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Pharmacokinetics of Intramuscular Adrenaline in Food--Allergic Teenagers (PIMAT)

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ClinicalTrials.gov Identifier: NCT03366298
Recruitment Status : Completed
First Posted : December 8, 2017
Last Update Posted : October 22, 2018
Sponsor:
Information provided by (Responsible Party):
Paul Turner, Imperial College London

Brief Summary:

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.

  1. 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.
  2. 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.

Condition or disease Intervention/treatment Phase
Anaphylaxis Combination Product: Epipen 0.3mg Combination Product: Emerade 300mcg Combination Product: Emerade 500mcg Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pharmacokinetics of Intramuscular Adrenaline in Food--Allergic Teenagers: Does Dose Matter?
Actual Study Start Date : November 24, 2017
Actual Primary Completion Date : October 2, 2018
Actual Study Completion Date : October 2, 2018


Arm Intervention/treatment
Active Comparator: 1
Visit 1: Emerade 300mcg then Epipen 0.3mg Visit 2: Emerade 500mcg
Combination Product: Epipen 0.3mg
Epipen 0.3mg auto-injector
Other Name: Epinephrine

Combination Product: Emerade 300mcg
Emerade 300mcg auto-injector
Other Name: Epinephrine

Combination Product: Emerade 500mcg
Emerade 500mcg auto-injector
Other Name: Epinephrine

Active Comparator: 2
Visit 1: Epipen 0.3mg then Emerade 300mcg Visit 2: Emerade 500mcg
Combination Product: Epipen 0.3mg
Epipen 0.3mg auto-injector
Other Name: Epinephrine

Combination Product: Emerade 300mcg
Emerade 300mcg auto-injector
Other Name: Epinephrine

Combination Product: Emerade 500mcg
Emerade 500mcg auto-injector
Other Name: Epinephrine

Active Comparator: 3
Visit 1: Emerade 500mcg Visit 2: Emerade 300mcg then Epipen 0.3mg
Combination Product: Epipen 0.3mg
Epipen 0.3mg auto-injector
Other Name: Epinephrine

Combination Product: Emerade 300mcg
Emerade 300mcg auto-injector
Other Name: Epinephrine

Combination Product: Emerade 500mcg
Emerade 500mcg auto-injector
Other Name: Epinephrine

Active Comparator: 4
Visit 1: Emerade 500mcg Visit 2: Epipen 0.3mg then Emerade 300mcg
Combination Product: Epipen 0.3mg
Epipen 0.3mg auto-injector
Other Name: Epinephrine

Combination Product: Emerade 300mcg
Emerade 300mcg auto-injector
Other Name: Epinephrine

Combination Product: Emerade 500mcg
Emerade 500mcg auto-injector
Other Name: Epinephrine




Primary Outcome Measures :
  1. Plasma catecholamine levels (maximum concentration, Cmax) [ Time Frame: 3 hours ]
    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.

  2. Plasma catecholamine levels (time to maximum concentration, Tmax) [ Time Frame: 3 hours ]
    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. Plasma catecholamine levels (maximum concentration, Area-under-curve (AUC)) [ Time Frame: 3 hours ]
    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.


Secondary Outcome Measures :
  1. Change in heart rate following self-injection of adrenaline (300mcg, 500mcg) on separate occasions. [ Time Frame: 3 hours ]
    Pharmacodynamics (heart rate) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.

  2. Change in blood pressure following self-injection of adrenaline (300mcg, 500mcg) on separate occasions. [ Time Frame: 3 hours ]
    Pharmacodynamics (blood pressure) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.

  3. Change in stroke volume following self-injection of adrenaline (300mcg, 500mcg) on separate occasions. [ Time Frame: 3 hours ]
    Pharmacodynamics (stroke volume) following intramuscular self-injection of 300mcg and 500mcg adrenaline using an auto-injector device, in food-allergic teenagers over 40kg.

  4. Impact of needle length on pharmacokinetics (plasma catecholamine levels: Cmax) [ Time Frame: 3 hours ]
    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.

  5. Impact of needle length on pharmacokinetics (plasma catecholamine levels: Tmax) [ Time Frame: 3 hours ]
    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.

  6. Impact of needle length on pharmacokinetics (plasma catecholamine levels: AUC) [ Time Frame: 3 hours ]
    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.

  7. Impact of needle length on pharmacodynamics (cardiovascular parameters: heart rate) [ Time Frame: 3 hours ]
    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.

  8. Impact of needle length on pharmacodynamics (cardiovascular parameters: blood pressure) [ Time Frame: 3 hours ]
    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.

  9. Impact of needle length on pharmacodynamics (cardiovascular parameters: stroke volume) [ Time Frame: 3 hours ]
    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.

  10. Adverse events following self-administration of adrenaline via autoinjector device [ Time Frame: 1 day ]
    Adverse events following self-administration of adrenaline via autoinjector device defined as in protocol

  11. Change in health-related quality of life (HRQL) as measured using FAQLQ [ Time Frame: 1 month ]
    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.



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Ages Eligible for Study:   13 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03366298


Locations
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United Kingdom
Imperial College London / Imperial College Healthcare NHS Trust
London, United Kingdom, W2 1NY
Sponsors and Collaborators
Imperial College London
Investigators
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Principal Investigator: Paul J Turner, FRACP PhD Imperial College London
  Study Documents (Full-Text)

Documents provided by Paul Turner, Imperial College London:

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Responsible Party: Paul Turner, MRC Clinician Scientist, Imperial College London
ClinicalTrials.gov Identifier: NCT03366298     History of Changes
Other Study ID Numbers: 17SM4137
2017-003239-13 ( EudraCT Number )
232931 ( Other Identifier: HRA )
First Posted: December 8, 2017    Key Record Dates
Last Update Posted: October 22, 2018
Last Verified: October 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Anaphylaxis
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Epinephrine
Racepinephrine
Epinephryl borate
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Adrenergic beta-Agonists
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Mydriatics
Sympathomimetics
Vasoconstrictor Agents