Regulatory Agency (MHRA) in 2014 into the clinical and quality considerations of AAIs. Two recommendations which came from the review was that companies 'should be encouraged to develop a 0.5mg [dose] AAI.' In the UK currently only Emerade, one of the three companies selling AAIs, manufactures a 0.5mg (500mcg) version. Emerade also has a longer needle length (23mm) compared to other AAIs (typically 15mm). The investigators plan to formally assess the pharmacokinetics (PK) and pharmacodynamics (PD) of self-injection with intramuscular adrenaline (epinephrine) in teenagers at risk of anaphylaxis due to food allergy, and have been prescribed AAI. The investigators will compare self-injection with 300mcg vs 500mcg in teenagers of body weight >40kg. In a 40kg person, an adrenaline dose of 300mcg results in an effective UNDER-dosing of 30% by body weight. The investigators will also assess the impact of needle length on injection, by comparing two different devices, both of which deliver 300mcg, but one via a 15mm needle and the other with a 23mm needle.

Official Title
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Pharmacokinetics of Intramuscular Adrenaline in Food--Allergic Teenagers: Does Dose Matter?

Conditions
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Anaphylaxis

Intervention / Treatment
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* Combination Product: Epipen 0.3mg
* Combination Product: Emerade 300mcg
* Combination Product: Emerade 500mcg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 13 - 18 years inclusive Body mass >40kg Prescription of AAI due to physician diagnosis of Immunoglobulin E-mediated food allergy. Written informed consent from parent/guardian together with patient assent, for participants under 16 years of age. For young people age 16+ years, consent will be obtained from the participant themselves. Exclusion Criteria: Known cardiac comorbidity (including hypertension, structural or electrophysiological diagnoses) or prescribed a medicine to control cardiovascular disease/hypertension. Known endocrine or renal disease Poorly controlled asthma requiring daily rescue treatment with a bronchodilator. Pregnancy Unwilling or unable to comply with study requirements

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Visit 1: Emerade 300mcg then Epipen 0.3mg Visit 2: Emerade 500mcg | Combination Product: Epipen 0.3mg<br>* Epipen 0.3mg auto-injector<br>* Other names: Epinephrine;Combination Product: Emerade 300mcg<br>* Emerade 300mcg auto-injector<br>* Other names: Epinephrine;Combination Product: Emerade 500mcg<br>* Emerade 500mcg auto-injector<br>* Other names: Epinephrine;|
| Active Comparator: 2<br>Visit 1: Epipen 0.3mg then Emerade 300mcg Visit 2: Emerade 500mcg | Combination Product: Epipen 0.3mg<br>* Epipen 0.3mg auto-injector<br>* Other names: Epinephrine;Combination Product: Emerade 300mcg<br>* Emerade 300mcg auto-injector<br>* Other names: Epinephrine;Combination Product: Emerade 500mcg<br>* Emerade 500mcg auto-injector<br>* Other names: Epinephrine;|
| Active Comparator: 3<br>Visit 1: Emerade 500mcg Visit 2: Emerade 300mcg then Epipen 0.3mg | Combination Product: Epipen 0.3mg<br>* Epipen 0.3mg auto-injector<br>* Other names: Epinephrine;Combination Product: Emerade 300mcg<br>* Emerade 300mcg auto-injector<br>* Other names: Epinephrine;Combination Product: Emerade 500mcg<br>* Emerade 500mcg auto-injector<br>* Other names: Epinephrine;|
| Active Comparator: 4<br>Visit 1: Emerade 500mcg Visit 2: Epipen 0.3mg then Emerade 300mcg | Combination Product: Epipen 0.3mg<br>* Epipen 0.3mg auto-injector<br>* Other names: Epinephrine;Combination Product: Emerade 300mcg<br>* Emerade 300mcg auto-injector<br>* Other names: Epinephrine;Combination Product: Emerade 500mcg<br>* Emerade 500mcg auto-injector<br>* Other names: Epinephrine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Catecholamine Levels (Maximum Concentration, Cmax) | Pharmacokinetics (plasma catecholamine levels: Cmax) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg. | 3 hours | 
| Plasma Catecholamine Levels (Time to Maximum Concentration, Tmax) | Pharmacokinetics (plasma catecholamine levels: Tmax) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg. | 3 hours | 
| Plasma Catecholamine Levels (Maximum Concentration, Area-under-curve (AUC)) | Pharmacokinetics (plasma catecholamine levels: AUC) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg. Baseline corrected. | At at the following timepoints following injection: 5, 10, 15, 20, 30, 45, 60, 80, 100, 120 and 180 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Heart Rate Following Self-injection of Adrenaline (300mcg, 500mcg) on Separate Occasions. | Pharmacodynamics (heart rate) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg. | 3 hours | 
| Change in Blood Pressure Following Self-injection of Adrenaline (300mcg, 500mcg) on Separate Occasions. | Pharmacodynamics (blood pressure) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg. | 3 hours | 
| Change in Stroke Volume Following Self-injection of Adrenaline (300mcg, 500mcg) on Separate Occasions. | Pharmacodynamics (stroke volume) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg. | 3 hours | 
| Impact of Needle Length on Pharmacokinetics (Plasma Catecholamine Levels: Cmax) | Pharmacokinetics (plasma catecholamine levels: Cmax) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg. | 3 hours | 
| Impact of Needle Length on Pharmacokinetics (Plasma Catecholamine Levels: Tmax) | Pharmacokinetics (plasma catecholamine levels: Tmax) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg. | 3 hours | 
| Impact of Needle Length on Pharmacokinetics (Plasma Catecholamine Levels: AUC) | Pharmacokinetics (plasma catecholamine levels: AUC) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg. | 3 hours | 
| Impact of Needle Length on Pharmacodynamics (Cardiovascular Parameters: Heart Rate) | The pharmacodynamics (cardiovascular parameters: heart rate) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg. | 3 hours | 
| Impact of Needle Length on Pharmacodynamics (Cardiovascular Parameters: Blood Pressure) | The pharmacodynamics (cardiovascular parameters: blood pressure) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg. | 3 hours | 
| Impact of Needle Length on Pharmacodynamics (Cardiovascular Parameters: Stroke Volume) | The pharmacodynamics (cardiovascular parameters: stroke volume) following intramuscular self-injection of 300mcg adrenaline using two auto-injector devices with different needle lengths (15mm vs 23mm), in food-allergic teenagers over 40kg. | 3 hours | 
| Adverse Events Following Self-administration of Adrenaline Via Autoinjector Device | Adverse events following self-administration of adrenaline via autoinjector device defined as in protocol | 1 day | 
| Change in Health-related Quality of Life (HRQL) as Measured Using FAQLQ | The impact of self-administration of adrenaline autoinjectors (in a non-reaction setting) on health-related quality of life (HRQL) measures in food-allergic teenagers and their parents. | 1 month |